Editors

Michael J. Aminoff

School of Medicine, University of California, San Francisco, California

Robert B. Daroff

University Hospitals of Cleveland, Cleveland, Ohio

Associate
Editors

Bruce O. Berg Hiroshi Mitsumoto

University of California, San Francisco
Sudhansu Chokroverty
St. Vincent’s Hospital and Medical Center
New York, NY
Columbia Presbyterian Medical Center
New York, NY
Mark J. Morrow
Hattiesburg Clinic, Hattiesburg, Mississippi

Lisa M. DeAngelis William J. Powers

Memorial Sloan-Kettering Cancer Center Washington University School of Medicine
New York, NY St. Louis, Missouri

Colin P. Derdeyn Stefan M. Pulst

Washington University School of Medicine Cedars Sinai Medical Center
St. Louis, Missouri Los Angeles, California

Jerome Engel, Jr. Richard Ransohoff

Reed Neurological Research Center Cleveland Clinic Foundation
Los Angeles, California
James L. Roberts
Christopher G. Goetz University of Texas Health Science Center
Rush-Presbyterian-St. Luke’s Medical San Antonio, Texas
Center, Chicago, Illinois
Karen L. Roos
David A. Greenberg Indiana University School of Medicine
Buck Institute for Age Research Indianapolis, Indiana
Novato, California
Marylou V. Solbrig
University of California, Irvine
Daryl Gress
University of California, San Francisco Robert F. Spetzler
Nathaniel Katz Barrow Neurosurgical Associates, Ltd.
Phoenix, Arizona
Pain Management Center, Brigham and Women’s
Hospital, Boston, Massachusetts Lowell Tong
University of California, San Francisco
John F. Kurtzke
Georgetown University (emeritus) and Kenneth L. Tyler
Veterans Administration Medical Center University of Colorado Health Sciences Center
Washington, DC Denver, Colorado

Joseph C. Masdeu K. Michael Welch

University of Navarre Medical School Finch University of Health Sciences
Navarre, Spain Chicago Medical School, Chicago, Illinois

Bruce L. Miller G. Bryan Young

University of California, San Francisco Victoria Hospital, London, Ontario
Preface
DURING the past 25 years, remarkable advances
have occurred in the clinical sciences of neurology,
neurosurgery, and psychiatry, as well as the many
different branches of the clinical and basic neuro-
sciences that impact on these fields. Because of the
pace of these advances, those not engaged in a
particular discipline have difficulty keeping abreast
with the field, and those who are not involved in the
neurosciences are faced with a daunting task when
attempting to seek information on a particular topic.
These difficulties created the need that prompted us
to develop this four-volume Encyclopedia of the
Neurological Sciences.
The encyclopedia is an alphabetically organized
compendium of more than 1,000 entries that relate
to different aspects of the neurosciences. It is
comprehensive in scope, with entries related to
clinical neurology, neurosurgery, neuroanatomy,
neurobiology, neuroepidemiology, neuroendocrinol-
ogy, neurogenetics, neuroimaging, neurotoxicology,
neuroimmunology, neuropharmacology, pediatric
neurology, neurooncology, neuropathology, develop-
mental neurology, behavioral neurology, neuro-
physiology, applied electrophysiology, neuro-
ophthalmology, neurotology, pain, psychiatry,
psychopharmacology, rehabilitation, critical care
medicine, and the history of the neurosciences. We
designed most entries to be understandable without
detailed background knowledge in the subject
matter. The entries are not intended for those
working directly in the field under consideration,
but rather for individuals from other disciplines who
wish to gain an understanding of the subjects.
Students and the lay public should benefit most from
entries providing general overviews of particular
topics, and might skip the more technical entries.
Cross references assist the reader to follow a theme
from a simple to a more advanced level, and from a
general to a focused outlook, or the reverse.
The entries are intended to provide relatively
succinct accounts. We have not included exhaustive
referencing but, rather, have placed suggestions for
further reading at the end of each entry. There is
some inevitable overlap between entries and, in some
instances, the same topic is discussed in several. This
overlap was deliberate, as we intended to provide
coherent accounts of topics without forcing the
reader to go from one entry to another, as if
traversing an obstacle course, to obtain the desired
information. In some instances, particularly with
areas of controversy, we included two entries on the
same topic, reflecting conflicting viewpoints, and
hope that this will stimulate readers to pursue the
topic further.
We are indebted to the many people who helped in
the creation of this encyclopedia. The associate editors
vii
viii PREFACE
(listed on page ii) guided the selection of contributors
and reviewed the individual entries in their subject
area. The contributors, all acknowledged experts in
their fields, prepared the entries. We reviewed all of
these entries, making suggestions for improvement in
content, style, and clarity, and are grateful to the
contributors and associate editors for working with
us in achieving the final product that we intended. Dr.
Graham Lees conceived this project while he was at
Academic Press, and his joyous encouragement and
support allowed the concept to evolve. Thereafter, Dr.
Jasna Markovac assumed oversight at Academic
Press (now part of Elsevier Science), providing
excellent advice and unfailing assistance at all stages
of the endeavor. Karen Dempsey of Academic Press
displayed great patience, good humor, and efficiency
in bringing the encyclopedia to fruition. She attended
painstakingly to a seemingly endless number of
administrative details, and coordinated all commu-
nications between us, the contributors, associate
editors, and publisher. She not only ensured that
necessary deadlines were met, but did so with grace
and charm. The production of this encyclopedia
involved many other people at Academic Press,
including Christopher Morris, with his particular
expertise in the production of major reference works.
Our secretaries provided invaluable assistance. In San
Francisco, the arrival electronically of each new batch
of entries brought the office staff a certain respite as
MJA disappeared behind his computer screen. In
Cleveland, the computer literacy of Vicki Fields,
RBD’s secretary, compensated for his Luddite predis-
position. Finally, we must record our indebtedness to
our wives and families, whose patience, forbearance,
and support enabled us to complete this undertaking.
Michael J. Aminoff
San Francisco, California
Robert B. Daroff
Cleveland, Ohio
 Plate 1

Bielschowsky silver staining reveals a typical Alzheimer’s plaque (left of center). Several neurofibrillary tangles are also present. See entry ALZHEIMER’S
DISEASE.
 Plate 2

Magnified view of a neurofibrillary tangle (Bielschowsky stain). See entry ALZHEIMER’S DISEASE.
 Plate 3

Functional anatomy of the attentional networks. The pulvinar, superior colliculus, superior parietal lobe, and frontal eye fields are often found active in studies
of the orienting network. The anterior cingulate gyrus is an important part of the executive network. Right frontal and parietal areas are active when people
maintain the alert state. See entry ATTENTIONAL MECHANISMS.
 Plate 4

Schematic diagram of the sympathetic division of the peripheral autonomic nervous system. See entry AUTONOMIC NERVOUS SYSTEM, OVERVIEW.
 Plate 5

Example of a frequency analysis EEG brain map. The scalp distribution of the slow delta band EEG brain waves (in the 0.1- to 4.0-Hz frequency range).
Abnormally increased delta activity is shown in yellow and red. Blue and green represent areas without much delta activity. The brain map shows that the delta
is maximal in the left posterior temporal region of the brain. See entry BRAIN MAPPING AND QUANTITATIVE EEG.
 Plate 6

The extrinsic and intrinsic pathways to apoptosis. See entry CELL DEATH.
 Plate 7

Top: Intranuclear inclusion of cytomegalovirus; cytoplasm is immunoreactive for cytomegalovirus antigen. Middle: Intracytoplasmic inclusion (Negri body)
(arrows) of rabies virus. Bottom: Microglial proliferation and neuronophagia in rabies encephalitis. See entry CENTRAL NERVOUS SYSTEM
INFECTIONS, OVERVIEW.
 Plate 8

Top: Acute inflammation with early proliferation of monocytes. Middle: Abscess with fibrous capsule (Masson trichrome). See entry CENTRAL NERVOUS
SYSTEM INFECTIONS, OVERVIEW
 Plate 9

Aspergillus fungus infiltrating brain tissue and artery. See entry CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW
 Plate 10

Bacterial meningitis with thick tan–gray purulent exudate in subarachnoid space that obscures the underlying brain. Left, adult with streptococcal meningitis
over lateral surface of the cerebral hemisphere. Right, infant with Escherichia coli meningitis over inferior surfaces of cerebral and cerebellar hemispheres and
brainstem. See entry CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW.
 Plate 11

Hemorrhage and necrosis of basal ganglia and cerebral white matter due to aspergillus infection. See entry CENTRAL NERVOUS SYSTEM INFECTIONS,
OVERVIEW.
 Plate 12

Top left (upper): The cerebellar cortex. Inputs are shown in blue, output (Purkinje cells) in red. Inhibitory interneurones are black; granule cells are green. Top
left (lower):The cerebellar circuit. Arrows indicate the direction of transmission across each synapse. Colors same as in upper illustration. Refer to entry
CEREBELLUM for explanation of abbreviations.
 Plate 13

Olivocerebellar and corticonuclear projections. Climbing fiber projection from regions of the contralateral inferior olive (bottom) to the cerebellar cortex (top)
are color coded. Sagittal olivocerebellar zones (A, X, B, etc.) are labeled at top right. Cerebellar output nuclei are shown in the middle. Refer to entry
CEREBELLUM for explanation of abbreviations.
 Plate 14

Transcranial color-coded Duplex sonography of the circle of Willis. See entry CIRCLE OF WILLIS.
 Plate 15

Top: (A) Multiple sclerosis (MS> affecting the cerebellum; the cortex (c) is spared, but there is a well-defined plaque (arrow) in the white matter. (B)
Histological slide showing multiple pale plaques (arrows) in the white matter. Middle: (C) Acute MS. Histological slide with heavy inflammatory infiltrate of
cells around a blood vessel (v). (D) Acute disseminated encephalomyelitis (ADEM): Multiple pale areas of demyelination around blood vessels. The normal
white matter (w) is stained a deep blue. Bottom: (E) Progressive multifocal leukencephalopathy (PML): Cut surface of the brain shows extensive granular
necrosis of the white matter. (F) PML: Histological section, in which the normal white matter (w) stains blue and numerous pale areas of various sizes
representing demyelination. See entry DEMYELINATING DISEASE, PATHOLOGY OF.
 Plate 16

Left, Intraoperative photograph of a microsurgical site after a frontobasal craniotomy showing the typical characteristics of the view through the surgical
microscope. Only the plane of the optic nerve and the internal carotid artery is in focus; all other structures remain indistinct. Right, Intraoperative photograph
of the same site showing the view obtained through an endoscope for comparison. Due to the fish-eye effect of the endoscope front lens, all structures at the
surgical site are in focus and brightly illuminated. See entry ENDOSCOPIC MICROSURGERY.
 Plate 17

Poliomyelitis pathogenesis. Poliovirus (PV) infection is initiated by ingestion of virus; the incubation period is usually between 7 and 14 days. Following
ingestion, the virus spreads into the oropharynx and traverses the stomach to reach intestine. From the primary replication sites PV moves to the regional lymph
nodes and into the blood, causing a transient and clinically silent viremia. PV reaches the central nervous system(CNS) principally via the bloodstream. In the
CNS, the main target of PV is the motor neurons of the ventral horn of the cervical and lumbar regions of the spinal cord. See entry ENTEROVIRUSES.
 Plate 18

Poliovirus-infected motor neurons of the spinal cord at the onset of paralysis. (A) Poliovirus RNA replication detected by in situ hybridization in motor
neuron of the monkey spinal cord. (B) Poliovirus-infected motor neurons(immunofluorescence labeling, green) with an apoptotic nucleus (TUNEL labeling,
red) in the mouse spinal cord. See entry ENTEROVIRUSES.
 Plate 19

Magnetic resonance imaging reveals left hippocampal formation atrophy in a patient with localization-related epilepsy. See entry EPILEPSY, DIAGNOSIS
OF.
 Plate 20

Causes of epilepsy in Iceland. All incidence cases 1999. See entry EPILEPSY, RISK FACTORS.
 Plate 21

Risk ratios of epilepsy for various factors. Note log scale. See entry EPILEPSY, RISK FACTORS.
 Plate 22

Pompe’s disease. Left, Gamori trichrome stain of muscle. Muscle cytoplasm stains green and the nuclei stain red. There are multiplevacuoles in the cytoplasm.
Right, PAS stain for glycogen in muscle.Many vacuoles stain intensely for glycogen. See entry GLYCOGEN STORAGE DISEASES.
 Plate 23

Cherry red spots on a child with Tay–Sachs Disease. See entry HEXOSAMINIDASE DEFICIENCY.
 Plate 24

MRI showing typical contrast-enhancing ‘‘ring’’ abscesses in cerebral toxoplasmosis. See entry HIV INFECTION, NEUROLOGICAL COMPLICATIONS
OF.
 Plate 25

Bloodstream Trypanosoma gambiense trypomastigote (May–Grunwald–Giemsa  1000).See entry HUMAN AFRICAN TRYPANOSOMIASIS.
 Plate 26

Perivasculitis in the brain parenchyma of Trypanosoma gambiense-infected Cercopithecus aethiops (hematoxylin and eosin,  120). See entry HUMAN
AFRICAN TRYPANOSOMIASIS.
 Plate 27

Astrocytosis in the brain parenchyma of Trypanosoma gambiense-infected Cercopithecus aethiops (immunoperoxydase staining of glial fibrillary acidic
protein, X120). See entry HUMAN AFRICAN TRYPANOSOMIASIS.
 Plate 28

Maturation of B cell and T cell antigen receptors. Immature pre-B cells express mature heavy chain and surrogate light chain called Vpre-B or l5. During
development, surrogate light chain is replaced by mature light chain composed of variable and constant regions of k or l chains. The antigen is recognized by a
groove of mature Ig receptor formed from three hypervariable complimentarily determining regions (CDRs) of each light and heavy chain. Each arm of the ‘‘Y’’
capable of binding antigen is called a Fab fragment.Developing ab T cell expresses mature b chain of TCR and incomplete pre-Ta chain (only from the constant
region). See entry IMMUNE SYSTEM, OVERVIEW.
 Plate 29

Effector functions of T cells. Intracellular pathogens such as viruses are eliminated by T cells recognizing MHC class I molecules and expressing CD8. CD8+ T
cells kill infected cells, preventing the spread of infection; therefore, they are called cytotoxic T cells. CD4+ Th cells recognizing antigen presented by MHC class
II might facilitate the cytotoxic reactions by producing IFN-g and IL-2 (Th1) or they might induce B cell responses by producing IL-4-Il-6 (Th2). See entry
IMMUNE SYSTEM, OVERVIEW.
 Plate 30

T cell maturation in the thymus. Immature T cells express CD4 and CD8. Many of these double-positive T cells do not recognize self-MHC class molecules and
undergo apoptosis (negative selection). T cells that recognize self-MHC complexes expressing autoantigen are also destined to die. Only T cells having weak
affinity to the self-MHC–antigen complex survive. See entry IMMUNE SYSTEM, OVERVIEW.
 Plate 31

The androgen receptor amino acid sequence codes for a protein with DNA-binding and ligand (hormone)-binding domains as well as unique poly-amino acid
tracts and a nuclear localization signal. Q, glutamine; P, proline; G, glycine. See entry KENNEDY’S DISEASE.
 Plate 32

The newly discovered cholesterol efflux regulatory protein (CERP) is necessary for the bulk transfer of free cholesterol (FC) and phospholipid (PL) out of cells.
In the extracellular fluid, apolipoprotein A1 (ApoA1) and nascent HDL act as acceptors for the cholesterol. The FC in mature HDL is esterified [cholesterol
ester (CE)] and transferred to LDL and to cells by scavenger receptor B (SRB1). ApoB is the main apolipoprotein in LDL and VLDL. Thus, in normal cells,
ApoA1 is recycled. In patients with Tangier’s disease, however, the absence of FC and PL aborts the formation of HDL due to defects in CERP. ApoA1 is
rapidly cleared from the circulation and degraded. Events that are defective in Tangier’s disease are shaded. See entry LIPOPROTEIN DISORDERS.
 Plate 33

Pathological features of subacute sclerosing panencephalitis (SSPE). (A) Perivascular inflammatory cells and neuronal loss in brain tissue from an SSPE
patient (H & Estain). (B) An eosinophilic intranuclear inclusion body. (C) Electron microscopy of intracytoplasmic (crescent-shape) inclusion bodies and
intranuclear filamentous course inclusions (magnification,  19,000). See entry MEASLES VIRUS, CENTRAL NERVOUS SYSTEM COMPLICATIONS
OF.
 Plate 34

(A) Ragged-red fibers (RRFs) revealed by the modified Gomori trichrome stain. Abnormal accumulations of mitochondria appear as reddish blotches, mostly
at the periphery of muscle fibers. (B and C) Serial cross sections from the muscle biopsy of a patient with Kearns–Sayre syndrome. In B, an RRF (asterisk) is
highlighted by the histochemical stain for succinate dehydrogenase, which is entirely encoded by nuclear DNA. In C, the same RRF (asterisk) shows no activity
for cytochrome c oxidase, an enzyme that contains three subunits encoded by mtDNA. See entry MITOCHONDRIAL ENCEPHALOMYOPATHIES,
OVERVIEW.
 Plate 35

Molecules, receptors, and their ligands involved in exiting of T cells through the endothelial cell wall and recognizing muscle antigens on the surface of muscle
fibers. Sequentially, the LFA-I/ICAM-I binding anchors the cytoskeletal molecules in the nascent immunological synapse. This allows the interaction of TCR/
MHC with the sampling of MHC–peptides complex and engagement of BB1 and CD40 costimulatory molecules with their ligands CD28, CTLA, and CD40L—
the prerequisites for antigen recognition. Metalloproteinases facilitate attachment of T cells to the muscle surface. Muscle fiber necrosis occurs via perforin
granules released by the autoinvasive T cells. A direct myocytotoxic effect exerted by the released IFN-g, IL-1 or TNF-a may also occur. See entry MYOSITIS,
INFLAMMATORY.
 Plate 36

Structural and functional neuroimages from a man with right carotid occlusion and transient ischemic attacks manifested by left arm and leg weakness. (A)
The structural x-ray CT image shows normal gray and white matter in both hemispheres with no evidence of any structural abnormality. (B) The physiological
PET cerebral blood flow image shows reduced cerebral blood flow in the part of the brain supplied by the occluded carotid artery. See entry
NEUROIMAGING, OVERVIEW.
 Plate 37

Magnetic resonance angiogram of a high-grade stenosis (arrow) of the origin of the internal carotid artery. See entry NEURORADIOLOGY, DIAGNOSTIC.
 Plate 38

Color Doppler ultrasound of a high-grade stenosis of the right internal carotid artery. The Doppler cursor (arrow) is placed at the site of the highest velocity.
The waveform on the lower aspect of the figure shows high peak systolic velocities, consistent with a high-grade stenosis, and high diastolic flow rates,
characteristic of the low-resistance cerebral circulation. See entry NEURORADIOLOGY, DIAGNOSTIC.
 Plate 39

The synthesis, storage, action, and termination of norepinephrine, a representative brain neurotransmitter. (A) Norepinephrine is synthesized in the nerve cell
and packaged into vesicles. In preparation for release, these vesicles are transported to the nerve terminal. (B) Upon arrival of an action potential at the axon
terminal and the resultant calcium entry, vesicles fuse with the nerve terminal membrane, thereby releasing their contents into the synapse. (C) Released
neurotransmitter diffuses across the synaptic cleft and can interact with postsynaptic receptor targets to cause excitatory or inhibitory postsynaptic potentials
and/or stimulate second messenger systems. Termination of the response is accomplished by removing free neurotransmitter from the synapse.(D) Simple
diffusion can carry the neurotransmitter out of the synapse, or (E) enzymes [e.g., monoamineoxidase (MAO)] can degrade or chemically modify the
neurotransmitter, rendering it incapable of further action. (F) Finally, reuptake of neurotransmitter back into the presynaptic neuron or into surrounding cells
can terminate the signal as well as recycle some of the neurotransmitter. See entry NEUROTRANSMITTER RECEPTORS.
 Plate 40

Ionotropic receptors (ligand-gated ion channels) are pore-forming proteins that can be activated and opened by neurotransmitter binding. (A) The g-
aminobenzoic acid (GABA) chloride channel is also the site of action of a group of drugs called benzodiazepines (BZDs) (e.g., alprazolam). (B) The receptor is
composed of five subunits and allows influx of chloride into the cell when the neurotransmitter GABA binds to it. (C) BZD binding alone is not sufficient to
open the channel. (D) The binding of both GABA and BZDs allows greater chloride influx than GABA binding alone. See entry NEUROTRANSMITTER
RECEPTORS.
 Plate 41

Overview of the development of oligodendrocytes. Immature bipolar oligodendrocyte precursors recognized by labeling with the mAb A2B5 proliferate
extensively in response to PDGF, are highly migratory, and mature into multiprocessed pro-oligodendroblasts.Oligodendroblasts proliferate primarily in
response to bFGF and can be recognized by labeling with mAb O4. Expression of the major glycolipid of myelin galactocerebroside (GC) and cessation of
proliferation accompany differentiation of the precursors into oligodendrocytes. This is a particularly susceptible stage in the lineage, and in the absence of
survival signals many of the cells die by apoptosis. Maturation of oligodendrocyte is accompanied by increased expression of myelin components (MBP and
PLP) and assembly of the myelin sheath. See entry OLIGODENDROCYTES.
 Plate 42

Developing myelin in the mouse spinal cord detected by antibodies to myelin basic protein (MBP). (A) Transverse section through the ventral region of the P7
mouse spinal cord. The myelin develops in a patchy manner, reflecting the differentiation and maturation of individual oligodendrocytes. (B) Higher power
micrograph of an individual MBP-labeled oligodendrocyte in the developing spinal cord that is myelinating several adjacent axons (arrows). The MBP myelin
sheaths cut in transverse section appear as dark circles with an unlabeled axon in the center. See entry OLIGODENDROCYTES.
 Plate 43

A 68-year-old man had sudden onset of painless visual loss in the right eye. The right optic nerve is edematous. The left optic nerve has a cup to disk ratio of
less than 0.1 (arrow).These are typical features of nonarteritic anterior ischemic optic neuropathy. See entry OPTIC NERVE DISORDERS.
 Plate 44

Milky swelling of the right optic nerve in an 80-year-old patient with giant cell arteritis. The normal left eye has a cup to disk ratio of 0.4 (arrow). See entry
OPTIC NERVE DISORDERS.
 Plate 45

Positive temporal artery biopsy performed 3 weeks after starting steroids. There are numerous lymphocytes present in the internal elastic lamina (arrow), a
pathognomonic sign of arteritis. See entry OPTIC NERVE DISORDERS.
 Plate 46

Effect of physiological brain stimulation on regional cerebral blood flow (CBF) and oxygen metabolism. All images are from the same subject. The left-hand
column shows images of cerebral blood blow, cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF) obtained with the eyes closed. OEF
is normally uniform throughout the resting brain, reflecting the close coupling of CBF and CMRO2.Corresponding images in the right-hand column were
obtained during vibrotactile stimulation of the left fingers. During stimulation, there is increased CBF in the contralateral sensori-motor cortex (top right) but
no increase in CMRO2 (middle right). OEF is decreased (lower right), reflecting the fact the CBF has increased more than CMRO2. This decrease in OEF results
in increased oxygen content of venous blood which can be detected by BOLD MRI. See entry PHYSIOLOGICAL BRAIN IMAGING.
 Plate 47

PET image of cerebrovascular disease in a 67-year-old man with transient ischemic attacks manifested by left arm numbness. Arteriography demonstrated
severe stenosis of the intracranial portion of the right internal carotid artery. PET measurements of cerebral blood flow (CBF) show reduced flow in the right
carotid artery territory (upper left). Cerebral blood volume (CBV) is increased in the same region due to autoregulatory vasodilation (upper right). Cerebral
oxygen metabolism (CMRO2) is slightly reduced (lower left) and cerebral oxygen extraction fraction (OEF) is elevated (lower right) on the right side. See entry
POSITRON EMISSION TOMOGRAPHY.
 Plate 48

PET images of [18F]fluorodopa radioactivity in a normal subject and in a patient with Parkinson’s disease. In the normal subject, there is high radioactivity
bilaterally in the caudate and putamen, reflecting uptake and metabolism of the radioactive fluorodopa by dopaminergic neurons. In the patient with
Parkinson’s disease, there is minimal uptake of radioactive fluorodopa because of degeneration and death of dopaminergic neurons. See entry POSITRON
EMISSION TOMOGRAPHY.
 Plate 49

Top: Sagittal cross section through central eyelids and anterior orbit at the level of the ocular lens. 1, Whitnall’s suspensory ligament; 2, levator muscle; 3, superior rectus muscle; 4, suspensory ligament of the superior fornix; 5,
superior conjunctival fornix; 6, inferior conjunctival fornix; 7, inferior rectus muscle; 8, inferior oblique muscle; 9, Lockwood’s suspensory ligament; 10, frontalis muscle; 11, orbital portion of orbicularis muscle; 12, superior orbital
septum; 13, superior preseptal orbicularis muscle; 14, superior tarsal plate; 15, superior pretarsal orbicularis muscle; 16, inferior tarsal plate; 17, inferior pretarsal orbicularis muscle; 18, inferior preseptal orbicularis muscle; 19, inferior
orbital septum; 20, inferior orbital orbicularis muscle. Bottom: Layered sagittal cross section through the eyelids showing the orbital septum and insertions of the levator aponeurosis. 1, Preaponeurotic fat pad; 2, Mueller’s muscle; 3,
inferior sympathetic muscle of Mueller; 4, precapsulopalpebral orbital fat pad; 5, arcus marginalis; 6, superior orbital septum; 7, levator aponeurosis; 8, superior pretarsal orbicularis muscle; 9, inferior pretarsal orbicularis muscle; 10,
orbital septum. See entry PTOSIS.
 Plate 50

Frontal view of the skull. See entry SKULL.

 Plate 51

Right exterior (left) and interior (right) view of the skull. See entry SKULL.
 Plate 52

Diagram of positions of major ascending (left) and descending (right) white matter tracts in the human spinal cord. It is clear that ascending and descending
tracts may be intermixed within parts of the white matter. See entry SPINAL CORD ANATOMY.
 Plate 53

The course of a typical large-diameter afferent fiber with cell body in the dorsal root ganglion, ascending and descending branches in the dorsal column, and
collateral branches distributed in the gray matter. In addition, the axonal course of a typical interneuron in the gray matter is depicted, with a local collateral,
ascending and descending branches in the ventrolateral white matter (fasciculus proprius), and axon collaterals reentering the gray matter to give off terminal
arborizations. See entry SPINAL CORD ANATOMY.
 Plate 54

Coronal sections of the human uncus: rostral (1), intermediate (2), and caudal (3) portions. Unc, uncus; AMYG, amygdala; BN, basal nucleus of Meynert;
Dent, dentate gyrus; ENT, entorhinal cortex; LV, lateral ventricle; OPT, optic tract. See entry UNCUS.
 Plate 55

The duration of zoster-associated pain by age groups. See entry VARICELLA ZOSTER VIRUS.
 Plate 56

Causes of dizziness (N=1461). BPPV, benign paroxysmal positional vertigo; BVL, bilateral vestibular loss; CVA, cerebral vascular accident; TIA, transient ischemic attack; UVL, unilateral vestibular loss. See entry VERTIGO
AND DIZZINESS.
 Plate 57

The bony labyrinth opened to show the membranous labyrinth and the vestibular nerves. See entry VESTIBULOCOCHLEAR NERVE.
 Plate 58

The labyrinth (inner ear) is located within the petrous portion of the temporal bone on each side of the head and is divided anatomically into membranous and
bony parts. 1, Eardrum; 2, malleus; 3, incus; 4, stapes; 5, semicircular canals; 6, auditory nerve; 7, facial nerve; 8, vestibular nerve; 9, cochlea; 10, Eustachian
tube; 11, vestibular vein. See entry VESTIBULAR REFLEXES.
 Plate 59

Visual cortical areas in human brain. Areas involved in form and color perception are shown in blue, and areas involved in motion analysis are shown in green.
See entry VISUAL EVOKED POTENTIALS.
Abducens Nerve (Cranial
Nerve VI)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE ABDUCENS NERVE has a relatively long course
with several important clinical relationships. The
abducens nucleus lies in close proximity to the
horizontal gaze center and facial nerve genu within
the lower pons at the floor of the fourth ventricle.
The nucleus houses not only motor neurons to
innervate the lateral rectus but also internuclear
neurons destined for the contralateral medial rectus
via the medial longitudinal fasciculus. These intra-
axial relationships have clinical significance in that
lesions affecting the abducens nucleus produce
ipsilateral horizontal gaze palsies (not just abduction
deficits), and lesions may affect the facial nerve or
internuclear neurons.
Upon exiting the ventral pontomedullary junction,
the nerve ascends along the clivus in close proximity
to the inferior petrosal sinus prior to entering
Dorello’s canal under the petroclinoid ligament to
access the cavernous sinus. The abducens nerve runs
lateral to the internal carotid artery within the body
of the sinus. Sympathetic fibers destined for the pupil
dilators and Mueller’s muscle of the lid run in
continuity with the abducens nerve for a few
millimeters before joining the ophthalmic division
of the trigeminal nerve within the cavernous sinus.
The abducens nerve gains access to the orbit via the
superior orbital fissure to innervate the lateral rectus
muscle.
ABDUCENS NERVE PALSY
The most common symptom of isolated abducens
neuropathy is binocular horizontal diplopia that
worsens in ipsilateral gaze. Impaired abduction is
readily apparent with complete abducens nerve
palsies but may be subtle with incomplete lesions.
Impaired abduction generally produces esotropia,
and alternate cover or red Maddox rod measure-
ments typically demonstrate increasing esotropia
with gaze ipsilateral to the lesion. Lesions that
involve the abducens nucleus produce ipsilateral
horizontal gaze palsy. Because the nerve takes a
relatively long course, the presence of associated
features is critical to localize the lesion. The presence
of headache, anisocoria, pain, papilledema, propto-
sis, ptosis, facial nerve palsy, or other evidence of
brainstem dysfunction should be sought.
DIFFERENTIAL DIAGNOSIS
Myasthenia is the great mimic of ocular motor
palsies. Whenever a painless, pupillary sparing
ocular misalignment syndrome is evaluated, the
diagnosis of myasthenia gravis must be considered.
Often, there are additional clues, such as ptosis,
fatigability, or clinical variability over time, but these
features may be absent initially. Similarly, other
disorders of the neuromuscular junction, such as
botulism, may mimic sixth nerve palsy; associated
features will usually aid in the diagnosis.
The differential diagnosis of abduction paresis
includes not only sixth nerve paresis but also
mechanical pathophysiologies. Any lesion involving
the medial rectus in a restrictive pattern will produce
1
2 ABDUCENS NERVE
limitation of abduction; perhaps the most common
mechanical process to preferentially affect the medial
rectus is thyroid eye disease. Other signs of an
orbitopathy, such as proptosis, accompany most
mechanical lesions of the extraocular muscles.
Myopathic disease of the lateral rectus may also
simulate sixth nerve paresis (e.g., oculopharyngeal
muscular dystrophy).
With volitional or involuntary convergence spasm,
an esotropia results. If convergence is increased while
in lateral gaze, the appearance may simulate uni-
lateral or bilateral abducens paresis. The pupils help
distinguish these entities with characteristic miosis
during convergence. It is often useful to measure the
ductions of the suspected eye individually with the
other eye covered to help inhibit convergence.
CLINICAL ASSOCIATIONS OF
SPECIFIC SYNDROMES
The isolated abducens nerve palsy is difficult to
localize. Accordingly, the presence of associated
features should be aggressively sought. These fea-
tures assist in localization, which helps narrow the
differential diagnosis.
The association of abducens nerve palsy with
ipsilateral Horner’s syndrome indicates cavernous
sinus localization. The sympathetic nerves destined
for the eye are briefly in contact with the abducens
nerve within the cavernous sinus.
The combination of abducens nerve palsy with
ipsilateral facial pain and serous otitis is a classic
presentation of nasopharyngeal carcinoma originat-
ing in the fossa of Rosenmüller with intracranial
extension through the foramen of lacerum. Blockage
of the eustachian tube leads to the otitis.
Duane’s syndrome involves agenesis of the sixth
nerve nucleus. All three subtypes display narrowing
of the palpebral fissure upon adduction due to
retraction of the globe. Duane’s syndrome type 1 is
characterized by abduction paresis, is the most
common of the three forms, and may be confused
with acquired abducens nerve palsy. Duane’s type 2 is
marked by limited adduction, whereas Duane’s type
3 displays limited abduction and adduction and is the
least common subtype. Duane’s syndrome type 1
appears to be caused by abducens nerve agenesis
with aberrant regeneration of the lateral rectus via
branches of the oculomotor nerve.
Möbius syndrome refers to congenital agenesis of
the abducens and facial nuclei. Clinically, absent
horizontal gaze and bifacial palsy are present. Several
other signs may be associated with Möbius syn-
drome, including hypoglossal dysfunction, endocri-
nopathies, or abnormalities of the great vessels.
An acquired abducens neuropathy with ipsilateral
facial palsy indicates a lesion of the ipsilateral pons
affecting the intra-axial abducens and facial nerve
fascicles prior to brainstem exit. This syndrome is
usually vascular in origin but may result from other
pathophysiologies, such as demyelination or neo-
plasm.
The one-and-one-half syndrome refers to ipsilat-
eral gaze palsy and internuclear ophthalmoplegia.
This is similar in location to the abducens neuro-
pathy and facial palsy described previously, but the
lesion involves the abducens nucleus instead of the
intra-axial fascicle, thus producing the gaze palsy.
Conceptualizing a scheme in which full horizontal
eye movements of both eyes sum to two, with half
‘‘points’’ each for abduction OD (right eye), abduc-
tion OS (left eye), adduction OD, and adduction OS,
the one-and-one-half syndrome demonstrates sparing
of abduction in the contralateral eye only.
The eight-and-one-half syndrome refers to the one-
and-one-half syndrome described previously with the
addition of an ipsilateral facial palsy. This lesion is
usually vascular in origin and localizes to the pontine
segment containing the sixth nerve nucleus and
seventh nerve in close proximity.
Bilateral abducens nerve palsies are most often
related to neoplasm, demyelination, meningitis,
increased intracranial pressure, or subarachnoid
hemorrhage.
Childhood sixth nerve palsy may be the presenting
sign of posterior fossa neoplasm, such as pontine
glioma, astrocytoma, medulloblastoma, or ependy-
moma. Additionally, childhood abducens neuropathy
may occur in the postviral or vaccine setting; in these
circumstances, sixth nerve palsy generally improves
spontaneously. Imaging with attention to the poster-
ior fossa is often required to assist in diagnosis.
Childhood sixth nerve palsy should be distinguished
from congenital esotropia, which demonstrates
comitant esotropia and is often accompanied by
amblyopia and impaired stereovision.
The triad of Wernicke’s encephalopathy is ophthal-
moplegia, ataxia, and mental status changes.
Although the prototypical eye movement disorder is
abducens nerve palsy, similar to the other feature of
the disease, variation is the rule. Most commonly
observed in alcoholic patients, the disease may strike
any patient at nutritional risk. Treatment with paren-
teral thiamine rapidly reverses ophthalmoparesis and

should be given in any suspected case. Without
proper therapy, progression to the largely irreversible
Korsakoff’s psychosis occurs.
PATHOPHYSIOLOGY
Microvascular
This scenario is similar to other ischemic mononeur-
itis situations, such as ‘‘diabetic’’ third nerve palsies.
Predisposing factors include the typical vascular risk
factors, such as diabetes, tobacco use, hypertension,
hyperlipidemia, and age older than 50 years. Micro-
vascular mononeuritis typically occurs in isolation
without other signs or symptoms, and it resolves
within approximately 3 months. Increased attention
should be directed at diagnosis and control of
vascular risk factors as well as therapy to mitigate
stroke recurrence (e.g., antiplatelet agents).
Tumor
The possibility of tumor should be considered for
any patient with unexplained abducens nerve palsy.
This is a relatively common presentation in pediatric
cerebral neoplasms, which have a propensity to
occur in the infratentorial, intra-axial space. Tumors
within the parasellar region or along the clivus, such
as chordoma, meningioma, or nasopharyngeal carci-
noma, often affect the sixth nerve (Figs. 1 and 2). In
addition, increased intracranial pressure related to
tumors distant from the course of the sixth nerve
may produce abducens neuropathy.
Intracranial Pressure Alteration
Increased intracranial pressure may result in abdu-
cens nerve palsy. Sixth nerve palsy accompanies
pseudotumor cerebri in approximately 15% of cases.
Neoplasms, intra- or extra-axial hemorrhage, or
other space-occupying lesions that increase intracra-
nial pressure may produce sixth nerve palsies (Fig. 3).
Alternatively, intracranial hypotension (idiopathic)
has also been associated with abducens neuropathy,
and sixth nerve palsy may occur following otherwise
uncomplicated lumbar puncture.
Brainstem Infarct
Ischemic lesions involving the pons may affect the
sixth nerve nucleus or fascicles. Infarcts within the
pons are usually associated with other symptoms of
brainstem dysfunction, such as contralateral weak-
ness, or other cranial nerve palsies. Millard–Gubler
syndrome is characterized by ipsilateral abducens
ABDUCENS NERVE 3
Figure 1
A 69-year-old patient with history of acute leukemia presented
with ipsilateral sixth nerve palsy and middle cerebral artery
territory infarct related to biopsy-proven mucormycosis. Note the
cavernous sinus and underlying sphenoid sinus abnormality on the
left. Mucormycosis often begins within the sinus but has a
predilection for vessels, often leading to occlusion.
and facial nerve palsies with contralateral hemiplegia
related to ventral paramedian pontine infarct.
Raymond’s syndrome involves ipsilateral abducens
neuropathy with contralateral hemiplegia.
Aneurysm
Aneurysm may produce sixth nerve palsy, especially
intracavernous carotid artery aneurysms. Intracranial
aneurysms involving the circle of Willis rarely produce
abducens nerve palsy (in contrast to the relatively
common aneurysmal oculomotor nerve palsy).
Trauma
Trauma is a relatively common cause of abducens
nerve palsies. The mechanisms of traumatic sixth
nerve palsy may involve the forces responsible for
temporal bone fractures; the nerve resides adjacent to
the petrous bone after exiting the subarachnoid
space. Most unilateral sixth nerve palsies related to
trauma improve spontaneously, although the prog-
nosis for traumatic bilateral abducens nerve palsies is
less favorable.
Infection
The sixth nerve is susceptible to infection of the pet-
rous bone from underlying mastoiditis. Gradenigo’s
syndrome consists of V1 trigeminal pain, sixth nerve
palsy, and often deafness. Although Gradenigo’s
4 ABDUCENS NERVE
Figure 2
A 49-year-old woman presented initially with unilateral
abducens palsy related to clivus chordoma; subsequent
progression to include the third and fourth cranial nerves
bilaterally was noted with tumor progression. (A) Extensive
chordoma involving the entirety of the clivus and both
cavernous sinuses and encompassing the carotid artery is
demonstrated. (B) Three-dimensional computed tomography
demonstrates the extent of clival destruction (black areas in
skull base).
syndrome was initially described in relation to
infectious causes, it is more commonly due to
neoplasm in industrialized countries.
Multiple Sclerosis
Multiple sclerosis is a common cause of sixth nerve
palsy in younger patients. The abducens nerve is the
most common ocular motor nerve affected by
demyelinating disease. Magnetic resonance imaging
(MRI) often demonstrates the characteristic lesions
on T2-weighted sequences.
EVALUATION
The initial evaluation should focus on excluding
sixth nerve palsy mimics, such as comitant strabis-
mus, neuromuscular junction disease, myopathy, or
restrictive mechanical processes such as thyroid eye
disease. Then, the lesion responsible for the abdu-
cens nerve palsy should be localized; associated
features are particularly helpful in this regard. The
isolated abducens nerve palsy in the elderly patient
with vascular risk factors is often related to
microvascular ischemia. This situation requires
Figure 3
A 6-year-old boy presented with abducens nerve palsy and
papilledema related to postinfectious subdural hygroma with
elevated intracranial pressure. Following resection, all symptoms
resolved. This case demonstrates the potential ‘‘false-localizing’’
feature of sixth nerve palsies.

diagnosis and treatment of identified vascular risks,
and the clinician may forego neuroimaging pending
resolution over a relatively short clinical course.
Unexplained sixth nerve palsy or disease localized to
orbit, cavernous sines, subarachnoid space, or
brainstem requires imaging. MRI is the study of
choice in most cases due to its superior resolution of
the cavernous sinus, clivus in sagittal plane, dura,
and brainstem. Trauma is often best imaged acutely
with computed tomography for superior bone
demonstration. Lumbar puncture may be required
in select cases (e.g., suspected meningeal processes
or altered intracranial pressure).
TREATMENT
Therapy is directed at the underlying cause. Initial
symptomatic treatment for diplopia may include
occlusion or prism placement. Typically, the
visually weaker or paretic eye is consistently
occluded (based on patient preference), thus avoid-
ing the visual ‘‘dizziness’’ that often results from
changing the side of the patch. Monocular occlu-
sion in an adult will not lead to visual decline. If
ocular alignment findings are stable for at least 6
months and prism therapy is not helpful, strabismus
surgery should be considered.
—Eric R. Eggenberger
See also–Accessory Nerve (Cranial Nerve XI);
Diplopia and Strabismus; Facial Nerve (Cranial
Nerve VII); Glossopharyngeal Nerve (Cranial
Nerve IX); Hypoglossal Nerve (Cranial Nerve XII);
Myasthenia Gravis; Oculomotor Nerve (Cranial
Nerve III); Olfactory Nerve (Cranial Nerve I);
Optic Nerve (Cranial Nerve II); Trigeminal Nerve
(Cranial Nerve V); Trochlear Nerve (Cranial Nerve
IV); Vagus Nerve (Cranial Nerve X);
Vestibulocochlear Nerve (Cranial Nerve VIII)
Further Reading
Holmes, J. M., Beck, R. W., Kip, K. E., et al. (2000). Botulinum
toxin treatment versus conservative management in acute
traumatic sixth nerve palsy or paresis. J. AAPOS 4, 145–149.
Keane, J. (1976). Bilateral sixth nerve palsy. Analysis of 125 cases.
Arch. Neurol. 33, 681–683.
Kodsi, S. R., and Younge, B. R. (1992). Acquired oculomotor,
trochlear and abducens nerve palsies in pediatric patients. Am.
J. Ophthalmol. 114, 568–574.
Leigh, R. J., and Zee, D. S. (1989). The Neurology of Eye
Movements, 3rd ed. Oxford Univ. Press, Oxford.
Smith, C. (1998). Nuclear and infranuclear ocular motility
disorders. In Walsh & Hoyt’s Clinical Neuro-Ophthalmology
ABETALIPOPROTEINEMIA 5
(N. R. Miller and N. J. Newman, Eds.), 5th ed. Williams &
Wilkins, Baltimore.
Abetalipoproteinemia (ABL,
Bassen–Kornzweig Disease)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ABETALIPOPROTEINEMIA (ABL), inherited as an
autosomal recessive trait, is a disorder resulting from
mutations in the microsomal triglyceride transfer
protein (MTP). The virtual absence of b-lipoprotein
in the circulation in patients with ABL results from
impaired transport of the protein, not mutations in
the apolipoprotein B (apo B) gene, which encodes the
b-lipoproteins. In theory, the observed deficiency of
circulating b-lipoprotein could be the consequence of
a number of defects in the transport machinery, but
all ABL patients studied to date have shown
mutations in MTP. MTP is believed to play a key
role in the attachment of lipids to apo B; when this
fails to occur, apo B is rapidly degraded.
The impaired secretion of b-lipoprotein in ABL
leads to the absence of very low-density lipoprotein
and low-density lipoprotein (LDL) from the circula-
tion, readily detected as very low cholesterol levels.
This finding is also seen in a closely related disorder,
familial hypo-b-lipoproteinemia (HBL). HBL resem-
bles ABL clinically, but it results from mutations of
apo B. Heterozygotes for HBL have hypocholester-
olemia, allowing them to be distinguished from
heterozygotes for ABL, who have normal cholesterol
levels. Among other things, b-lipoprotein serves to
transport lipids and vitamin E, and it is apparent that
the neurological manifestations of this disorder
largely reflect vitamin E deficiency. Children with
ABL usually present with diarrhea, fatty stools, and
steatorrhea. They frequently have growth retardation
and may develop osteomalacia.
Approximately one-third of affected individuals
develop neurological symptoms before the age of 10
years. The neurological manifestations of ABL begin
with a slowly progressive sensory neuronopathy
associated with diminished vibratory and proprio-
ceptive sense. The pathological changes are char-
acterized by demyelination of the dorsal columns of
the spinal cord. This process gradually results in
sensory ataxia and loss of deep tendon reflexes.
Untreated patients eventually lose the ability to walk
or stand. Scoliosis is common, and bulbar function is

diagnosis and treatment of identified vascular risks,
and the clinician may forego neuroimaging pending
resolution over a relatively short clinical course.
Unexplained sixth nerve palsy or disease localized to
orbit, cavernous sines, subarachnoid space, or
brainstem requires imaging. MRI is the study of
choice in most cases due to its superior resolution of
the cavernous sinus, clivus in sagittal plane, dura,
and brainstem. Trauma is often best imaged acutely
with computed tomography for superior bone
demonstration. Lumbar puncture may be required
in select cases (e.g., suspected meningeal processes
or altered intracranial pressure).
TREATMENT
Therapy is directed at the underlying cause. Initial
symptomatic treatment for diplopia may include
occlusion or prism placement. Typically, the
visually weaker or paretic eye is consistently
occluded (based on patient preference), thus avoid-
ing the visual ‘‘dizziness’’ that often results from
changing the side of the patch. Monocular occlu-
sion in an adult will not lead to visual decline. If
ocular alignment findings are stable for at least 6
months and prism therapy is not helpful, strabismus
surgery should be considered.
—Eric R. Eggenberger
See also–Accessory Nerve (Cranial Nerve XI);
Diplopia and Strabismus; Facial Nerve (Cranial
Nerve VII); Glossopharyngeal Nerve (Cranial
Nerve IX); Hypoglossal Nerve (Cranial Nerve XII);
Myasthenia Gravis; Oculomotor Nerve (Cranial
Nerve III); Olfactory Nerve (Cranial Nerve I);
Optic Nerve (Cranial Nerve II); Trigeminal Nerve
(Cranial Nerve V); Trochlear Nerve (Cranial Nerve
IV); Vagus Nerve (Cranial Nerve X);
Vestibulocochlear Nerve (Cranial Nerve VIII)
Further Reading
Holmes, J. M., Beck, R. W., Kip, K. E., et al. (2000). Botulinum
toxin treatment versus conservative management in acute
traumatic sixth nerve palsy or paresis. J. AAPOS 4, 145–149.
Keane, J. (1976). Bilateral sixth nerve palsy. Analysis of 125 cases.
Arch. Neurol. 33, 681–683.
Kodsi, S. R., and Younge, B. R. (1992). Acquired oculomotor,
trochlear and abducens nerve palsies in pediatric patients. Am.
J. Ophthalmol. 114, 568–574.
Leigh, R. J., and Zee, D. S. (1989). The Neurology of Eye
Movements, 3rd ed. Oxford Univ. Press, Oxford.
Smith, C. (1998). Nuclear and infranuclear ocular motility
disorders. In Walsh & Hoyt’s Clinical Neuro-Ophthalmology
ABETALIPOPROTEINEMIA 5
(N. R. Miller and N. J. Newman, Eds.), 5th ed. Williams &
Wilkins, Baltimore.
Abetalipoproteinemia (ABL,
Bassen–Kornzweig Disease)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ABETALIPOPROTEINEMIA (ABL), inherited as an
autosomal recessive trait, is a disorder resulting from
mutations in the microsomal triglyceride transfer
protein (MTP). The virtual absence of b-lipoprotein
in the circulation in patients with ABL results from
impaired transport of the protein, not mutations in
the apolipoprotein B (apo B) gene, which encodes the
b-lipoproteins. In theory, the observed deficiency of
circulating b-lipoprotein could be the consequence of
a number of defects in the transport machinery, but
all ABL patients studied to date have shown
mutations in MTP. MTP is believed to play a key
role in the attachment of lipids to apo B; when this
fails to occur, apo B is rapidly degraded.
The impaired secretion of b-lipoprotein in ABL
leads to the absence of very low-density lipoprotein
and low-density lipoprotein (LDL) from the circula-
tion, readily detected as very low cholesterol levels.
This finding is also seen in a closely related disorder,
familial hypo-b-lipoproteinemia (HBL). HBL resem-
bles ABL clinically, but it results from mutations of
apo B. Heterozygotes for HBL have hypocholester-
olemia, allowing them to be distinguished from
heterozygotes for ABL, who have normal cholesterol
levels. Among other things, b-lipoprotein serves to
transport lipids and vitamin E, and it is apparent that
the neurological manifestations of this disorder
largely reflect vitamin E deficiency. Children with
ABL usually present with diarrhea, fatty stools, and
steatorrhea. They frequently have growth retardation
and may develop osteomalacia.
Approximately one-third of affected individuals
develop neurological symptoms before the age of 10
years. The neurological manifestations of ABL begin
with a slowly progressive sensory neuronopathy
associated with diminished vibratory and proprio-
ceptive sense. The pathological changes are char-
acterized by demyelination of the dorsal columns of
the spinal cord. This process gradually results in
sensory ataxia and loss of deep tendon reflexes.
Untreated patients eventually lose the ability to walk
or stand. Scoliosis is common, and bulbar function is
6 ABSCESS, SURGERY
ultimately affected, resulting in dysarthria and
dysphagia. Untreated patients may also develop a
degenerative pigmentary retinopathy leading to
nyctalopia and ultimately impaired visual acuity.
Microscopic examination of the tissues in ABL
shows degeneration of posterior columns and corti-
cospinal and spinocerebellar tracts in the spinal cord,
with loss of myelin in the cerebellum and peripheral
nerves. Neurons are diminished in the cerebellar nuclei
and anterior horns of the spinal cord. Retinal
photoreceptors and pigment epithelium are lost, and
the optic nerve may be atrophic. Ceroid pigments may
be found in intestine, heart, and skeletal muscle.
Ultrastructural studies show splitting of myelin sheaths
and an increase in lysosomes in peripheral nerves.
Varying proportions of red blood cells develop
irregular, ‘‘spiky or star-like’’ shapes, described as
acanthocytosis. This deformation is attributed to
altered distribution of lipids between the lipid bilayers
of the plasma membrane. Acanthocytes fail to
congregate normally with one another, leading to
diminished formation of rouleaux and thus a very low
erythrocyte sedimentation rate. Some children with
ABL also develop anemia that is often responsive to
therapy with iron or folic acid. The deficiency of
vitamin E may contribute to anemia by reducing
protection from free radicals. Abnormal bleeding may
occur because of deficiency of vitamin K-dependent
coagulation factors, or reduced platelet aggregation,
another consequence of altered lipid composition of
the plasma membrane. Measurement of LDLs de-
monstrates their complete absence from the plasma.
Levels of plasma cholesterol, triglycerides, and
vitamins E and A are proportionately reduced.
The intestinal villi are normally formed, allowing
ABL to be distinguished from celiac disease, with
which it is otherwise easily confused. The epithelium
may appear yellow macroscopically and contains
excess lipid droplets on microscopic examination.
Definitive treatment is not available for ABL, but
symptomatic treatment is generally effective. Most
important, restriction of fats, particularly triglycer-
ides containing long-chain fatty acids, is effective in
managing the gastrointestinal symptoms and their
secondary consequences. In addition, patients require
supplementation with vitamin E in pharmacological
doses. Usually, 1 or 2 g per day is administered to
infants and 5–10 g per day for older children and
adults. In general, therapy with large doses of
vitamin E prevents the emergence of neurological
symptoms and signs and in some cases may lead to
their reversal. Vitamin A supplementation is also
generally recommended. Vitamin K should be
administered if the prothrombin time is prolonged.
Long-term follow-up of patients with ABL suggests
that even the early aggressive use of vitamin E may
not entirely prevent the emergence of neurological
symptoms and signs over many years. Clearly, this
subject requires further investigation and may provide
further impetus toward developing definitive therapy.
Gene therapy would be a logical curative approach
for ABL, particularly since effective correction would
not require targeting to the nervous system.
ABL occurs with increased frequency in the
Ashkenazic population, and a number of mutations
in the MTP gene have been identified. Thus, reliable
heterozygote identification is potentially possible,
which should be helpful in improving genetic
counseling for this disorder.
—Marc C. Patterson
See also–Fabry’s Disease; Gaucher’s Disease;
Krabbe’s Disease; Lipidosis; Lipoprotein
Disorders
Further Reading
Berriot-Varoqueaux, N., Aggerbeck, L. P., Samson-Bouma, M.-E.,
et al. (2000). The role of the microsomal triglyceride transfer
protein in abetalipoproteinemia. Annu. Rev. Nutr. 20, 663–697.
Kane, J. P., and Havel, R. J. (2001). Disorders of the biogenesis
and secretion of lipoproteins containing the B apolipoproteins.
In The Metabolic and Molecular Bases of Inherited Diseases (C.
R. Scriver, A. L. Beaudet, D. Valle, and W. S. Sly, Eds.), 8th ed.,
pp. 2717–2752. McGraw-Hill, New York.
Rader, D. J., and Tietge, U. J. (1999). Gene therapy for dyslipidemia:
Clinical prospects. Curr. Atheroscler. Rep. 1, 58–69.
Abscess, Surgery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AN ABSCESS is defined as a collection of cellular
debris that has formed in response to localized
infection. The abscess may have an associated
capsule, depending on whether the body has had a
strong response to it and has attempted to isolate it.
Abscesses can occur in almost any tissue in the body.
When an abscess forms within neural tissues,
specifically the brain or spinal cord, treatment must
be directed toward eradicating the infection as well
as the mass of the abscess.
Abscesses involving the brain or spinal cord can
arise in one of three ways. They can spread
hematogenously—that is, through the bloodstream
6 ABSCESS, SURGERY
ultimately affected, resulting in dysarthria and
dysphagia. Untreated patients may also develop a
degenerative pigmentary retinopathy leading to
nyctalopia and ultimately impaired visual acuity.
Microscopic examination of the tissues in ABL
shows degeneration of posterior columns and corti-
cospinal and spinocerebellar tracts in the spinal cord,
with loss of myelin in the cerebellum and peripheral
nerves. Neurons are diminished in the cerebellar nuclei
and anterior horns of the spinal cord. Retinal
photoreceptors and pigment epithelium are lost, and
the optic nerve may be atrophic. Ceroid pigments may
be found in intestine, heart, and skeletal muscle.
Ultrastructural studies show splitting of myelin sheaths
and an increase in lysosomes in peripheral nerves.
Varying proportions of red blood cells develop
irregular, ‘‘spiky or star-like’’ shapes, described as
acanthocytosis. This deformation is attributed to
altered distribution of lipids between the lipid bilayers
of the plasma membrane. Acanthocytes fail to
congregate normally with one another, leading to
diminished formation of rouleaux and thus a very low
erythrocyte sedimentation rate. Some children with
ABL also develop anemia that is often responsive to
therapy with iron or folic acid. The deficiency of
vitamin E may contribute to anemia by reducing
protection from free radicals. Abnormal bleeding may
occur because of deficiency of vitamin K-dependent
coagulation factors, or reduced platelet aggregation,
another consequence of altered lipid composition of
the plasma membrane. Measurement of LDLs de-
monstrates their complete absence from the plasma.
Levels of plasma cholesterol, triglycerides, and
vitamins E and A are proportionately reduced.
The intestinal villi are normally formed, allowing
ABL to be distinguished from celiac disease, with
which it is otherwise easily confused. The epithelium
may appear yellow macroscopically and contains
excess lipid droplets on microscopic examination.
Definitive treatment is not available for ABL, but
symptomatic treatment is generally effective. Most
important, restriction of fats, particularly triglycer-
ides containing long-chain fatty acids, is effective in
managing the gastrointestinal symptoms and their
secondary consequences. In addition, patients require
supplementation with vitamin E in pharmacological
doses. Usually, 1 or 2 g per day is administered to
infants and 5–10 g per day for older children and
adults. In general, therapy with large doses of
vitamin E prevents the emergence of neurological
symptoms and signs and in some cases may lead to
their reversal. Vitamin A supplementation is also
generally recommended. Vitamin K should be
administered if the prothrombin time is prolonged.
Long-term follow-up of patients with ABL suggests
that even the early aggressive use of vitamin E may
not entirely prevent the emergence of neurological
symptoms and signs over many years. Clearly, this
subject requires further investigation and may provide
further impetus toward developing definitive therapy.
Gene therapy would be a logical curative approach
for ABL, particularly since effective correction would
not require targeting to the nervous system.
ABL occurs with increased frequency in the
Ashkenazic population, and a number of mutations
in the MTP gene have been identified. Thus, reliable
heterozygote identification is potentially possible,
which should be helpful in improving genetic
counseling for this disorder.
—Marc C. Patterson
See also–Fabry’s Disease; Gaucher’s Disease;
Krabbe’s Disease; Lipidosis; Lipoprotein
Disorders
Further Reading
Berriot-Varoqueaux, N., Aggerbeck, L. P., Samson-Bouma, M.-E.,
et al. (2000). The role of the microsomal triglyceride transfer
protein in abetalipoproteinemia. Annu. Rev. Nutr. 20, 663–697.
Kane, J. P., and Havel, R. J. (2001). Disorders of the biogenesis
and secretion of lipoproteins containing the B apolipoproteins.
In The Metabolic and Molecular Bases of Inherited Diseases (C.
R. Scriver, A. L. Beaudet, D. Valle, and W. S. Sly, Eds.), 8th ed.,
pp. 2717–2752. McGraw-Hill, New York.
Rader, D. J., and Tietge, U. J. (1999). Gene therapy for dyslipidemia:
Clinical prospects. Curr. Atheroscler. Rep. 1, 58–69.
Abscess, Surgery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AN ABSCESS is defined as a collection of cellular
debris that has formed in response to localized
infection. The abscess may have an associated
capsule, depending on whether the body has had a
strong response to it and has attempted to isolate it.
Abscesses can occur in almost any tissue in the body.
When an abscess forms within neural tissues,
specifically the brain or spinal cord, treatment must
be directed toward eradicating the infection as well
as the mass of the abscess.
Abscesses involving the brain or spinal cord can
arise in one of three ways. They can spread
hematogenously—that is, through the bloodstream
 ABSCESS, SURGERY 7

from another infected body part. They can also

originate from adjacent tissues and spread locally.
For example, severe infections of the facial sinuses
can erode the skull base, spreading the infection to
the brain. Finally, localized infections of the brain or
spinal cord can follow invasive procedures, surgeries,
or penetrating trauma, where bacteria from the
‘‘outside world’’ may be brought into direct contact
with the neural tissues.
The mechanisms behind the formation of abscesses
in the brain and spinal cord depend on the interplay
between the body’s immune system and the infecting
organism. In the presence of a healthy immune
system, the body is often able to wall off most
pathogens. The purulent material, or pus, within the
abscess is primarily composed of dead white cells
that the body sent to fight the infection along with
living and dead infectious organisms. The infectious
organism can be a bacterium, a fungus, or even a
protozoan. Unless a person lives within an area
endemic for protozoal or fungal diseases or is
immunocompromised, bacteria are responsible for
most brain and spinal abscesses.
The particular strain of bacteria often depends on
how the abscess was acquired. Abscesses that
develop after surgery or invasive procedures are
often composed of bacteria that live on human skin,
namely Staphylococcus aureus and Staphylococcus
epidermidis. Aggressive infections of the facial
sinuses or middle ear that extend through the skull
base typically involve more virulent species of
bacteria, such as Pseudomonas or Haemophilus.
Finally, abscesses that result from hematogenous
spread most likely are caused by a bacterial strain
involving other body parts at that time. For example,
in patients with heart valve vegetations or infections,
small pieces of infected material can become
dislodged and travel through the bloodstream to
the brain or spinal cord, where an abscess can form.
In this example, a likely pathogen might be
Streptococcus viridans. Some abscesses may also
involve multiple strains of bacteria.
Abscesses can involve neural tissues at several
levels. They can occur epidurally or outside the lining
of the brain and spinal cord (Fig. 1). Even in this
location, they can exert pressure on vital brain or Figure 1
spinal cord structures and incite localized swelling. Sagittal magnetic resonance images showing a spinal epidural
Subdural abscesses or empyemas occur on the surface abscess (arrows) involving the posterior cervicothoracic spinal
cord. (A) The abscess is the compressive mass just posterior to the
of the brain or spinal cord but beneath the dural
spinal cord that (B) rim enhances with the administration of
lining. Abscesses can also directly distort the brain, intravenous contrast. (C) Special T2-weighted images further
spinal cord, or parenchyma, causing swelling in emphasize the mass effect of the lesion. Edema and swelling in the
surrounding structures (Fig. 2). adjacent spinal cord are present.
8 ABSCESS, SURGERY
Figure 2
Coronal magnetic resonance image showing an intraparenchymal
abscess involving the right temporal lobe. Intravenous contrast
was administered before the study; consequently, the rim of the
abscess enhances or ‘‘lights up’’ strongly. The dark area within the
abscess represents necrotic material.
How an abscess manifests clinically depends on
the specific neural tissues involved. Abscesses can
affect neural tissues by causing direct tissue inflam-
mation or edema or by exerting mass effect on
Figure 3
(A) Axial magnetic resonance image showing the cystic structure of a left cerebellar abscess. With intravenous contrast, the rim of the abscess
enhances. (B) T2-weighted image showing the extent of surrounding tissue swelling, which appears as an increased high-intensity signal
(arrow) around the abscess.
surrounding tissue if they occupy a large volume.
Cerebral abscesses can manifest with a nonspecific
headache or more severe neurological deficits,
including weakness, sensory changes, speech difficul-
ties, personality changes, seizures, and decreased
level of consciousness. The severity of presentation
reflects the involvement of vital cerebral areas. Most
patients also develop a fever, possibly even with
chills, although immunosuppressed patients may lack
the capacity to mount this sort of immune response.
Spinal abscesses can cause progressive neurological
dysfunction, including paralysis, sensory changes,
and loss of bowel and bladder functions. In
particular, spinal epidural abscesses may initially
manifest with localized back pain, fever, and
progressive neurological dysfunction.
The diagnosis of cerebral or spinal abscesses must
first be suspected on the basis of the patient’s history.
Patients exhibiting neurological decline after a recent
surgery or intravenous (iv) drug use should be
suspected for neurological infections. Likewise, pre-
disposing conditions, such as valvular heart disease
or immunocompromise, should also raise the level of
suspicion. A detailed neurological examination often
helps to localize a cerebral or spinal abscess.
Diagnostic imaging more precisely identifies and
defines the cause of the lesion. Computed tomo-
graphic (CT) images of the brain using intravenous
contrast or dye demonstrate cerebral abscesses very

well. However, magnetic resonance imaging (MRI) is
the diagnostic modality of choice. It demonstrates
not only the abscess and any localized mass effect but
also associated swelling or edema (Fig. 3). In the
spine, only MRI offers the precise resolution of soft
tissue to delineate an epidural, subdural, or intrapar-
enchymal abscess.
Even when focused neurological examination and
imaging studies point to what appears to be a brain
or spinal abscess, the diagnosis is sometimes un-
certain. The presence of fever, positive blood
cultures, or both may further suggest abscess.
However, tumors, blood clots, and cystic structures
can mimic an abscess on imaging studies and in
clinical presentation. Ultimately, a definitive diag-
nosis can only be obtained by direct tissue sampling
during a surgical procedure.
The proper treatment of brain and spinal cord
abscesses depends on the severity of presentation.
Lesions associated with neurological decline from
mass effect should be considered for urgent evacua-
tion. In the case of a cerebral abscess, a craniotomy
can be performed. Intraoperative localization techni-
ques, such as frameless stereotaxy or ultrasonog-
raphy, may help localize deep-seated abscesses. An
abscess can also be drained through minimally
invasive stereotactic aspiration. As soon as the
diagnosis of cerebral abscess is suspected, the patient
should be started on broad-spectrum antibiotics such
as vancomycin with cefotaxime and metronidazole to
cover all possible pathogens. Once abscess material is
obtained for cultures, the antibiotic regimen can be
tailored to treat the specific organisms identified.
These same principles apply to spinal abscesses. In the
case of an epidural spinal abscess, a spinal laminect-
omy may be needed just over the lesion. In both
instances, surgery is therapeutic and diagnostic.
Not all brain and spinal abscesses, however,
require surgical evacuation. For example, if a patient
with a cerebral abscess has headaches and positive
blood cultures, a trial of iv antibiotics may be
appropriate. If the patient’s symptoms improve and
the abscess resolves on subsequent serial imaging
studies, the presumed diagnosis of cerebral abscess is
confirmed. Likewise, if a patient with a spinal
epidural abscess presents with back pain and fever,
a prolonged course of antibiotics is the first line of
treatment. The decision for surgical evacuation must
only be entertained when the continued presence of
the abscess can cause irreversible neurological injury.
The prognosis for persons with brain or spinal
cord abscesses depends greatly on their neurological
ABULIA 9
status at presentation. Patients with severe neurolog-
ical deficits related to mass effect may recover some
function once the abscess is evacuated, especially if
the neurological deficit is partially related to edema.
However, the degree of improvement after surgery is
not entirely predictable. If the abscess is treated
successfully with either surgery or antibiotic therapy
before severe neurological impairment develops,
subsequent neurological deficits are unlikely. Regular
follow-up with CT or MRI is recommended to verify
abscess resolution after intervention. Initial studies
are obtained 2–4 weeks after start of treatment and
continued every 2–4 months until the lesion com-
pletely resolves. Naturally, any worsening of neuro-
logical status requires prompt diagnostic imaging.
This scenario is true of spinal epidural abscesses that
are treated promptly with iv antibiotics and possibly
surgical evacuation before paralysis or bowel and
bladder deficits appear.
—G. Michael Lemole Jr., Jeffrey S. Henn,
Volker K. H. Sonntag, and Robert F. Spetzler
See also–Bacterial Abscess, Cerebral; Central
Nervous System Infections, Overview; Fungal
Abscess, Cerebral
Further Reading
Cahill, D. W. (1996). Pyogenic infections in the spine. In Principles
of Spinal Surgery (A. H. Menezes and V. K. H. Sonntag, Eds.),
pp. 1453–1465. McGraw-Hill, New York.
Carey, M. E. (1996). Infections of the spine and spinal cord. In
Youmans Neurological Surgery (J. R. Youmans, Ed.), pp. 3270–
3304. Saunders, Philadelphia.
Gormley, W. B., del Busto, R., Saravolatz, L. D., et al. (1996).
Cranial and intracranial bacterial infections. In Youmans
Neurological Surgery (J. R. Youmans, Ed.), pp. 3191–3220.
Saunders, Philadelphia.
Greenberg, M. S. (1997). Cerebral abscess. In Handbook of
Neurosurgery (M. S. Greenberg, Ed.), pp. 621–626. Greenberg
Graphics, Lakeland, FL.
Loftus, C. M., and Biller, J. (1994). Brain abscess. In Principles of
Neurosurgery (S. Rengachary and R. Wilkins, Eds.), pp. 24.1–
24.9. Mosby-Year Book, London.
Abulia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ABULIA is defined as a state of a lack of spontaneity
and initiative with relative preservation of alertness
and awareness. Such individuals appear apathetic,
with reduced emotional response, speech, and

well. However, magnetic resonance imaging (MRI) is
the diagnostic modality of choice. It demonstrates
not only the abscess and any localized mass effect but
also associated swelling or edema (Fig. 3). In the
spine, only MRI offers the precise resolution of soft
tissue to delineate an epidural, subdural, or intrapar-
enchymal abscess.
Even when focused neurological examination and
imaging studies point to what appears to be a brain
or spinal abscess, the diagnosis is sometimes un-
certain. The presence of fever, positive blood
cultures, or both may further suggest abscess.
However, tumors, blood clots, and cystic structures
can mimic an abscess on imaging studies and in
clinical presentation. Ultimately, a definitive diag-
nosis can only be obtained by direct tissue sampling
during a surgical procedure.
The proper treatment of brain and spinal cord
abscesses depends on the severity of presentation.
Lesions associated with neurological decline from
mass effect should be considered for urgent evacua-
tion. In the case of a cerebral abscess, a craniotomy
can be performed. Intraoperative localization techni-
ques, such as frameless stereotaxy or ultrasonog-
raphy, may help localize deep-seated abscesses. An
abscess can also be drained through minimally
invasive stereotactic aspiration. As soon as the
diagnosis of cerebral abscess is suspected, the patient
should be started on broad-spectrum antibiotics such
as vancomycin with cefotaxime and metronidazole to
cover all possible pathogens. Once abscess material is
obtained for cultures, the antibiotic regimen can be
tailored to treat the specific organisms identified.
These same principles apply to spinal abscesses. In the
case of an epidural spinal abscess, a spinal laminect-
omy may be needed just over the lesion. In both
instances, surgery is therapeutic and diagnostic.
Not all brain and spinal abscesses, however,
require surgical evacuation. For example, if a patient
with a cerebral abscess has headaches and positive
blood cultures, a trial of iv antibiotics may be
appropriate. If the patient’s symptoms improve and
the abscess resolves on subsequent serial imaging
studies, the presumed diagnosis of cerebral abscess is
confirmed. Likewise, if a patient with a spinal
epidural abscess presents with back pain and fever,
a prolonged course of antibiotics is the first line of
treatment. The decision for surgical evacuation must
only be entertained when the continued presence of
the abscess can cause irreversible neurological injury.
The prognosis for persons with brain or spinal
cord abscesses depends greatly on their neurological
ABULIA 9
status at presentation. Patients with severe neurolog-
ical deficits related to mass effect may recover some
function once the abscess is evacuated, especially if
the neurological deficit is partially related to edema.
However, the degree of improvement after surgery is
not entirely predictable. If the abscess is treated
successfully with either surgery or antibiotic therapy
before severe neurological impairment develops,
subsequent neurological deficits are unlikely. Regular
follow-up with CT or MRI is recommended to verify
abscess resolution after intervention. Initial studies
are obtained 2–4 weeks after start of treatment and
continued every 2–4 months until the lesion com-
pletely resolves. Naturally, any worsening of neuro-
logical status requires prompt diagnostic imaging.
This scenario is true of spinal epidural abscesses that
are treated promptly with iv antibiotics and possibly
surgical evacuation before paralysis or bowel and
bladder deficits appear.
—G. Michael Lemole Jr., Jeffrey S. Henn,
Volker K. H. Sonntag, and Robert F. Spetzler
See also–Bacterial Abscess, Cerebral; Central
Nervous System Infections, Overview; Fungal
Abscess, Cerebral
Further Reading
Cahill, D. W. (1996). Pyogenic infections in the spine. In Principles
of Spinal Surgery (A. H. Menezes and V. K. H. Sonntag, Eds.),
pp. 1453–1465. McGraw-Hill, New York.
Carey, M. E. (1996). Infections of the spine and spinal cord. In
Youmans Neurological Surgery (J. R. Youmans, Ed.), pp. 3270–
3304. Saunders, Philadelphia.
Gormley, W. B., del Busto, R., Saravolatz, L. D., et al. (1996).
Cranial and intracranial bacterial infections. In Youmans
Neurological Surgery (J. R. Youmans, Ed.), pp. 3191–3220.
Saunders, Philadelphia.
Greenberg, M. S. (1997). Cerebral abscess. In Handbook of
Neurosurgery (M. S. Greenberg, Ed.), pp. 621–626. Greenberg
Graphics, Lakeland, FL.
Loftus, C. M., and Biller, J. (1994). Brain abscess. In Principles of
Neurosurgery (S. Rengachary and R. Wilkins, Eds.), pp. 24.1–
24.9. Mosby-Year Book, London.
Abulia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ABULIA is defined as a state of a lack of spontaneity
and initiative with relative preservation of alertness
and awareness. Such individuals appear apathetic,
with reduced emotional response, speech, and
10 ACCESSORY NERVE
ideation. Motor activity may be reduced or greatly
slowed, with resistance to the physician’s attempts to
move or motivate the patient. Patients may persist in
a posture or activity. The limbs may sustain a posture
for prolonged periods (catatonia). Motor inactivity
may be accompanied by emotional depression, but
motor activity and emotion can be dissociated. The
site of lesions that produce abulia include the
prefrontal regions on the orbital or the dorsolateral
convexity surfaces.
—G. Bryan Young
See also–Catatonia; Stupor
Further Reading
Barrett, K. (1991). Treating organic abulia with bromocriptine and
lisuride: Four case studies. J. Neurol. Neurosurg. Psychiatry 54,
718–721.
Marin, R. S. (1996). Apathy: Concept, syndrome, neural mechan-
isms and treatment. Semin. Clin. Neuropsychiatry 1, 304–314.
Acalculia
see Angular Gyrus Syndrome
Acanthocytosis
see Neuroacanthocytosis
Accessory Nerve (Cranial
Nerve XI)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE 11TH cranial nerve was named the accessory
nerve by Thomas Willis in Cerebri Anatome (1664)
because he realized that it receives additional, or
‘‘accessory,’’ fibers from rostral cervical spinal roots.
FUNCTIONAL COMPONENTS
The accessory nerve is predominantly a motor nerve
that supplies sternocleidomastoid and trapezius.
Some texts consider the ‘‘cranial’’ root, which arises
from the caudal portion of the nucleus ambiguus, as
part of the accessory nerve. The nerve fibers of the
cranial root arise from the 10th cranial (vagus) nerve
nucleus and supply the same target musculature as
the vagus nerve. Axons of the cranial root run with
the vagus nerve for all but a few millimeters, when
joined with the accessory nerve through the jugular
foramen. Consequently, we consider the cranial root
part of the vagus nerve and therefore do not discuss it
here.
ANATOMY
Supranuclear Pathways
Cerebral influence on the accessory nerve nucleus is
derived cortically from the lower part of the
precentral gyrus, which receives information from
premotor association cortex and other cortical areas
by association fibers. Fibers descend from the cortex
through the posterior limb of the internal capsule,
cross the midline at the pyramidal decussation, and
innervate the contralateral accessory nucleus.
Spinal Accessory Nucleus
The accessory nucleus is located within the upper five
or six segments of the cervical spinal cord, approxi-
mately in line with the nucleus ambiguus. In addition
to its primary input from the contralateral cortex, the
accessory nucleus also receives input from the
ipsilateral cortex, other cranial nuclei, and the
reticular formation. Nerve fibers from the accessory
nucleus emerge as rootlets from the lateral spinal
cord to form the accessory nerve.
Accessory Nerve
Intraspinal and Intracranial Course: Spinal root-
lets exit from the lateral aspect of the spinal cord
between the dorsal and ventral roots. These unite as
the accessory nerve (Fig. 1), which ascends in the
spinal canal posterior to dentate ligaments and
anterior to the dorsal roots. The accessory nerve
enters the skull through the foramen magnum, only
to turn and exit the cranium through the jugular
foramen. As mentioned previously, as it exits through
the jugular foramen it is joined by the lower fibers of
the vagus nerve. Within the jugular foramen, the
accessory nerve and caudal vagal fibers travel within
a common dural sheath but are kept separated by a
fold of arachnoid.
Extracranial Course: Emerging from the jugular
foramen into the neck, the accessory nerve usually
10 ACCESSORY NERVE
ideation. Motor activity may be reduced or greatly
slowed, with resistance to the physician’s attempts to
move or motivate the patient. Patients may persist in
a posture or activity. The limbs may sustain a posture
for prolonged periods (catatonia). Motor inactivity
may be accompanied by emotional depression, but
motor activity and emotion can be dissociated. The
site of lesions that produce abulia include the
prefrontal regions on the orbital or the dorsolateral
convexity surfaces.
—G. Bryan Young
See also–Catatonia; Stupor
Further Reading
Barrett, K. (1991). Treating organic abulia with bromocriptine and
lisuride: Four case studies. J. Neurol. Neurosurg. Psychiatry 54,
718–721.
Marin, R. S. (1996). Apathy: Concept, syndrome, neural mechan-
isms and treatment. Semin. Clin. Neuropsychiatry 1, 304–314.
Acalculia
see Angular Gyrus Syndrome
Acanthocytosis
see Neuroacanthocytosis
Accessory Nerve (Cranial
Nerve XI)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE 11TH cranial nerve was named the accessory
nerve by Thomas Willis in Cerebri Anatome (1664)
because he realized that it receives additional, or
‘‘accessory,’’ fibers from rostral cervical spinal roots.
FUNCTIONAL COMPONENTS
The accessory nerve is predominantly a motor nerve
that supplies sternocleidomastoid and trapezius.
Some texts consider the ‘‘cranial’’ root, which arises
from the caudal portion of the nucleus ambiguus, as
part of the accessory nerve. The nerve fibers of the
cranial root arise from the 10th cranial (vagus) nerve
nucleus and supply the same target musculature as
the vagus nerve. Axons of the cranial root run with
the vagus nerve for all but a few millimeters, when
joined with the accessory nerve through the jugular
foramen. Consequently, we consider the cranial root
part of the vagus nerve and therefore do not discuss it
here.
ANATOMY
Supranuclear Pathways
Cerebral influence on the accessory nerve nucleus is
derived cortically from the lower part of the
precentral gyrus, which receives information from
premotor association cortex and other cortical areas
by association fibers. Fibers descend from the cortex
through the posterior limb of the internal capsule,
cross the midline at the pyramidal decussation, and
innervate the contralateral accessory nucleus.
Spinal Accessory Nucleus
The accessory nucleus is located within the upper five
or six segments of the cervical spinal cord, approxi-
mately in line with the nucleus ambiguus. In addition
to its primary input from the contralateral cortex, the
accessory nucleus also receives input from the
ipsilateral cortex, other cranial nuclei, and the
reticular formation. Nerve fibers from the accessory
nucleus emerge as rootlets from the lateral spinal
cord to form the accessory nerve.
Accessory Nerve
Intraspinal and Intracranial Course: Spinal root-
lets exit from the lateral aspect of the spinal cord
between the dorsal and ventral roots. These unite as
the accessory nerve (Fig. 1), which ascends in the
spinal canal posterior to dentate ligaments and
anterior to the dorsal roots. The accessory nerve
enters the skull through the foramen magnum, only
to turn and exit the cranium through the jugular
foramen. As mentioned previously, as it exits through
the jugular foramen it is joined by the lower fibers of
the vagus nerve. Within the jugular foramen, the
accessory nerve and caudal vagal fibers travel within
a common dural sheath but are kept separated by a
fold of arachnoid.
Extracranial Course: Emerging from the jugular
foramen into the neck, the accessory nerve usually

Figure 1
Relationship of the accessory nerve to the vagus and glossopharyngeal nerves. Note how the inferior fibers of the vagus nerve accompany the
accessory nerve through the jugular foramen (reproduced with permission from Haerer, 1992, p. 244).
lies ventral (occasionally dorsal) to the internal
jugular vein. The accessory nerve passes inferiorly
over the lateral mass of the atlas, posteromedial to
the styloid process. It descends posterior to the
digastric and stylohyoid muscles, sending branches
into sternocleidomastoid, which it supplies. It con-
tinues to descend within the posterior triangle of the
neck over levator scapulae to supply trapezius from
its deep surface. Within the neck, the accessory nerve
is accompanied by communicating fibers, which
carry sensory (proprioceptive) information from
trapezius and sternocleidomastoid muscles centrally
via the dorsal root ganglia of C2–C4.
ACCESSORY NERVE PALSY
The most common cause of accessory nerve injury is
iatrogenic, involving surgery for biopsy or block
ACCESSORY NERVE 11
dissection of lymph nodes in the posterior triangle of
the neck. A thorough understanding of the anatomy
of the nerve can help avoid this complication; it is the
practice of some surgeons to draw the position of the
nerve on the neck prior to beginning the operation.
Less common causes of accessory nerve injury in the
neck include blunt and sharp trauma and brachial
plexus neuritis.
Intracranial accessory nerve injury is less common
but can occur as a complication of intracranial
surgery and in the presence of tumors such as
schwannomas (nerve sheath tumors), meningiomas,
or metastases that involve the area of the jugular
foramen.
Most patients with an accessory nerve palsy
complain of shoulder discomfort of variable severity.
Weakness of the shoulder is the major symptom,
noticeable as sagging of the ipsilateral shoulder. An
12 ACCESSORY NERVE
Figure 2
Physical examination of a patient with an accessory nerve palsy. (A) Normal action of sternocleidomastiod in head movement. Accessory
nerve palsy results in weakness of sternocleidomastoid and is detected by impaired turning of the head to the opposite side. (B) Shoulder drop
due to loss of action of trapezius. Also note the downward and rotated position of the scapula (reproduced with permission from Wilson-
Pauwels et al., 1988).
astute patient may also notice weakness in turning
the head to the side opposite the injured accessory
nerve.
Physical examination in unilateral accessory nerve
palsy shows no abnormality in the position of the
head. Sternocleidomastoid weakness is detected by
rotating the head to the opposite side (Fig. 2A).
Flexion of the neck in neutral position results in the
chin deviating slightly to the paralyzed side due to
the unopposed action of the normal contralateral
sternocleidomastoid. In cases of long-standing acces-
sory nerve injury, the sternocleidomastoid muscle
undergoes complete atrophy. Examination of trape-
zius muscle function (Fig. 2B) is also important
because this muscle can be affected separately when
the accessory nerve is injured in the posterior triangle
of the neck distal to the branch to sternocleidomas-
toid. In trapezius palsy, shoulder drop may be
noticed. The scapula is rotated downward and
laterally so that its flared inferior angle is closer to
the spine than the superior angle. This position is due
to the action of the normal levator scapulae and
rhomboids on the scapula at the acromioclavicular
joint. The scapular position in trapezius palsy is
accentuated when the arm is moved laterally against
resistance, but on forward flexion the flaring of the
inferior angle virtually disappears because of serratus
anterior muscle action. The effect of trapezius
weakness on the shoulder can interfere with the
function of deltoid, supraspinatus, and infraspinatus
muscles that may be misinterpreted as weakness.
The prognosis for recovery is highly dependent on
the cause of injury and tends to be more favorable
following neuritis or idiopathic stretch injury. If
accessory nerve injury is suspected following neck
surgery, surgical reexploration (and nerve repair if
necessary) should be considered. In long-standing
nerve injuries or failure of nerve repair, surgical
stabilization of the scapula may improve shoulder
and arm function. Orthotic devices to stabilize the
scapula are generally not very effective.
—Bassam M. Addas and David B. Clarke
See also–Abducens Nerve (Cranial Nerve VI);
Facial Nerve (Cranial Nerve VII);
Glossopharyngeal Nerve (Cranial Nerve IX);
Hypoglossal Nerve (Cranial Nerve XII);
Oculomotor Nerve (Cranial Nerve III); Olfactory
Nerve (Cranial Nerve I); Optic Nerve (Cranial
Nerve II); Trigeminal Nerve (Cranial Nerve V);

Trochlear Nerve (Cranial Nerve IV); Vagus Nerve
(Cranial Nerve X); Vestibulocochlear Nerve
(Cranial Nerve VIII)
Further Reading
Haerer, A. F. (1992). DeJong’s ‘‘The Neurological Examination,’’
5th ed. Lippincott, Philadelphia.
Haymaker, W., and Woodhall, B. (1953). Peripheral Nerve
Injuries. Saunders, Philadelphia.
Kline, D. G., and Hudson, A. R. (1995). Nerve Injuries: Operative
Results for Major Nerve Injuries, Entrapments, and Tumors.
Saunders, Philadelphia.
Pryse-Phillips, W. (1995). Companion to Clinical Neurology.
Little, Brown, Boston.
Stewart, J. D. (1993). Focal Peripheral Neuropathy. Raven Press,
Baltimore.
Wilson-Pauwels, L., Akesson, E. J., and Stewart, P. A. (1988).
Cranial Nerves, Anatomy and Clinical Comments. Dekker,
New York.
Acetylcholine
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACETYLCHOLINE (ACh) is a neurotransmitter in
several different neural systems and plays a role in
the pathophysiology of a variety of neurological and
psychiatric diseases.
HISTORY
In the late 19th century, a major issue in neuroscience
was whether neurotransmission was electrical or
chemical. Observations in peripheral organs such as
the heart indicated that various chemicals could
affect the heart rate and blood pressure. The
‘‘autonomic’’ nervous system, which regulated these
functions, was thought to be characterized by a
balance between inhibitory and excitatory activity.
‘‘Sympathin,’’ later identified as noradrenaline, and
‘‘vagusstoff,’’ later identified as ACh, played critical
roles in the development of the conceptual frame-
work for a system’s neuroscience based on specific
synaptic connections using neurotransmitters. The
Nobel Prize was given to Otto Loewi and Henry
Dale for their work characterizing these neurotrans-
mitters and their actions in the nervous system.
Loewi’s experimental design and deduction that
demonstrated that the heart rate was controlled by
chemicals rather than directly by electrical impulses
is a classic in the history of science. Dale went
ACETYLCHOLINE 13
beyond Loewi’s characterization of ACh as a
neurotransmitter to study drugs that acted on
cholinergic systems, such as physostigmine, a choli-
nesterase inhibitor. Such drugs had been used in
various indigenous people’s traditions and were
known to be able to cause death and changes in
mental status. The cholinergic story evolved quickly
as different receptor responses were associated with
the drugs muscarine and nicotine. Today, many drugs
that act on cholinergic receptors are in use in clinical
neuroscience and other branches of medicine. These
drugs can be used in anesthesia to control secretions
and muscle movement, in gastroenterology to alter
bowel mobility, in urology to influence bladder
function, and in neurology and psychiatry to change
motor and mental function.
METABOLISM
ACh is an ester whose effects were first demonstrated
in bioassays involving, for example, contraction of
muscle strips. Now a variety of other techniques can
be used to measure levels of this neurotransmitter,
but many studies of cholinergic systems have been
conducted using other cholinergic system markers
such as metabolic enzymes. Choline acetyltransferase
(molecular weight approximately 65 kDa) was first
studied in the electric organ of the electric eel. It
catalyzes the final step in the synthesis of ACh, the
acetylation of choline with acetyl coenzyme A. The
degradative enzyme acetyl cholinesterase (AChE),
which has attracted much attention as a therapeutic
target, rapidly hydrolyzes ACh. Butyryl cholinester-
ase is another cholinesterase in the central nervous
system, but its role is unclear. A high-affinity uptake
site for choline is also used as a marker for the
presence of cholinergic neurons in the central
nervous system.
The anatomical distribution of ACh is complex, as
it is found throughout the nervous system. ACh is the
neurotransmitter at the neuromuscular junction.
Cholinergic neurons in the brainstem play important
roles in sleep and other basic physiological activities.
Cholinergic neurons in the basal forebrain play a role
in attention, and those in the basal ganglia have been
implicated in movement disorders, such as Parkin-
son’s disease and Huntington’s disease.
A variety of cholinergic neurotransmitter receptors
have been characterized, building on the original
observations of the selective effects of muscarine and
nicotine. Five muscarinic receptor subtypes (M1–M5)
have been defined by identifying their cloned DNAs,

Trochlear Nerve (Cranial Nerve IV); Vagus Nerve
(Cranial Nerve X); Vestibulocochlear Nerve
(Cranial Nerve VIII)
Further Reading
Haerer, A. F. (1992). DeJong’s ‘‘The Neurological Examination,’’
5th ed. Lippincott, Philadelphia.
Haymaker, W., and Woodhall, B. (1953). Peripheral Nerve
Injuries. Saunders, Philadelphia.
Kline, D. G., and Hudson, A. R. (1995). Nerve Injuries: Operative
Results for Major Nerve Injuries, Entrapments, and Tumors.
Saunders, Philadelphia.
Pryse-Phillips, W. (1995). Companion to Clinical Neurology.
Little, Brown, Boston.
Stewart, J. D. (1993). Focal Peripheral Neuropathy. Raven Press,
Baltimore.
Wilson-Pauwels, L., Akesson, E. J., and Stewart, P. A. (1988).
Cranial Nerves, Anatomy and Clinical Comments. Dekker,
New York.
Acetylcholine
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACETYLCHOLINE (ACh) is a neurotransmitter in
several different neural systems and plays a role in
the pathophysiology of a variety of neurological and
psychiatric diseases.
HISTORY
In the late 19th century, a major issue in neuroscience
was whether neurotransmission was electrical or
chemical. Observations in peripheral organs such as
the heart indicated that various chemicals could
affect the heart rate and blood pressure. The
‘‘autonomic’’ nervous system, which regulated these
functions, was thought to be characterized by a
balance between inhibitory and excitatory activity.
‘‘Sympathin,’’ later identified as noradrenaline, and
‘‘vagusstoff,’’ later identified as ACh, played critical
roles in the development of the conceptual frame-
work for a system’s neuroscience based on specific
synaptic connections using neurotransmitters. The
Nobel Prize was given to Otto Loewi and Henry
Dale for their work characterizing these neurotrans-
mitters and their actions in the nervous system.
Loewi’s experimental design and deduction that
demonstrated that the heart rate was controlled by
chemicals rather than directly by electrical impulses
is a classic in the history of science. Dale went
ACETYLCHOLINE 13
beyond Loewi’s characterization of ACh as a
neurotransmitter to study drugs that acted on
cholinergic systems, such as physostigmine, a choli-
nesterase inhibitor. Such drugs had been used in
various indigenous people’s traditions and were
known to be able to cause death and changes in
mental status. The cholinergic story evolved quickly
as different receptor responses were associated with
the drugs muscarine and nicotine. Today, many drugs
that act on cholinergic receptors are in use in clinical
neuroscience and other branches of medicine. These
drugs can be used in anesthesia to control secretions
and muscle movement, in gastroenterology to alter
bowel mobility, in urology to influence bladder
function, and in neurology and psychiatry to change
motor and mental function.
METABOLISM
ACh is an ester whose effects were first demonstrated
in bioassays involving, for example, contraction of
muscle strips. Now a variety of other techniques can
be used to measure levels of this neurotransmitter,
but many studies of cholinergic systems have been
conducted using other cholinergic system markers
such as metabolic enzymes. Choline acetyltransferase
(molecular weight approximately 65 kDa) was first
studied in the electric organ of the electric eel. It
catalyzes the final step in the synthesis of ACh, the
acetylation of choline with acetyl coenzyme A. The
degradative enzyme acetyl cholinesterase (AChE),
which has attracted much attention as a therapeutic
target, rapidly hydrolyzes ACh. Butyryl cholinester-
ase is another cholinesterase in the central nervous
system, but its role is unclear. A high-affinity uptake
site for choline is also used as a marker for the
presence of cholinergic neurons in the central
nervous system.
The anatomical distribution of ACh is complex, as
it is found throughout the nervous system. ACh is the
neurotransmitter at the neuromuscular junction.
Cholinergic neurons in the brainstem play important
roles in sleep and other basic physiological activities.
Cholinergic neurons in the basal forebrain play a role
in attention, and those in the basal ganglia have been
implicated in movement disorders, such as Parkin-
son’s disease and Huntington’s disease.
A variety of cholinergic neurotransmitter receptors
have been characterized, building on the original
observations of the selective effects of muscarine and
nicotine. Five muscarinic receptor subtypes (M1–M5)
have been defined by identifying their cloned DNAs,
14 ACOUSTIC NEUROMA
and these act through guanine nucleotide-binding
proteins (G proteins) and second messenger systems.
Nicotinic receptors are composed of a variety of
subunits, designated a, b, g, d, and e, that are
clustered in different ways and distributed differently
in the nervous system. For example, the subunit
composition of nicotinic ACh receptors of the adult
neuromuscular junction is a12b1ed, whereas recep-
tors with the subunit composition a3b4 or a3b4a5
are found in autonomic ganglia. Nicotinic receptors
are associated with ion channels that conduct Na þ
or Ca2 þ .
Studies in animals have shown that agents that
block both nicotinic and muscarinic cholinergic
transmission cause impairment in mentation, includ-
ing confusion, amnesia, and attention deficits. Build-
ing on these observations, the most notable success in
the use of cholinergic therapy has been the develop-
ment of AChE inhibitors to treat Alzheimer’s disease
and related dementias in which neuronal loss in the
cholinergic basal forebrain occurs. Currently, done-
pezil is the most widely used cholinesterase inhibitor,
but rivastigmine and galantamine offer therapeutic
options. Tacrine, the first drug approved for this
purpose, is no longer used because it causes gastro-
intestinal distress (nausea, cramps, and diarrhea) and
reversible liver toxicity. Of the other three, rivastig-
mine causes the most side effects. Galantamine, in
addition to being an AChE inhibitor, is an allosteric
nicotinic receptor modulator, although the clinical
advantage of this is unclear. Muscarinic receptor
antagonists are used clinically to treat Parkinson’s
disease and gastrointestinal or bladder disturbances.
CURRENT AND FUTURE ISSUES
Greater understanding of the molecular biology of
ACh receptors may lead to drugs that are more
effective than those currently available, with fewer
side effects. Drugs are being developed that act on
pre- and postsynaptic receptors selectively or that
modulate the receptor activity by an allosteric
mechanism. Understanding the interactions between
cholinergic systems and other neurotransmitter
systems, such as those that employ dopamine and
serotonin, will continue to contribute to our under-
standing of brain function and may lead to new
drugs for dementia, schizophrenia, and movement
disorders. Efforts to slow the death of cholinergic
nerve cells through, for example, studying the actions
of growth factors such as nerve growth factor will
continue. The current clinical benefits of these
cholinergic drugs in dementia are modest. Further
studies of their impact on quality of life and health
economics will also be important.
—Peter J. Whitehouse
See also–Dopamine; Lambert–Eaton Myasthenic
Syndrome; Muscle Contraction, Overview;
Myasthenia Gravis; Myasthenic Syndromes,
Congenital; Serotonin; Vagus Nerve (Cranial
Nerve X)
Further Reading
Eglen, R. M., Choppin, A., and Watson, N. (2001). Therapeutic
opportunities from muscarinic receptor research. Trends
Pharmacol. Sci. 22, 409–414.
Itier, V., and Bertrand, D. (2001). Neuronal nicotinic receptors:
From protein structure to function. FEBS Lett. 504, 118–125.
Kimura, F. (2000). Cholinergic modulation of cortical function: A
hypothetical role in shifting the dynamics in cortical network.
Neurosci. Res. 38, 19–26.
Loewi, O., and Dale, H. (1999). The discovery of neurotransmit-
ters. In Minds behind the Brain: A History of the Pioneers and
Their Discoveries, pp. 259–279. Oxford Univ. Press, New York.
Mayeux, R., and Sano, M. (1999). Treatment of Alzheimer’s
disease. N. Engl. J. Med. 341, 1670–1679.
Perry, E., Walker, M., and Perry, R. (1999). Reply: Consciousness
in mind: A correlate for ACh? Trends Neurosci. 22, 542–543.
Acid Maltase Deficiency
see Glycogen Storage Diseases
Acoustic Neuroma
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACOUSTIC NEUROMAS (ANs), correctly defined as
vestibular schwannomas, are benign tumors that
originate from the abnormal growth of Schwann
cells on the superior vestibular portion of the eighth
cranial nerve (Fig. 1). Typically, and if unchecked,
the tumors extend out of the internal auditory canal
to fill the cerebellopontine angle. The misnomer
‘‘acoustic neuroma’’ is well established in the medical
community and unlikely to change. Although the
radiographic appearance of ANs is distinct, the
differential diagnosis includes meningiomas, epider-
moid tumors, and other small lesions that can inhabit
the internal auditory canal.
14 ACOUSTIC NEUROMA
and these act through guanine nucleotide-binding
proteins (G proteins) and second messenger systems.
Nicotinic receptors are composed of a variety of
subunits, designated a, b, g, d, and e, that are
clustered in different ways and distributed differently
in the nervous system. For example, the subunit
composition of nicotinic ACh receptors of the adult
neuromuscular junction is a12b1ed, whereas recep-
tors with the subunit composition a3b4 or a3b4a5
are found in autonomic ganglia. Nicotinic receptors
are associated with ion channels that conduct Na þ
or Ca2 þ .
Studies in animals have shown that agents that
block both nicotinic and muscarinic cholinergic
transmission cause impairment in mentation, includ-
ing confusion, amnesia, and attention deficits. Build-
ing on these observations, the most notable success in
the use of cholinergic therapy has been the develop-
ment of AChE inhibitors to treat Alzheimer’s disease
and related dementias in which neuronal loss in the
cholinergic basal forebrain occurs. Currently, done-
pezil is the most widely used cholinesterase inhibitor,
but rivastigmine and galantamine offer therapeutic
options. Tacrine, the first drug approved for this
purpose, is no longer used because it causes gastro-
intestinal distress (nausea, cramps, and diarrhea) and
reversible liver toxicity. Of the other three, rivastig-
mine causes the most side effects. Galantamine, in
addition to being an AChE inhibitor, is an allosteric
nicotinic receptor modulator, although the clinical
advantage of this is unclear. Muscarinic receptor
antagonists are used clinically to treat Parkinson’s
disease and gastrointestinal or bladder disturbances.
CURRENT AND FUTURE ISSUES
Greater understanding of the molecular biology of
ACh receptors may lead to drugs that are more
effective than those currently available, with fewer
side effects. Drugs are being developed that act on
pre- and postsynaptic receptors selectively or that
modulate the receptor activity by an allosteric
mechanism. Understanding the interactions between
cholinergic systems and other neurotransmitter
systems, such as those that employ dopamine and
serotonin, will continue to contribute to our under-
standing of brain function and may lead to new
drugs for dementia, schizophrenia, and movement
disorders. Efforts to slow the death of cholinergic
nerve cells through, for example, studying the actions
of growth factors such as nerve growth factor will
continue. The current clinical benefits of these
cholinergic drugs in dementia are modest. Further
studies of their impact on quality of life and health
economics will also be important.
—Peter J. Whitehouse
See also–Dopamine; Lambert–Eaton Myasthenic
Syndrome; Muscle Contraction, Overview;
Myasthenia Gravis; Myasthenic Syndromes,
Congenital; Serotonin; Vagus Nerve (Cranial
Nerve X)
Further Reading
Eglen, R. M., Choppin, A., and Watson, N. (2001). Therapeutic
opportunities from muscarinic receptor research. Trends
Pharmacol. Sci. 22, 409–414.
Itier, V., and Bertrand, D. (2001). Neuronal nicotinic receptors:
From protein structure to function. FEBS Lett. 504, 118–125.
Kimura, F. (2000). Cholinergic modulation of cortical function: A
hypothetical role in shifting the dynamics in cortical network.
Neurosci. Res. 38, 19–26.
Loewi, O., and Dale, H. (1999). The discovery of neurotransmit-
ters. In Minds behind the Brain: A History of the Pioneers and
Their Discoveries, pp. 259–279. Oxford Univ. Press, New York.
Mayeux, R., and Sano, M. (1999). Treatment of Alzheimer’s
disease. N. Engl. J. Med. 341, 1670–1679.
Perry, E., Walker, M., and Perry, R. (1999). Reply: Consciousness
in mind: A correlate for ACh? Trends Neurosci. 22, 542–543.
Acid Maltase Deficiency
see Glycogen Storage Diseases
Acoustic Neuroma
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACOUSTIC NEUROMAS (ANs), correctly defined as
vestibular schwannomas, are benign tumors that
originate from the abnormal growth of Schwann
cells on the superior vestibular portion of the eighth
cranial nerve (Fig. 1). Typically, and if unchecked,
the tumors extend out of the internal auditory canal
to fill the cerebellopontine angle. The misnomer
‘‘acoustic neuroma’’ is well established in the medical
community and unlikely to change. Although the
radiographic appearance of ANs is distinct, the
differential diagnosis includes meningiomas, epider-
moid tumors, and other small lesions that can inhabit
the internal auditory canal.

Figure 1
Contrast enhanced magnetic resonance image of an acoustic
neuroma (large arrowhead). The tumor extends from the internal
auditory canal (small arrowhead).
INCIDENCE AND ETIOLOGY
An estimated 2200 ANs are diagnosed annually in
the United States, with an incidence of 0.78–1.15
cases/100,000. ANs are caused by a spontaneous or
inherited loss of a tumor supressor gene on chromo-
some 22. ANs are one of the hallmarks of the
inherited and spontaneous neurofibromatosis type II
syndrome.
SIGNS AND SYMPTOMS
ANs most often present with a loss of hearing on the
side of tumor growth, tinnitus (ringing in the ear), or
difficulty with balance. As the tumors grow within
the auditory canal, they compress the vestibular and
cochlear nerves, causing loss of hearing and balance.
As the tumors grow within the cerebellopontine
angle, the facial nerve is stretched over the superior,
anterior surface of the tumor capsule. Other initial
presentations include headaches, loss of sensation on
the same side of the face, facial weakness, double
vision, nausea, vomiting, difficulty swallowing, and
ACOUSTIC NEUROMA 15
loss of taste. As the tumor extends along the
brainstem, it can compress the trigeminal nerve
(TN) above or cranial nerves below. Interestingly,
facial sensation is often impaired before facial
weakness occurs, even though the nerve for facial
movement is displaced earlier and more extensively
by the tumor. As tumors grow, they can compress the
brainstem, causing progressive weakness, difficulty
with balance and coordination, hyperactive reflexes,
and hydrocephalus. Occasionally, smaller ANs can
cause hydrocephalus by secreting proteins that
obstruct the absorption of cerebrospinal fluid.
NATURAL HISTORY
The growth of ANs may be quite variable. Tumors
may grow at a consistent rate, or they may have
periods of rapid growth alternating with periods of
minimal growth. Overall, the growth rate of ANs is
estimated to be 2 mm annually. Unfortunately, the
growth rate of any one tumor cannot be predicted
with any certainty.
TREATMENT OPTIONS AND RESULTS
The current treatment options for ANs include
observation, a variety of microsurgical excision
techniques, or stereotactic radiosurgery. With the
new diagnosis of a small or asymptomatic AN, many
clinicians used to recommend observation with serial
imaging studies. Surgery was only recommended
when growth was documented or symptoms devel-
oped. With the advent of stereotactic radiosurgery,
this may no longer be the best option. Radiosurgery
techniques allow minimally invasive treatment of
tumors, providing a better than 97% chance of
tumor control, with few risks. Stereotactic radio-
surgery focuses many small beams of radiation on
the tumor to arrest tumor growth while exposing the
surrounding brainstem and cranial nerves to a very
small dose of radiation. Observation may still be a
reasonable option for older patients with tumors
causing no or few symptoms.
When an AN is diagnosed, the approach is often
chosen according to the tumor size, the status of
hearing, the patient’s related signs and symptoms,
and the surgeon’s experience. Among the microsur-
gical options, the translabyrinthine approach was
designed to allow the removal of small or large
tumors within the auditory canal and early identifi-
cation and preservation of the facial nerve. This
approach unfortunately sacrifices any functional
16 ACOUSTIC NEUROMA, TREATMENT
hearing. Selected small tumors, particularly when
hearing preservation is the goal, can be approached
via a middle fossa approach. Larger tumors tend to
be removed through the posterior fossa (behind the
ear) approach. The greatest risk of surgical resection
is facial weakness or paralysis. Other risks of
microsurgery include deafness, dysequilibrium, dou-
ble vision, cerebrospinal fluid fistulas, and infection.
In choosing the best therapy, patients and their
physicians must consider the age and health of the
patient, the size of the tumor, the symptoms, the risks
of each procedure, and the treatment goals.
—Todd P. Thompson and Douglas Kondziolka
See also–Nerve Sheath Tumors; Tinnitus;
Vestibulocochlear Nerve (Cranial Nerve VIII)
Further Reading
Flickinger, J. C., Lunsford, L. D., Coffey, R. J., et al. (1991).
Radiosurgery of acoustic neurinomas. Cancer 67, 345–353.
Kondziolka, D., Lunsford, L. D., McLaughlin, M. R., et al. (1998).
Long-term outcomes after radiosurgery for acoustic neuromas.
N. Engl. J. Med. 339, 1426–1433.
Samii, M., and Matthies, C. (1997). Management of 1000
vestibular schwannomas (acoustic neuromas): Surgical manage-
ment and results with an emphasis on complications and how to
avoid them. Neurosurgery 40, 11–21.
Acoustic Neuroma, Treatment
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SCHWANNOMAS are benign neoplasms that comprise
5–8% of intracranial tumors. They predominantly
involve the vestibular part of the eighth cranial nerve
and occur 1.25 to 2 times as often in women as in
men. Neurofibromatosis type 2 (NF-2) generally
causes bilateral acoustic tumors, representing less
than 1% of intracranial tumors. These tumors occur
throughout life, with a peak incidence between 50
and 70 years; they are uncommon in children.
TUMOR GENETICS
Mutations in the NF-2 gene on chromosome
22.q12.2 have been reported in approximately 25–
50% of sporadic unilateral vestibular schwannomas
(VS) and are much more common in VS in patients
with NF-2. The NF-2 gene product is a structured
protein called merlin or schwannomin. Its mechan-
ism of action is not entirely clear, but related proteins
modulate cellular remodeling, cell apoptosis, and
cell–cell signaling that may be involved in cell
adhesion, motility, and metastasis.
CLINICAL PRESENTATION
Patients with VS present most commonly with
unilateral hearing reduction or loss, between 77 and
95% depending on tumor size. Hearing loss is often
present 5 years or longer before a tumor is diagnosed,
although with the availability of magnetic resonance
imaging (MRI), smaller tumors are now being found
sooner after the onset of hearing changes than in
decades past. Approximately 50% of patients have
tinnitus at the time of tumor discovery. Other
symptoms may include gait disturbance or imbalance
(37–71% depending on tumor size) and occasionally
vertigo (10–27%). When large tumors are identified,
trigeminal dysfunction (numbness or pain) or facial
numbness [48% with tumors larger than 30 mm in the
cerebellopontine angle (CPA)]. With extremely large
tumors, facial weakness or hemifacial spasm may be
present at the time of tumor diagnosis. However, this
symptom is uncommon, being present in only 10% of
patients with tumors larger than 30 mm.
Audiometry in the setting of unilateral hearing loss
from VS usually shows a worsening of the speech
reception threshold (SRT; the average of the pure
tone reception thresholds for 250, 500, 1000, and
2000 Hz) and word recognition score (WRS; the
percentage of correct answers while trying to repeat a
list of 25 short words). If hearing is asymmetric as
measured by SRT and WRS, MRI with gadolinium,
the most accurate diagnostic test for VS, is indicated.
Scans can demonstrate with extraordinary sensitivity
the presence of very small tumors. MRI is also an
excellent screening tool for other tumors, such as
bilateral VS or meningiomas or epidermoid tumors
at or within the internal auditory canal that can
affect hearing or balance. Screening for VS with
noncontrast, fast spin echo, T2-weighted images has
been advocated by some, but this modality is
relatively insensitive for small tumors and other
causes of asymmetrical hearing loss.
TREATMENT
VS may be treated in several ways based on a number
of factors, such as tumor size, quality of hearing, the
patient’s age, and the patient’s preference of treat-
ment modalities. If a patient’s life expectancy is less
16 ACOUSTIC NEUROMA, TREATMENT
hearing. Selected small tumors, particularly when
hearing preservation is the goal, can be approached
via a middle fossa approach. Larger tumors tend to
be removed through the posterior fossa (behind the
ear) approach. The greatest risk of surgical resection
is facial weakness or paralysis. Other risks of
microsurgery include deafness, dysequilibrium, dou-
ble vision, cerebrospinal fluid fistulas, and infection.
In choosing the best therapy, patients and their
physicians must consider the age and health of the
patient, the size of the tumor, the symptoms, the risks
of each procedure, and the treatment goals.
—Todd P. Thompson and Douglas Kondziolka
See also–Nerve Sheath Tumors; Tinnitus;
Vestibulocochlear Nerve (Cranial Nerve VIII)
Further Reading
Flickinger, J. C., Lunsford, L. D., Coffey, R. J., et al. (1991).
Radiosurgery of acoustic neurinomas. Cancer 67, 345–353.
Kondziolka, D., Lunsford, L. D., McLaughlin, M. R., et al. (1998).
Long-term outcomes after radiosurgery for acoustic neuromas.
N. Engl. J. Med. 339, 1426–1433.
Samii, M., and Matthies, C. (1997). Management of 1000
vestibular schwannomas (acoustic neuromas): Surgical manage-
ment and results with an emphasis on complications and how to
avoid them. Neurosurgery 40, 11–21.
Acoustic Neuroma, Treatment
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SCHWANNOMAS are benign neoplasms that comprise
5–8% of intracranial tumors. They predominantly
involve the vestibular part of the eighth cranial nerve
and occur 1.25 to 2 times as often in women as in
men. Neurofibromatosis type 2 (NF-2) generally
causes bilateral acoustic tumors, representing less
than 1% of intracranial tumors. These tumors occur
throughout life, with a peak incidence between 50
and 70 years; they are uncommon in children.
TUMOR GENETICS
Mutations in the NF-2 gene on chromosome
22.q12.2 have been reported in approximately 25–
50% of sporadic unilateral vestibular schwannomas
(VS) and are much more common in VS in patients
with NF-2. The NF-2 gene product is a structured
protein called merlin or schwannomin. Its mechan-
ism of action is not entirely clear, but related proteins
modulate cellular remodeling, cell apoptosis, and
cell–cell signaling that may be involved in cell
adhesion, motility, and metastasis.
CLINICAL PRESENTATION
Patients with VS present most commonly with
unilateral hearing reduction or loss, between 77 and
95% depending on tumor size. Hearing loss is often
present 5 years or longer before a tumor is diagnosed,
although with the availability of magnetic resonance
imaging (MRI), smaller tumors are now being found
sooner after the onset of hearing changes than in
decades past. Approximately 50% of patients have
tinnitus at the time of tumor discovery. Other
symptoms may include gait disturbance or imbalance
(37–71% depending on tumor size) and occasionally
vertigo (10–27%). When large tumors are identified,
trigeminal dysfunction (numbness or pain) or facial
numbness [48% with tumors larger than 30 mm in the
cerebellopontine angle (CPA)]. With extremely large
tumors, facial weakness or hemifacial spasm may be
present at the time of tumor diagnosis. However, this
symptom is uncommon, being present in only 10% of
patients with tumors larger than 30 mm.
Audiometry in the setting of unilateral hearing loss
from VS usually shows a worsening of the speech
reception threshold (SRT; the average of the pure
tone reception thresholds for 250, 500, 1000, and
2000 Hz) and word recognition score (WRS; the
percentage of correct answers while trying to repeat a
list of 25 short words). If hearing is asymmetric as
measured by SRT and WRS, MRI with gadolinium,
the most accurate diagnostic test for VS, is indicated.
Scans can demonstrate with extraordinary sensitivity
the presence of very small tumors. MRI is also an
excellent screening tool for other tumors, such as
bilateral VS or meningiomas or epidermoid tumors
at or within the internal auditory canal that can
affect hearing or balance. Screening for VS with
noncontrast, fast spin echo, T2-weighted images has
been advocated by some, but this modality is
relatively insensitive for small tumors and other
causes of asymmetrical hearing loss.
TREATMENT
VS may be treated in several ways based on a number
of factors, such as tumor size, quality of hearing, the
patient’s age, and the patient’s preference of treat-
ment modalities. If a patient’s life expectancy is less
 ACOUSTIC NEUROMA, TREATMENT 17

than 10 years due to health or estimated longevity

due to age at the time of tumor diagnosis, it may be
appropriate to follow the patient with serial MRI.
Tumors show little growth in 50–75% of older
patients within 6–36 months of follow-up. In other
patients, the tumor usually grows more than 2 mm
per year. If the tumor seems likely to impair brain
function within the lifetime of the patient, then
intervention is appropriate.
In the past decade, stereotactic radiation has been
used to treat increasing numbers of patients. Stereo-
tactic irradiation is associated with fewer immediate
complications compared to surgical intervention.
Patients can undergo treatment in a single day with
little ill effect. They return to their usual life and work
within a few days. The early results have been well
documented and indicate excellent growth control in
the early years. Tumor growth has occurred in 4–9%
of patients with a 30-month median follow-up. Only
2 or 3% of patients have required surgery after
irradiation. Facial nerve weakness has occurred in 4–
20% of patients, and often resolves. Preoperative
hearing has worsened in 13–51% of patients. Because
radiosurgery does not eliminate the tumor, patients
must be followed with MRI for many years to
evaluate tumor growth. Available follow-up is still Figure 1
too short to ensure the long-range efficacy of Axial schematic illustration of transtemporal approaches to the
posterior fossa. The retrosigmoid approach requires more
stereotactic radiation. As longer follow-up becomes cerebellar retraction than the translabyrinthine approach, but
available, this treatment may or may not become provides a better view of the petrous bone medial to the internal
more useful as a definitive treatment of VS. auditory canal and better visualization of the jugular foramen.
Surgical therapy hinges substantially on the spe-
cifics of tumor size and location and on the status of
the patient’s hearing preoperatively. Surgical treat- The MFA is used for tumors smaller than
ment options include a translabyrinthine approach approximately 15 mm within the cerebellopontine
(TLA), retrosigmoid–posterior fossa approach (RSA), angle in patients with good or serviceable hearing,
and middle fossa approach (MFA) (Figs. 1 and 2). defined as o50 dB SRT and Z50% speech discrimi-
Hearing is rarely preserved with removal of tumors nation score (AAO-HNS class A and B). The MFA is
larger than 25 mm in the cerebellopontine angle. associated with the highest rate of hearing preserva-
Improved hearing is also rare after tumor treatment. tion and is being adopted more widely by centers that
Therefore, if a patient has poor hearing before specialize in surgical removal of VS. The disadvantage
surgery [American Academy of Otolaryngology-Head of the MFA is that the seventh cranial nerve appears
and Neck Surgery (AAO-HNS) class C or D or SRT superiorly in the internal auditory canal above the
450 dB and WRS o50%) or a tumor 25 mm or tumor. Thus, after removing the roof of the internal
larger in the cerebellopontine angle, a TLA is chosen. auditory canal and viewing the internal auditory
This procedure offers excellent views of both the canal contents from above, the surgeon often finds
internal auditory canal and the cerebellopontine that the seventh cranial nerve lies directly in the way
angle. However, it destroys hearing on the operated of tumor removal. In addition, the angle of approach
side because the vestibular apparatus is removed from the temporal region provides limited visualiza-
during tumor exposure. Therefore, it is reserved for tion of the lateral end of the internal auditory canal
patients without serviceable hearing in the affected (Fig. 2). However, the MFA seems to allow the best
ear or large tumors for which hearing conservation is identification of arachnoid planes between the co-
not feasible. chlear portion of the eighth cranial nerve and the
18 ACOUSTIC NEUROMA, TREATMENT
Figure 2
The MFA offers a view of the internal auditory canal from above.
The exposure of the posterior fossa is limited by temporal lobe
retraction superiorly, by the superior semicircular canal below, and
by the cochlea and vestibule of the semicircular canals laterally.
The illustration depicts a small intracanalicular inferior vestibular
nerve tumor with the seventh cranial nerve and superior vestibular
nerves located on top of the tumor.
tumor. Thus, the tumor can be removed, while the
cochlear portion of the nerve is spared. The use of an
angled endoscope or small mirror may allow the
surgeon to visualize possible unresected tumor in the
lateral internal auditory canal.
For 15- to 25-mm tumors in the cerebellopontine
angle associated with functional hearing (class A and
B), we recommend the RSA. Other surgical teams
with extensive experience with this procedure prefer
to use it for all patients with vestibular schwannomas
and serviceable hearing. It is an excellent procedure
for exposing the posterior fossa component of the
tumor. The medial end of the internal auditory canal
must be drilled away to expose tumors within the
internal auditory canal, and tumors lying in the far
lateral extent of the internal auditory canal are
sometimes difficult to remove under direct visualiza-
tion. Because of the position of the posterior
semicircular canal, it is sometimes impossible to drill
sufficient bone from the posterior lip of the internal
auditory canal to fully expose tumors at the lateral-
most portion of the internal auditory canal at the
vestibule without injuring the inner ear. Again, as
with the MFA, the use of a small mirror or an
endoscope may help visualize the lateral end of the
internal auditory canal with the RSA. We believe that
the most likely source of tumor recurrences is
residual tumor left at the lateral most end of the
internal auditory canal when either the RSA or MFA
are used.
We strongly recommend intraoperative monitoring
of facial nerve electromyograms (EMGs). Stimulat-
ing the seventh cranial nerve during the procedure
and recording facial EMGs can help to identify the
seventh cranial nerve during surgery. This technique
both improves the ability to spare the seventh cranial
nerve and shortens surgery time by allowing more
rapid resection of tumor and capsule in regions in
which the seventh cranial nerve is not present. When
attempting to preserve hearing by using the MFA or
RSA, we also monitor auditory brainstem responses
(ABRs). When ABRs deteriorate during tumor
removal, we try to modify the dissection along the
cochlear portion of the eighth cranial nerve to
improve the ABR.
Postoperative complications are remarkably simi-
lar for the three approaches. The frequency of
cerebrospinal fluid leaks is approximately 10%:
Only approximately one in five cases return to the
operating room for definitive cerebrospinal fluid
closure. Often, cerebrospinal fluid leaks can be
treated using lumbar subarachnoid cerebrospinal
fluid drainage for 3–5 days after surgery. Sometimes
we recommend acetalzolamide (250 mg four times
per day for 10–14 days) as an additional conservative
approach. Headaches are common soon after sur-
gery, occurring in 27–54% of patients. The majority
resolve within 3–6 months of the operation.
Approximately 10% persist longer than 1 year.
These long-term headaches are slightly more com-
mon after a retrosigmoid surgery than after either of
the other two approaches. They may be associated
with large craniotomies and intracranial drilling.
Facial palsies are somewhat less common after RSA
or TLA (approximately 80% of patients have normal
or almost normal facial movement 1 year after
surgery) for tumors 10–15 mm in the CPA than after
MFA (approximately 80% normal or almost normal
facial movement). Tumor removal can improve
imbalance or gait disturbances, although balance
does not always improve after surgery. Almost all
patients have at least a slight imbalance associated
with rapid head movement after tumor removal. In a
small number of patients, vascular injury to small
penetrating arteries of the middle and superior
cerebellar peduncles yields a long-term unilateral
dysmetria. It often improves with time but seldom
entirely. Wound infections and meningitis are un-
common, both with a frequency of o1%.

When useful hearing is present before surgery, it
frequently can be maintained (in 27–68% of cases).
If hearing is preserved with operative removal of the
tumor, it tends to be maintained over time. The risk
of tumor recurrence after apparent total resection is
very low.
Hospitalization is usually 3–5 days. Generally,
only elderly patients and those with tumors larger
than 25 mm in the cerebellopontine angle are placed
in the intensive care unit after surgery. Although
patients feel quite ill 1 or 2 days after surgery and
often feel somewhat lethargic 4–8 weeks after
surgery, most patients recover almost completely
from the operation and return to their usual
occupations. Only 2% have become unemployed
after surgery, although 12%, many of whom were
near retirement age, retired in part because of their
surgery. Surgical morbidity 1 or 2 months after the
operation is significantly worse than with stereotactic
irradiation.
When we believe that we have completely removed
the tumor, we recommend follow-up MRI 3 years
after surgery. After patients undergo stereotactic
radiation, MRIs are obtained annually for 5 years
and every 2 or 3 years for 10 more years. If resection
is subtotal or near total (a tiny fragment of tumor left
on the seventh cranial nerve), we obtain an MRI 1
year after surgery and then periodically thereafter,
depending on whether the residual tumor can be seen.
Treatment of VS has evolved greatly during the
past 30 years. Surgical management has advanced
from primarily removing a life-threatening tumor to
contemporary therapy that strives to remove the
tumor or to eliminate the threat of growth while
sparing all neurological function present at the time
of tumor discovery. The literature indicates that
substantial progress has been made toward achieving
these goals.
—Lawrence H. Pitts, Philip Theodosopoulos, and
Robert K. Jackler
See also–Facial Nerve (Cranial Nerve VII);
Hearing Loss
Further Reading
Deen, H. G., Ebersold, M. J., Harner, S. G., et al. (1996).
Conservative management of acoustic neuroma: An outcome
study. Neurosurgery 39, 260–264.
Driscoll, C. L. (2000). Vestibular schwannoma (acoustic neuro-
ma). In Tumors of the Ear and Temporal Bone (R. K. Jackler
and C. L. Driscoll, Eds.). Lippincott Williams & Wilkins,
Philadelphia.
ACTIGRAPHY 19
Flickinger, J. C., Kondziolka, D., Niranjan, A., et al. (2001).
Results of acoustic neuroma radiosurgery: An analysis of 5
years’ experience using current methods. J. Neurosurg. 94, 1–6.
Gormley, W. B., Sekhar, L. N., Wright, D. C., et al. (1997).
Acoustic neuromas: Results of current surgical management.
Neurosurgery 41, 50–58.
Guerin, C., Sampath, P., and Long, D. M. (1999). Acoustic
neuroma: Outcome of surgical resection and study on the
anatomy of facial and cochlear nerves. Ann. Acad. Med.
Singapore 28, 402–408.
Gutmann, D. H. (2001). The neurofibromatoses: When less is
more. Hum. Mol. Genet. 10, 747–755.
Irving, R. M., Harada, T., Moffat, D. A., et al. (1997). Somatic
neurofibromatosis type 2 gene mutations and growth character-
istics in vestibular schwannoma. Am. J. Otol. 18, 754–760.
Irving, R. M., Jackler, R. K., and Pitts, L. H. (1998). Hearing
preservation in patients undergoing vestibular schwannoma
surgery: Comparison of middle fossa and retrosigmoid
approaches. J. Neurosurg. 88, 840–845.
Kondziolka, D., Lunsford, L. D., McLaughlin, M. R., et al. (1998).
Long-term outcomes after radiosurgery for acoustic neuromas.
N. Engl. J. Med. 339, 1426–1433.
Pitts, L. H., and Jackler, R. K. (1998). Treatment of acoustic
neuromas. N. Engl. J. Med. 339, 1471–1473.
Samii, M., and Matthies, C. (1997). Management of 1000
vestibular schwannomas (acoustic neuromas): Hearing function
in 1000 tumor resections. Neurosurgery 40, 248–260.
Acquired Immunodeficiency
Syndrome
see AIDS/HIV; HIV Infection
Actigraphy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SMITH AND COLBURN first discovered that piezo-
electric sensors permit easy, continuous recording of
physical activity over several days by mounting them
in a device the size of a wristwatch easily worn on the
wrist or waist of a subject. Their device contained a
battery, a small amount of solid-state memory, and
electronics for detecting and recording when the
electricity generated by moving the sensors exceeded
a threshold indicating a significant body movement.
The seductive simplicity and data richness of this
approach led to many studies, particularly in rela-
tion to sleep medicine. Unfortunately, technical
development overshadowed somewhat critical

When useful hearing is present before surgery, it
frequently can be maintained (in 27–68% of cases).
If hearing is preserved with operative removal of the
tumor, it tends to be maintained over time. The risk
of tumor recurrence after apparent total resection is
very low.
Hospitalization is usually 3–5 days. Generally,
only elderly patients and those with tumors larger
than 25 mm in the cerebellopontine angle are placed
in the intensive care unit after surgery. Although
patients feel quite ill 1 or 2 days after surgery and
often feel somewhat lethargic 4–8 weeks after
surgery, most patients recover almost completely
from the operation and return to their usual
occupations. Only 2% have become unemployed
after surgery, although 12%, many of whom were
near retirement age, retired in part because of their
surgery. Surgical morbidity 1 or 2 months after the
operation is significantly worse than with stereotactic
irradiation.
When we believe that we have completely removed
the tumor, we recommend follow-up MRI 3 years
after surgery. After patients undergo stereotactic
radiation, MRIs are obtained annually for 5 years
and every 2 or 3 years for 10 more years. If resection
is subtotal or near total (a tiny fragment of tumor left
on the seventh cranial nerve), we obtain an MRI 1
year after surgery and then periodically thereafter,
depending on whether the residual tumor can be seen.
Treatment of VS has evolved greatly during the
past 30 years. Surgical management has advanced
from primarily removing a life-threatening tumor to
contemporary therapy that strives to remove the
tumor or to eliminate the threat of growth while
sparing all neurological function present at the time
of tumor discovery. The literature indicates that
substantial progress has been made toward achieving
these goals.
—Lawrence H. Pitts, Philip Theodosopoulos, and
Robert K. Jackler
See also–Facial Nerve (Cranial Nerve VII);
Hearing Loss
Further Reading
Deen, H. G., Ebersold, M. J., Harner, S. G., et al. (1996).
Conservative management of acoustic neuroma: An outcome
study. Neurosurgery 39, 260–264.
Driscoll, C. L. (2000). Vestibular schwannoma (acoustic neuro-
ma). In Tumors of the Ear and Temporal Bone (R. K. Jackler
and C. L. Driscoll, Eds.). Lippincott Williams & Wilkins,
Philadelphia.
ACTIGRAPHY 19
Flickinger, J. C., Kondziolka, D., Niranjan, A., et al. (2001).
Results of acoustic neuroma radiosurgery: An analysis of 5
years’ experience using current methods. J. Neurosurg. 94, 1–6.
Gormley, W. B., Sekhar, L. N., Wright, D. C., et al. (1997).
Acoustic neuromas: Results of current surgical management.
Neurosurgery 41, 50–58.
Guerin, C., Sampath, P., and Long, D. M. (1999). Acoustic
neuroma: Outcome of surgical resection and study on the
anatomy of facial and cochlear nerves. Ann. Acad. Med.
Singapore 28, 402–408.
Gutmann, D. H. (2001). The neurofibromatoses: When less is
more. Hum. Mol. Genet. 10, 747–755.
Irving, R. M., Harada, T., Moffat, D. A., et al. (1997). Somatic
neurofibromatosis type 2 gene mutations and growth character-
istics in vestibular schwannoma. Am. J. Otol. 18, 754–760.
Irving, R. M., Jackler, R. K., and Pitts, L. H. (1998). Hearing
preservation in patients undergoing vestibular schwannoma
surgery: Comparison of middle fossa and retrosigmoid
approaches. J. Neurosurg. 88, 840–845.
Kondziolka, D., Lunsford, L. D., McLaughlin, M. R., et al. (1998).
Long-term outcomes after radiosurgery for acoustic neuromas.
N. Engl. J. Med. 339, 1426–1433.
Pitts, L. H., and Jackler, R. K. (1998). Treatment of acoustic
neuromas. N. Engl. J. Med. 339, 1471–1473.
Samii, M., and Matthies, C. (1997). Management of 1000
vestibular schwannomas (acoustic neuromas): Hearing function
in 1000 tumor resections. Neurosurgery 40, 248–260.
Acquired Immunodeficiency
Syndrome
see AIDS/HIV; HIV Infection
Actigraphy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SMITH AND COLBURN first discovered that piezo-
electric sensors permit easy, continuous recording of
physical activity over several days by mounting them
in a device the size of a wristwatch easily worn on the
wrist or waist of a subject. Their device contained a
battery, a small amount of solid-state memory, and
electronics for detecting and recording when the
electricity generated by moving the sensors exceeded
a threshold indicating a significant body movement.
The seductive simplicity and data richness of this
approach led to many studies, particularly in rela-
tion to sleep medicine. Unfortunately, technical
development overshadowed somewhat critical
20 ACTIGRAPHY
thought about the basic measurement and its relation
to sleep medicine. The following section on technical
developments serves to explain the subsequent dis-
cussion of the potential utility of activity monitoring
technology. The common measurements of activity
meters are classified as surrogate and direct.
TECHNICAL CONSIDERATIONS
Almost all activity monitors use piezoelectric
sensors to measure activity levels. Altering the shape
of these sensors, such as when bending them,
produces an electric current proportional, within a
limited range, to the distortion of the sensor. When
suitably placed with part of the sensor anchored,
movements of the sensor produce the bending or
other distortion resulting in an electric current that
can then be amplified and appropriately modified to
reflect the degree of movement. Acceleration from
movement distorts the units but not the velocity of
the movement. Given the limitations of the mea-
surement accuracy from the piezoelectric sensors,
the initial activity monitors set a detection threshold
for the acceleration indicating that a physiologically
significant movement occurred. Since the accelera-
tion could be either negative or positive, the signal
was generally rectified to remove information about
direction. The number of detected movement events,
defined by the number of times the piezoelectric
sensor output exceeded the acceleration threshold,
generally defines the basic measurement unit.
Although these units were then defined as a count
of movement events, they actually relate to a count
of changes in movement acceleration that may occur
many times in one physiological movement. Thus,
this count represents a somewhat abstract concept
roughly proportional to the amount of activity, but
it fails to provide a measurement of activity in any
of the usual physical units related to force or
acceleration of the body motion. Further refine-
ments of the techniques and sensors led to improve-
ments in accuracy of measurements, facilitating
development of two alternate methods for measur-
ing the activity: time over movement threshold and
digital averaging of acceleration. Both of these
produce physical units, one of time and the other
of average force (measured in acceleration units
such as g units). The latter method provides the
measure most closely related to a physical measure-
ment of body movements.
The sampling time for currently available activity
monitors varies considerably. The frequency of
movements to be detected is judged to be at
most 10 Hz. The sampling for detection of 10-Hz
frequency should ideally exceed 20 Hz, but for
averaging of the force in a 10-Hz event the samp-
ling should probably be at least 40 Hz, using
four samples taken during the event, with two
likely occurring in each phase. Since most body
movements actually occur with a much lower
frequency, these are conservative sampling require-
ments and somewhat lower sampling rates probably
suffice. Data storage clearly does not need to be
at the same density as the acceleration sampling
rate, depending on the intended use of the data.
For full representation of the body acceleration
provided by the averaging of the acceleration
units, storage should be at least at 10 Hz, but for
most measurements concerning the cumulative
amount of movement over a period of time the
information can be averaged over much longer
periods of seconds or even minutes, thus reducing
storage demands.
A final technical consideration often ignored in
reviews of accelerometers is the dynamic range of
acceleration detection. This range is limited by the
storage unit used, with 8-bit words providing a
maximum of 255 units and 12-bit words providing
4096 units. Some activity meters that use the 8-bit
word for storage provide alternate sensitivity adjust-
ments or log transforms of the data to increase the
dynamic range. These are not necessary for units that
use 12-bit words for data storage. Limitation occurs
more from the data storage methods than from the
measurement system.
In evaluating any activity meter, the following
technical considerations should be considered: cali-
bration of the sensor, methods of movement mea-
surement, sampling rate, storage rate, amount of
memory, duration of battery power, and dynamic
range.
SURROGATE MEASURE OF SLEEP–WAKE
Activity has an intuitive appeal as a possible
surrogate measure for the sleep–wake state. Clearly,
activity is alerting, and to some extent lack of activity
or rest is required for sleep. Unfortunately, the
reverse is not true: Rest is not incompatible with
waking, and lack of rest is not required for waking.
Therefore, inactivity as a surrogate measure of sleep,
no matter how it is recorded, has obvious limitations.
Moreover, these limitations increase for conditions of

long periods of rest without sleep. Thus, the measure
becomes increasingly less accurate in proportion to
the degree of any sleep disorder in which sleep does
not occur even though the patient is resting and
inactive in bed. The measure is also likely to be
disturbed by any abnormal condition in which the
patient develops movements during sleep, such as
occurs with parasomnias, movement disorders in
sleep, and sleep-related epilepsy.
The data largely confirm the limited accuracy of
this surrogate measure of sleep–wake state. For
example, in 2001 Pollack and colleagues carefully
examined the issue and also evaluated older as well
as younger healthy sleepers. They compared the
predictive power of activity meters to detect sleep
with the use of only bedtimes to predict sleep. They
used several different measurement methods in an
attempt to maximize predictive accuracy for the
activity meters, and their best result was 82%
compared to 78% predictive accuracy using only
bedtime estimates. This small gain was statisti-
cally significant if the authors ignored the need
to correct for choosing the best of several measures.
The small gain in predictive value, even if statisti-
cally significant, seems unlikely to be clinically
significant. Moreover, these measurements were
taken from only the nocturnal recordings; when an
attempt was made to predict sleep times from the
recordings during the full 24-hr day, the accuracy
decreased to approximately 77%, less than that of
the bedtime estimates. The authors attempted several
algorithms to detect sleep events during the usual
wake or ‘‘out-of-bed’’ times, but all predictions failed
(none exceeded 0%). In general, activity meters have
not been found to accurately predict sleep time
during the usual waking period. Conversely, they
also poorly detect wake time during the usual sleep
period.
Failure to detect wake times during the sleep
period severely limits the utility of the activity meter
for conditions involving poor sleep. Data from
validation studies of insomnia patients indicate that
nocturnal-only activity measures generally overesti-
mate sleep times by 20–40 min, with low correlations
(e.g., r ¼ 0.40) to total sleep times. The error is the
same order of magnitude as the expected improve-
ment with treatment.
Sleep logs and records of bedtimes appear to be as
good as or even better than activity measures as a
surrogate measure of wake during sleep or sleep
during the daytime. Inactive alert and relaxed
awake states have been described for many species,
ACTIGRAPHY 21
including some birds and the large cats as well as
humans. For these species, activity probably fails to
provide a good surrogate measure of sleep–wake in
proportion to the amount of other inactive wake
states.
DIRECT MEASURE OF REST–ACTIVITY
PATTERNS
It is likely that humans and other animals regulate
activity in relation to such things as body position
and time of day. Disruption or abnormal patterns of
this regulation could inform about disease, particu-
larly for sleep disorders. Verbeek and colleagues
noted that although activity measures were essen-
tially useless as a surrogate measure of sleep for
insomnia patients, they provided a potentially
important measure of disrupted regulation of activity
for some insomnia patients.
SURROGATE MEASURE FOR
CIRCADIAN PHASE
No direct measure exists for the circadian cycles
regulated by the suprachiasmatic nuclei. The rest–
activity cycle provides a noninvasive and continuous
surrogate measure for the circadian phase that
Lockley and colleagues found to match well the
phase estimates from dim-light melatonin onset for
30 entrained and 4 free-running subjects.
However, three major problems limit the use of
activity recording for determining circadian phase.
First, during the sleep period, most activity meters
record a large number of zeros. This low-end
truncation of the values complicates the usual
mathematical models for measuring circadian phase.
Improved sensitivity of the activity monitors and
increased dynamic range may minimize this problem.
A second problem involves the weekly or shift-work
modulation of the rest–activity cycle. Humans are
the only animals with weekends. The relation of the
activity cycle to the circadian phase undoubtedly
changes from weekdays to weekends and with shift-
work demands. The third problem involves the
probable alteration of the relation between activity
levels and circadian phase with disorders related to
sleep and waking. Thus, for any sleep disorder the
rest–activity cycle should be analyzed in relation to
the phase determined by dim-light melatonin onset
prior to using the measure to assess the circadian
phase for patients with the disorder.
22 ACTIGRAPHY
DIRECT MEASURE FOR PERIODIC
LIMB MOVEMENTS
Leg movements are particularly significant with
regard to sleep medicine. When they are periodic,
they provide a defining characteristic of the periodic
limb movement (PLM) disorder of sleep and also
provide support for the diagnosis of the restless legs
syndrome. The characteristics defining PLMs when
they occur in sleep (PLMS) and when they occur
during wakefulness (PLMW) have been well de-
scribed (Fig. 1). Each leg movement for PLMS must
last for 0.5–5.0 sec, and at least four such leg
movements must occur in a series, with each
successive movement onset separated by 5–90 sec.
Also, they must all occur during sleep. PLMWs have
the same characteristics, except the duration may be
longer (0.5–10 sec) and they must all occur during
the awake period. PLMWs have been used to support
the diagnosis of restless legs syndrome when they
occur either during wake times in the sleep period or
during an immobilization test, in which the subject is
asked to sit up in bed with legs stretched out while
remaining awake and inactive without cognitive
stimulation for 30–60 min.
A suitably sensitive activity meter with an adequate
dynamic range and frequent sampling could be used
Figure 1
Activity meter showing periodic leg movements and leg position for 30 min beginning when the patient puts his feet up to start the sleep
period. Note the development of the periodic leg movements (PLMs) after the legs are in the lying ‘‘down’’ position. The frequency and
intensity of the PLMs increase with the duration of rest time.
to measure these movements and to determine which
meet the criteria of PLMs. The basic sample duration
needs to be a minimum of 0.1 sec to measure with
reasonable accuracy the minimum duration of move-
ment of 0.5 sec. The 0.1-sec sample duration gives a
marginally acceptable error rate of 20% for the
shortest duration of movement. A faster sampling
rate reduces the error rate, whereas slower sampling
rates are unlikely to suffice for accurate measurement
of these events over the full range of PLMs observed.
Activity measures have obvious advantages com-
pared to physiological recordings of PLMs; namely
better access, reduced cost, and multiple night
recordings. The latter is particularly noteworthy
given the marked night-to-night variation in PLMs.
The leg activity meter should therefore have a good
dynamic range, the samples should be recorded at
0.1 Hz or faster, and recording should occur for at
least three consecutive nights.
The activity meter cannot detect sleep or waking
states, but a recently developed meter distinguishes
leg movements by leg position, either horizontal or
vertical. This distinguishes the movements during
sitting and standing/walking from those during lying.
Such a distinction may be particularly useful for
restless leg syndrome, in which the patient may get
up and walk a fair amount during the night.

DIRECT MEASURE FOR BODY MOVEMENTS
DURING SLEEP
Assessing body movements during sleep may help
with the diagnoses of several sleep disorders, includ-
ing the major parasomnias of sleep walking/night
terrors and rapid eye movement behavior disorder.
An appropriate form of evaluation might be devel-
oped to help detect sleep-related seizures, particu-
larly those associated with frontal lobe or
supplemental motor area seizures. These conditions
involve abnormal body movements during sleep,
although it is unclear if the amount and timing of
activity suffice for either event detection or support
of a diagnosis of these conditions. In this regard, the
combination of activity with some assessment of
body position might be particularly useful, and one
attempt has been reported. Unfortunately, there has
been little systematic work on developing standards
for the use of activity for detection of events that
produce significant body movements associated with
sleep, nor has there been any significant work on
using these measures to support diagnoses of these
events. There has also been virtually no work
integrating ambulatory activity and body position
measures. This overall lack of development seems
particularly regrettable since these events may occur
only occasionally during nights and may not occur
during the one or two nights of physiological
recording in a sleep lab. In most cases, individuals
may be largely unaware of the events, so self-report is
also insufficient. Thus, the ambulatory monitoring of
activity and/or body position for protracted periods
of time could potentially capture significant events
even when they are relatively uncommon and
unrecognized by the patient.
DIRECT MEASURE FOR TREMOR OR
DYSKINESIAS DURING SLEEP
Although both tics and tremors largely diminish
during sleep, they do not always disappear. Their
persistence may disrupt sleep and may contribute to
the reported sleep problems associated with disorders
producing these abnormal movements, such as
Parkinson’s disease or Tourette’s syndrome. These
movements may be detected by increased activity on
a wrist activity meter with a dynamic range permit-
ting sensitivity to smaller movements. However, data
from most wrist activity meters are insufficient for
analyses of the movements needed for detection of
tremor and dyskinesias. A specialized activity meter
ACTIGRAPHY 23
has been developed that provides a continuous fast
Fourier analysis of movement and stores data for
later download. This should be useful, but the utility
of this approach to assessing these conditions
remains to be evaluated.
CONCLUSION
Ambulatory activity monitoring for sleep medicine
has many potential uses, including recording of
PLMs, assessment of circadian phase, detection of
significant motor events associated with sleep, and
evaluation of motor regulation during sleep. It also
provides a surrogate measure for sleep–wake states,
but there remains considerable doubt regarding the
accuracy and utility of this measure of sleep. As
noted previously, many of the areas of potential use
for activity monitoring of sleep remain inchoate but
are promising for future development.
—Richard P. Allen
See also–Melatonin; Periodic Limb Movements
Sleep (PLMS); Polysomnography, Clinical; Sleep
Disorders; Sleep-Wake Cycle; Suprachiasmatic
Nucleus (SCN)
Further Reading
Chambers, M. J. (1994). Actigraphy and insomnia: A closer look.
Part 1. Sleep 17, 405–408.
Colburn, T. R., Smith, B. M., Gaurini, J. J., et al. (1976). An
ambulatory activity monitor with solid state memory. ISA
Trans. 15, 149–154.
Gorny, S. W., Allen, R. P., Krausman, D. T., et al. (2001). Initial
demonstration of the accuracy and utility of an ambulatory,
three-dimensional body position monitor with normals, sleep-
walkers and restless legs patients. Sleep Med. 2, 135–143.
Hauri, P. J., and Wisbey, J. (1992). Wrist actigraphy in insomnia.
Sleep 15, 293–301.
Lockley, S. W., Skene, D. J., and Arendt, J. (1999). Comparison
between subjective and actigraphic measurement of sleep and
sleep rhythms. J. Sleep Res. 8, 175–183.
Pollak, C. P., Tryon, W. W., Nagaraja, H., et al. (2001). How
accurately does wrist actigraphy identify the states of sleep and
wakefulness? Sleep 24, 957–965.
Redmond, D. P., and Hegge, F. W. (1985). Observations on the
design and specification of a wrist-worn human activity
monitoring system. Behavior Research Methods, Instruments
and Computers 17, 659–669.
Tachibana, N., Shinde, A., Ikeda, A., et al. (1996). Supplementary
motor area seizure resembling sleep disorder. Sleep 19, 811–
816.
Verbeek, I., Klip, E. C., and Declerck, A. C. (2001). The use of
actigraphy revised: The value for clinical practice in insomnia.
Percept. Motor Skills 92, 852–856.
24 ACTION POTENTIAL, GENERATION OF
Action Potential,
Generation of
Encyclopedia of the Neurological Sciences
THE IMPORTANT CHANNELS for understanding mem-
þ þ
brane excitability are Na channels, K channels,
and Cl channels. In a small subset of neurons, Ca2 þ
channels take over the role normally served by Na þ
channels and the Ca2 þ channels contribute the
depolarizing current during an action potential. The
skeletal muscle chloride channel is gated by ion
concentrations. The other important skeletal muscle
ion channels are gated by membrane potential.
SODIUM CHANNEL GATING PROPERTIES
Membrane depolarization activates sodium channels
via conformation changes from closed, nonconduct-
ing states to an open, current-conducting state
lk
Membrane Current
l Na
1 ms
Time
Figure 1
Na þ and K þ currents produced in response to sustained
membrane depolarization. The inward Na þ current is
traditionally depicted as downward and the outward K þ current is
depicted as upward. The Na þ current increases due to Na þ
channel opening and then declines due to Na þ channel
inactivation. The K þ current, produced by delayed rectifier type of
K þ channels, is delayed with respect to the Na þ current because
the K þ channels open slower. The K þ current declines little with
sustained depolarization because inactivation is less prominent in
K þ channels compared with Na þ channels.
SI SI
C O
FI FI
Figure 2
Possible transitions that a sodium channel can undergo. C, closed;
O, open; FI, fast inactivated; SI, slow inactivated.
(Fig. 1). The declining portion of INa elicited by
prolonged depolarization results from late openings of
Na þ channels and the transition of open channels to a
nonconducting, fast-inactivated state. Sodium chan-
nels can also transit directly between closed and fast-
inactivated states. Inactivated channels do not open
when the membrane is depolarized. The transition
rate from the open to the fast-inactivated state is
independent of voltage over part of its operative
range, and the transition rate increases with depolar-
ization at potentials more positive than approximately
30 mV. The transition rate from the closed to the
fast-inactivated state increases with depolarization.
Figure 2 shows the Na þ channel gating states.
Na þ channels have two inactivation processes
with different kinetics and voltage dependence. Fast
inactivation closes channels on a millisecond time-
scale, whereas slow inactivation takes seconds to
minutes. In mammalian tissue, fast inactivation helps
to terminate the action potential. Slow inactivation is
too slow to affect action potential termination.
However, slow inactivation operates at more nega-
tive potentials than fast inactivation so that the
distribution of channels between the closed and
slow-inactivated state regulates the number of
excitable sodium channels as a function of the
membrane potential. Fast- and slow-inactivated
states are distinct conformations of the sodium
channel. Protease treatment of the intracellular
membrane surface or other chemical treatments
may selectively alter slow inactivation or fast
inactivation. Sodium channel mutations can inde-
pendently change fast or slow inactivation. Slow
inactivation represents the accumulation of sodium
channels into the inexcitable slow-inactivated state.
Slow inactivation changes the number of excitable
channels but does not change the single channel
conductance or open time.
Different potassium channels are responsible
for the resting membrane conductance and for
 ACTION POTENTIAL, GENERATION OF 25

terminating the action potential. The potassium Membrane Potential

channel that is responsible for the resting membrane
conductance is called the inward rectifier or anom-
alous rectifier potassium channel. This channel has
unique properties that enable it to provide the resting
membrane conductance for potassium without re- Sodium Conductance
sulting in excessive potassium loss during an action
potential. The inward rectifier potassium channel is
so named because it has a larger conductance for
inward potassium currents. When the membrane is
depolarized more than 10–15 mV with respect to the
equilibrium potential for potassium, the conductance
Potassium Conductance
of the inward rectifier potassium channel decreases.
Consequently, once the membrane has depolarized to
approximately the threshold for triggering an action
potential, the conductance of the inward rectifier
potassium channel decreases and little potassium
exits the cell during the rising phase of the action
potential. The nonlinear conductance properties of
the inward rectifier potassium channel enable it to set
the membrane potential and not cause excessive
potassium loss during an action potential. Since the
Figure 3
cell has to utilize ATP to pump potassium back into
The time course of the membrane Na þ and K þ conductance
it, the conductance properties of the inward rectifier changes during an action potential.
potassium channel reduce the energy expenditure of
the muscle cells. Note that in skeletal muscle cells, an
action potential indirectly triggers much ATP break- tal muscle is caused by the endplate potential. In
down to fuel the movement of the contractile neurons, an action potential is triggered by the
proteins and the reuptake of calcium released from collective depolarization produced by excitatory
the sarcoplasmic reticulum. synapses onto the neuron. The depolarization causes
The second potassium channel in skeletal muscle is some voltage-gated sodium channels to open, which
the delayed rectifier potassium channel (Fig. 1). This augments the membrane depolarization. This process
voltage-gated channel is so named because at continues until threshold is reached. At threshold,
physiological temperatures the delayed rectifier the sodium conductance just exceeds the combined
potassium channel opens slower than the voltage- chloride and potassium conductances that are resist-
gated sodium channel. Delayed rectifier potassium ing membrane depolarization. The factors that
channels are opened by the membrane depolarization contribute to determining threshold membrane po-
produced by the action potential. However, due to tential for triggering an action potential are the
the delay in opening, most of the delayed rectifier voltage dependence of sodium channel opening and
channels do not open until after the rising phase of the decreasing conductance of the inward rectifier
the action potential has completed. The delayed potassium channel with depolarization. Once thresh-
opening of these potassium channels enables them to old is reached, the membrane potential depolarizes
assist in terminating the action potential without very quickly during the rising phase of the action
hindering the rising phase of the action potential. potential. During the rising phase, most of the
Hence, the gating properties of the delayed rectifier voltage-gated sodium channels are in the open state.
potassium also conserve intracellular potassium. The large membrane conductance for sodium results
in the membrane potential approaching the equili-
brium potential for sodium. The declining phase of
THE COURSE OF EVENTS DURING AN
the action potential results from two processes: (i)
ACTION POTENTIAL
The membrane depolarization triggers sodium chan-
The first step in generating an action potential nels to undergo conformation changes from the open
(Fig. 3) is membrane depolarization, which in skele- state to the fast-inactivated state and (ii) the delayed
26 ACTION POTENTIAL, GENERATION OF
rectifier potassium channels begin to open. The
membrane repolarizes because the sodium conduc-
tance decreases and potassium conductance in-
creases, causing the membrane to move toward the
potassium equilibrium potential.
Immediately after an action potential, most
sodium channels remain in the fast-inactivated state.
Consequently, there are not enough excitable sodium
channels to trigger a second action potential im-
mediately after the first action potential. The period
during which the population of excitable sodium
channels (those in the closed state) is too small to
support an action potential (i.e., there are not enough
excitable sodium channels to overcome the chloride
and inward rectifier potassium conductances) is
referred to as the absolute refractory period. During
the absolute refractory period, an action potential
cannot be triggered by even a very large depolariza-
tion. The period of time from the end of the absolute
refractory period until the sodium channels have
redistributed among their possible states to return to
the steady-state population of channels in the closed
and inactivated states is referred to as the relative
refractory period. During this period, a larger than
normal stimulus is needed to trigger an action
potential. During refractory periods, sodium chan-
nels change from the fast-inactivated to the closed
state.
The all-or-none (nothing) principle refers to the
generation of an action potential. The concept is that
in response to membrane depolarization, either an
action potential is generated or there is a nonregen-
erating response. The principle hinges on the
regenerative character of the Na þ channel opening
during the rising phase of the action potential. Once
threshold is exceeded and the depolarizing Na þ
conductance exceeds the hyperpolarizing K þ con-
ductance and the inhibitory Cl conductance, the
Na þ conductance rapidly increases and depolarizes
the membrane to produce the upstroke of the action
potential. If the Na þ conductance does not exceed
the combined Cl and K þ conductances, then the
membrane returns to the resting potential. With
membrane depolarizations precisely to the threshold
potential, either an action potential is generated (all)
or it is not (none). The all-or-none principle does not
imply that the action potential is always the same
size. The size of the peak of the action potential
depends on the number of Na þ channels that are
open. If the membrane is held at a depolarized
potential so that an appreciable fraction of Na þ
channels are in the slow- or fast-inactivated states,
then fewer Na þ channels will be open at the peak of
the action potential and the peak will be smaller.
A membrane will become hyperexcitable if some
sodium channels do not undergo fast inactivation,
resulting in a persistent inward sodium current
during the normal relative refractory period. In
addition, a membrane will become hyperexcitable
if sodium channels rapidly recover from the inacti-
vated state, which will reduce the duration of both
the relative and the absolute refractory periods.
Congenital myotonia, paramyotonia, and hyperka-
lemic periodic paralysis are often caused by Na þ
channel mutations that disrupt the inactivated states
of the Na þ channel. Next, the effect of potassium
accumulation in the transverse tubules on the
membrane electrical stability of skeletal muscle is
discussed.
Skeletal muscle needs a large resting chloride
conductance to counter the destabilizing effect of
its transverse tubule (T-tubule) system. The T-tubules
are relatively thin and long, and they serve to
conduct the action potential to inside a muscle fiber.
The T-tubules are essential for coupling surface
membrane action potentials with release of calcium
from the sarcoplasmic reticulum inside a muscle
fiber. Because they are very thin, potassium leaving
the muscle fiber during an action potential can
accumulate in the T-tubule. The elevated extracel-
lular potassium in the T-tubules makes the equili-
brium potential for potassium across the T-tubule
membrane less negative. For example, increasing the
potassium concentration in the T-tubule space to
12 mm, which likely happens after a series of action
potentials, would result in the potassium equilibrium
potential depolarizing by more than 40 mV to
64 mV. The membrane potential of the T-tubules
will remain depolarized after an action potential
until the sodium–potassium pumps are able to
remove the excess extracellular potassium. Under
physiological conditions, sodium channels recover
from inactivation faster than the sodium–potassium
pump can remove the excess potassium in the T-
tubules. The depolarized T-tubules can depolarize
adjacent membrane and trigger repeated action
potentials. Therefore, the T-tubules provide a depo-
larizing current that can trigger subsequent action
potentials. Muscle must have a high resting chloride
conductance to hinder the ability of the T-tubules to
depolarize the muscle membrane and to prevent
repeated action potentials from developing after a
single depolarizing stimulus. Removing the T-tubules
by chemically disrupting them prevents skeletal

muscle membrane from generating a string of action
potentials in response to a depolarizing stimulus.
—Robert L. Ruff
See also–Action Potential, Regeneration of; Ion
Channels, Overview; Membrane Potential
Acknowledgments
This work was supported by the Office of Research and
Development, Medical Research Service of the Department of
Veterans Affairs.
Further Reading
Almers, W., Roberts, W. M., and Ruff, R. L. (1984). Voltage clamp
of rat and human skeletal muscle: Measurements with an
improved loose-patch clamp technique. J. Physiol. 347, 751–
768.
Armstrong, C. M. (1981). Sodium channels and gating currents.
Physiol. Rev. 61, 644–683.
Cummins, T. R. (1996). Molecular pathophysiology of a mutant
sodium channel. PhD dissertation. Yale University, New Haven,
CT.
Hille, B. (1992). Ionic Channels of Excitable Membranes, 2nd ed.
Sinauer, Sunderland, MA.
Oxford, G. S. (1981). Some kinetic and steady-state properties of
sodium channels after removal of inactivation. J. Gen. Physiol.
77, 1–22.
Quandt, F. N. (1988). Modification of slow inactivation of single
sodium channels by phenytoin in neuroblastoma cells. Mol.
Pharmacol. 34, 557–565.
Ruff, R. L. (1986). Ionic channels: I. The biophysical basis for ion
passage and channel gating. Muscle Nerve 9, 675–699.
Ruff, R. L. (1986). Ionic channels: II. Voltage- and agonist-gated
and agonist-modified channel properties and structure. Muscle
Nerve 9, 767–786.
Ruff, R. L. (1996). The single channel basis of slow inactivation of
Na þ channels in rat skeletal muscle. Am. J. Physiol. 271(Cell
Physiol. 40), C971–C981.
Action Potential,
Regeneration of
Encyclopedia of the Neurological Sciences
THE WORD REGENERATION has many meanings in
neuroscience. This entry addresses action potential
propagation along a membrane. Regeneration of the
action potential requires an adjacent region of
membrane with a sufficient density of excitable
Na þ channels to support an action potential. Figure
1 shows that the action potential depolarizes the
ACTION POTENTIAL, REGENERATION OF 27
Extracellular side
45 mV 40 mV
Na K
Equilibrium Equilibrium
Potential Potential
Intracellular Side of Membrane
Figure 1
A circuit model of an action potential (left) regenerating into an
adjacent region of membrane. Due to the large number of open
Na þ channels at the peak of the action potential, Na þ is the
dominant membrane conductance so the action potential
approaches the equilibrium potential for Na þ . The current
flowing into the cell through the Na þ channels opened by the
action potential depolarizes an adjacent segment of membrane as
the action potential regenerates in the adjacent portion of
membrane as it propagates from left to right.
membrane. The depolarization occurs because the
dominant membrane conductance in the region of
the action potential is Na þ conductance. Hence, the
membrane potential approximates the equilibrium
potential for Na þ . At the site of the action potential,
current flows across the membrane into the cell
through the open Na þ channels. The current flowing
into the cell must leave the cell to complete a circuit.
The current exits the cell through the regions of
membrane adjacent to the site of the action potential.
In the region of the membrane where the action
potential had been, the Na þ channels are inactivated
and incapable of opening in response to the
membrane depolarization produced by the current
flowing outward across the membrane. In contrast,
in the region of membrane with excitable Na þ
channels, the depolarizing current opens the Na þ
channels. The open Na þ channels reduce the
membrane resistance, which directs the current from
the action potential to leave the cell through the
region of excitable Na þ channels that form a path of
least resistance. The increasing current flowing
through the membrane region with excitable Na þ
channels further depolarizes the membrane and
opens more Na þ channels. The process continues
until the complement of open Na þ channels is
sufficient for the Na þ conductance to equal the
conductance of other ions (K þ and Cl) that oppose

muscle membrane from generating a string of action
potentials in response to a depolarizing stimulus.
—Robert L. Ruff
See also–Action Potential, Regeneration of; Ion
Channels, Overview; Membrane Potential
Acknowledgments
This work was supported by the Office of Research and
Development, Medical Research Service of the Department of
Veterans Affairs.
Further Reading
Almers, W., Roberts, W. M., and Ruff, R. L. (1984). Voltage clamp
of rat and human skeletal muscle: Measurements with an
improved loose-patch clamp technique. J. Physiol. 347, 751–
768.
Armstrong, C. M. (1981). Sodium channels and gating currents.
Physiol. Rev. 61, 644–683.
Cummins, T. R. (1996). Molecular pathophysiology of a mutant
sodium channel. PhD dissertation. Yale University, New Haven,
CT.
Hille, B. (1992). Ionic Channels of Excitable Membranes, 2nd ed.
Sinauer, Sunderland, MA.
Oxford, G. S. (1981). Some kinetic and steady-state properties of
sodium channels after removal of inactivation. J. Gen. Physiol.
77, 1–22.
Quandt, F. N. (1988). Modification of slow inactivation of single
sodium channels by phenytoin in neuroblastoma cells. Mol.
Pharmacol. 34, 557–565.
Ruff, R. L. (1986). Ionic channels: I. The biophysical basis for ion
passage and channel gating. Muscle Nerve 9, 675–699.
Ruff, R. L. (1986). Ionic channels: II. Voltage- and agonist-gated
and agonist-modified channel properties and structure. Muscle
Nerve 9, 767–786.
Ruff, R. L. (1996). The single channel basis of slow inactivation of
Na þ channels in rat skeletal muscle. Am. J. Physiol. 271(Cell
Physiol. 40), C971–C981.
Action Potential,
Regeneration of
Encyclopedia of the Neurological Sciences
THE WORD REGENERATION has many meanings in
neuroscience. This entry addresses action potential
propagation along a membrane. Regeneration of the
action potential requires an adjacent region of
membrane with a sufficient density of excitable
Na þ channels to support an action potential. Figure
1 shows that the action potential depolarizes the
ACTION POTENTIAL, REGENERATION OF 27
Extracellular side
45 mV 40 mV
Na K
Equilibrium Equilibrium
Potential Potential
Intracellular Side of Membrane
Figure 1
A circuit model of an action potential (left) regenerating into an
adjacent region of membrane. Due to the large number of open
Na þ channels at the peak of the action potential, Na þ is the
dominant membrane conductance so the action potential
approaches the equilibrium potential for Na þ . The current
flowing into the cell through the Na þ channels opened by the
action potential depolarizes an adjacent segment of membrane as
the action potential regenerates in the adjacent portion of
membrane as it propagates from left to right.
membrane. The depolarization occurs because the
dominant membrane conductance in the region of
the action potential is Na þ conductance. Hence, the
membrane potential approximates the equilibrium
potential for Na þ . At the site of the action potential,
current flows across the membrane into the cell
through the open Na þ channels. The current flowing
into the cell must leave the cell to complete a circuit.
The current exits the cell through the regions of
membrane adjacent to the site of the action potential.
In the region of the membrane where the action
potential had been, the Na þ channels are inactivated
and incapable of opening in response to the
membrane depolarization produced by the current
flowing outward across the membrane. In contrast,
in the region of membrane with excitable Na þ
channels, the depolarizing current opens the Na þ
channels. The open Na þ channels reduce the
membrane resistance, which directs the current from
the action potential to leave the cell through the
region of excitable Na þ channels that form a path of
least resistance. The increasing current flowing
through the membrane region with excitable Na þ
channels further depolarizes the membrane and
opens more Na þ channels. The process continues
until the complement of open Na þ channels is
sufficient for the Na þ conductance to equal the
conductance of other ions (K þ and Cl
) that oppose
28 ACTION POTENTIAL, REGENERATION OF
membrane depolarization. The membrane potential
in the region of excitable Na þ channels is now at the
threshold for generating an action potential. Addi-
tional depolarization results in Na þ conductance
exceeding that of the opposing ions and the
membrane rapidly depolarizes due to the positive
feedback mechanism of Na þ channel opening,
leading to more Na þ channels opening, which
further depolarizes the membrane. The action
potential has now propagated into the adjacent
region of excitable membrane.
FACTORS AFFECTING THE RATE OF ACTION
POTENTIAL REGENERATION
Several factors influence the rate of action potential
regeneration, including temperature, the density of
excitable Na þ channels in the membrane, and the
ease with which current flows through the cell. Ion
channels, including Na þ and K þ channels, are large
glycoproteins. The different states of ion channels
(open, closed, and inactivated) represent different
conformations of the channel proteins. The speed
with which channels imbedded in the membrane can
change from closed to open states is very sensitive to
temperature. Within a physiological range of tem-
perature, the rate of ion channel opening in response
to membrane depolarization increases more than
threefold for a 101C increase (Q1043). Because
channel opening in response to membrane depolar-
ization and other ion channel conformation changes
are very sensitive to temperature, the rate of action
potential propagation increases dramatically with
temperature. Hence, it is critical to record tissue
temperature when measuring action potential con-
duction velocity.
The density of excitable Na þ channels in a
membrane and the density of opposing ion channels
influence the rate of action potential propagation.
With a high density of Na þ channels, a smaller
fraction of Na þ channels need be open for the
membrane to reach the threshold potential for
generating an action potential. As the Na þ channel
density increases, the action potential threshold
decreases. Hence, it takes less current to depolarize
the membrane beyond the action potential threshold,
which enables the action potential to regenerate
faster. Conversely, reducing the density of excitable
Na þ channels will slow and eventually block action
potential propagation. Local anesthetics prevent
action potential propagation in peripheral nerves by
blocking Na þ channels along a region of nerve
membrane.
Nature stops action potentials from reverberating
in excitable cells by utilizing regions that are devoid
of Na þ channels to arrest action potential propaga-
tion. Consider a motor neuron. An action potential
generated in the cell body and axon hillock
propagates down the axon into the nerve terminals.
The action potential does not regenerate in the nerve
terminals, and it does not reverberate up the axon
back to the cell body because the nerve terminals are
devoid of Na þ channels. If the motor axon is
artificially stimulated in midcourse, as occurs during
clinical neurophysiological testing, two action po-
tentials are generated. One travels anterograde to the
nerve terminals and is dissipated there. The other
travels retrograde to the axon hillock, which has a
high density of Na þ channels. The axon membrane
adjacent to the axon hillock is in a relatively
refractory state due to residual Na þ channel
inactivation. However, in many axons Na þ channels
near the axon hillock recover from inactivation
before the depolarization of the axon hillock
dissipates. Consequently, the depolarized axon hil-
lock is able to trigger an action potential in the
proximal axon that travels anterograde to the nerve
terminals. If the nerve terminals had a high density of
Na þ channels, action potentials would reverberate
up and down the axon. The ability of a retrograde-
traveling action potential to trigger an anterograde
action potential at the axon hillock is the basis of the
‘‘f’’ response, which is a clinical neurophysiological
test of the electrical integrity of proximal motor
axons. In skeletal muscle fibers, action potentials do
not reverberate along the length of a muscle fiber
because the tendon ends are devoid of Na þ channels.
Consequently, action potentials generated at the
neuromuscular junction travel to the tendon ends
and are dissipated there by the electrically inexcitable
membrane.
MECHANISMS FOR ACTION
POTENTIAL REGENERATION
For unmyelinated nerve fibers and skeletal muscle
fibers, action potentials propagate by the action
potential exciting the adjacent region of membrane.
The only way to speed up this mechanism of action
potential propagation is to facilitate the passage of
current through the cell by reducing the cell’s internal
resistance. Invertebrates increase the rate of action
potential regeneration in axons by producing giant

axons with very low internal resistances. Vertebrates
utilize a different mechanism of action potential
regeneration to speed action potential propagation.
In myelinated axons, sodium channels are concen-
trated in regions called nodes of Ranvier (Fig. 2),
which are separated by stretches of axon covered
with multiple layers of membrane called myelin. In
the central nervous system, myelin is produced by
oligodendroglia, whereas in the peripheral nervous
system, it is produced by Schwann cells. The
internodes are the regions of axon membrane
covered by myelin between the nodes of Ranvier.
Action potentials propagate along myelinated axons
by saltatory conduction. The inward current pro-
duced at a node of Ranvier travels inside the
internodal axon to the next node (Fig. 2). In this
manner, the action potential moves from node to
node. The key factor is that the layers of myelin
greatly increase the resistance between the cytoplasm
of the axon (axoplasm) and the myelin decreases the
capacitive coupling between the axoplasm and the
extracellular space. Myelin reduces current loss
across the internodal membrane by reducing the
resistive and capacitive leak of current across the
internodal axon. By reducing current loss across the
internodes, myelin enables almost all of the current
produced by one node of Ranvier to excite the next
node.
Demyelination, as occurs in the central nervous
system in multiple sclerosis or in the peripheral
nervous system in diphtheria or Guillain–Barré
Node Myelin
Figure 2
Myelinated axons are composed of nodes of Ranvier that have
high densities of Na þ channels and internodes. The internodal
membrane of the axon has few channels and is covered by myelin.
(Top) The myelin covering insulates the internodal region so that
little current entering the axon via an active node leaves the axon
in the internode region. (Bottom) In the setting of segmental
demyelination, too much current leaves the axon in the internode.
Consequently, there is not enough current remaining to trigger an
action potential in the next node of Ranvier.
ACTIVITIES OF DAILY LIVING 29
syndrome, can block action potential propagation
(Fig. 2). Damage to myelin allows current to leak
from the axon in the internodal region. Leakage
resulting from small degrees of myelin loss lengthens
the amount of time it takes for one node to excite the
next node, which reduces the conduction velocity.
More severe myelin loss results in the loss of so much
current that there is not enough remaining to excite
the next node, which blocks action potential
propagation. Hence, small degrees of myelin loss
will slow action potential conduction velocity, and
more severe myelin loss will block action potential
propagation.
—Robert L. Ruff
See also–Action Potential, Generation of; Ion
Channels, Overview; Membrane Potential
Acknowledgments
This work was supported by the Office of Research and
Development, Medical Research Service of the Department of
Veterans Affairs.
Further Reading
Hille, B. (1992). Ionic Channels of Excitable Membranes, 2nd ed.
Sinauer, Sunderland, MA.
Ruff, R. L. (1986). Ionic channels: I. The biophysical basis for ion
passage and channel gating. Muscle Nerve 9, 675–699.
Activities of Daily Living
(ADLs)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
A CHANGE in a patient’s ability to complete everyday
activities and meet the typical demands of his or her
day is often the reason the patient or family members
decide to seek medical attention. The goal of a
functional assessment in both clinical and research
settings is to identify deficits and changes in a
patient’s ability to carry out normal daily activities,
referred to as activities of daily living (ADLs). The
ADLs are divided into two levels of function, basic
and instrumental, in most tools and instruments
designed to measure a patient’s level of functioning.
Basic ADLs include mobility and personal self-care
tasks. Instrumental activities of daily living (IADLs)

axons with very low internal resistances. Vertebrates
utilize a different mechanism of action potential
regeneration to speed action potential propagation.
In myelinated axons, sodium channels are concen-
trated in regions called nodes of Ranvier (Fig. 2),
which are separated by stretches of axon covered
with multiple layers of membrane called myelin. In
the central nervous system, myelin is produced by
oligodendroglia, whereas in the peripheral nervous
system, it is produced by Schwann cells. The
internodes are the regions of axon membrane
covered by myelin between the nodes of Ranvier.
Action potentials propagate along myelinated axons
by saltatory conduction. The inward current pro-
duced at a node of Ranvier travels inside the
internodal axon to the next node (Fig. 2). In this
manner, the action potential moves from node to
node. The key factor is that the layers of myelin
greatly increase the resistance between the cytoplasm
of the axon (axoplasm) and the myelin decreases the
capacitive coupling between the axoplasm and the
extracellular space. Myelin reduces current loss
across the internodal membrane by reducing the
resistive and capacitive leak of current across the
internodal axon. By reducing current loss across the
internodes, myelin enables almost all of the current
produced by one node of Ranvier to excite the next
node.
Demyelination, as occurs in the central nervous
system in multiple sclerosis or in the peripheral
nervous system in diphtheria or Guillain–Barré
Node Myelin
Figure 2
Myelinated axons are composed of nodes of Ranvier that have
high densities of Na þ channels and internodes. The internodal
membrane of the axon has few channels and is covered by myelin.
(Top) The myelin covering insulates the internodal region so that
little current entering the axon via an active node leaves the axon
in the internode region. (Bottom) In the setting of segmental
demyelination, too much current leaves the axon in the internode.
Consequently, there is not enough current remaining to trigger an
action potential in the next node of Ranvier.
ACTIVITIES OF DAILY LIVING 29
syndrome, can block action potential propagation
(Fig. 2). Damage to myelin allows current to leak
from the axon in the internodal region. Leakage
resulting from small degrees of myelin loss lengthens
the amount of time it takes for one node to excite the
next node, which reduces the conduction velocity.
More severe myelin loss results in the loss of so much
current that there is not enough remaining to excite
the next node, which blocks action potential
propagation. Hence, small degrees of myelin loss
will slow action potential conduction velocity, and
more severe myelin loss will block action potential
propagation.
—Robert L. Ruff
See also–Action Potential, Generation of; Ion
Channels, Overview; Membrane Potential
Acknowledgments
This work was supported by the Office of Research and
Development, Medical Research Service of the Department of
Veterans Affairs.
Further Reading
Hille, B. (1992). Ionic Channels of Excitable Membranes, 2nd ed.
Sinauer, Sunderland, MA.
Ruff, R. L. (1986). Ionic channels: I. The biophysical basis for ion
passage and channel gating. Muscle Nerve 9, 675–699.
Activities of Daily Living
(ADLs)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
A CHANGE in a patient’s ability to complete everyday
activities and meet the typical demands of his or her
day is often the reason the patient or family members
decide to seek medical attention. The goal of a
functional assessment in both clinical and research
settings is to identify deficits and changes in a
patient’s ability to carry out normal daily activities,
referred to as activities of daily living (ADLs). The
ADLs are divided into two levels of function, basic
and instrumental, in most tools and instruments
designed to measure a patient’s level of functioning.
Basic ADLs include mobility and personal self-care
tasks. Instrumental activities of daily living (IADLs)
30 ACTIVITIES OF DAILY LIVING
describe more complex tasks required to live
independently in the community and include trans-
portation, financial management, shopping, and
household management duties. Multiple areas of
function are involved in these activities and include
cognitive, physical, and psychological performances.
Clinicians use many different scales to measure and
clarify the scope of impairment or disability and to
determine the fundamental deficit in behavior
responsible for the decline from premorbid level of
function.
Increasing impairment of cognitive capacities
eventually results in a patient losing his or her ability
to function independently. The clinical diagnosis of
dementia, according to the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition, requires
evidence that the cognitive impairment interferes
with the individual’s work or social functioning. The
workgroup of the National Institute of Neurological
and Communicative Disorders and Stroke and the
Alzheimer’s Disease and Related Disorders Associa-
tion recommends assessment of objective functional
capacities. The literature clearly shows that a
structured functional assessment in which perfor-
mance is assessed reveals functional differences
between cognitively impaired adults and normal
controls. The evaluation of the patient’s ADLs is
one part of the assessment for dementia and required
in establishing a diagnosis. Clinicians collect infor-
mation from patients and caregivers as well as
observe performance to measure the impact on the
patient’s everyday life. Functional measures must be
used in conjunction with cognitive measures and
physical examination findings to determine the cause
of functional decline. For example, a person’s
inability to dress himself or herself in the morning
may be related to physical weakness, depression, a
spatial deficit, an inability to successfully complete a
multiple-step task, or a combination of factors.
Many functional assessment instruments are com-
monly used as an integral part of the standard
medical evaluation of the elderly. One of the first
instruments was introduced in 1959 by Katz and
colleagues as a means to measure the effect of
rehabilitation on poststroke patients and designed to
measure disability benchmarks in six basic activities
of living: bathing, dressing, going to the toilet,
transferring from bed to chair, continence, and
feeding. This instrument was designed to measure
organized motor and neurological aspects of basic
self-care activities independent of cultural and social
factors. In the late 1960s, Lawton and Brody were
the first to use the ‘‘instrumental activities of daily
living’’ terminology with the aim of further specifying
performance in these areas.
In addition to the patient’s current level of
performance, it is important to note if his or her
function has declined from a previously more
competent level. Minimizing the influence of educa-
tional background, cultural background, and gender
differences should also optimize the use of such
measurement instruments. Many instruments are
based on informant or caregivers reports. The source
of the report is vital in behavioral neurology. Because
the diagnosis of dementia is made earlier in the
course of the disease, instruments are under devel-
opment to improve reliability in detecting subtle
declines in function and include self-report formats.
FUNCTIONAL SCALES
Functional scales such as the Functional Activities
Questionnaire (FAQ), the scale of everyday ADLs,
and the Instrumental Activities of Daily Living Scale
(IADLS) are used in assessing the clinical importance
and decline of functional competence. They help
guide effective rehabilitation and selection of appro-
priate devices and services for specific functional
deficits.
The FAQ, consisting of 10 questions about basic
and more complex activities of daily life, helps tease
out initial signs of functional deficits. Although the
FAQ has been shown to have a high reliability, it is
relatively insensitive to patients with mild to
moderate dementia. The IADLS, analogous to the
higher level ADLs, assesses capabilities in tasks such
as cooking, cleaning, shopping, washing clothes,
maintaining a house, managing money, using the
telephone, taking medications, working in an occu-
pation, and meeting transportation needs. This
assessment shows substantial sensitivity to patients
with mild dementia, whereas measuring the progress
of change in patients with moderate to severe
dementia is diminished because of the ceiling on
the scale.
The overall clinical condition of a patient can be
assessed using staging instruments such as a clinical
dementia rating scale (CDR) or Functional Assess-
ment Staging (FAST), which evaluate patients ac-
cording to fixed external standards and can provide a
more meaningful representation of a person’s dis-
ability. The scales are highly reliable and have a high
correlation with performance-based cognitive mea-
sures. The CDR scale assesses cognitive losses that

influence the ability to conduct activities in the areas
of memory, orientation, judgment and problem
solving, community affairs, home and hobbies, and
personal care. The FAST evaluates functional dete-
rioration in dementia patients throughout the entire
course of the illness. It evaluates the ability of an
individual to ambulate, dress and bathe without
assistance, retain urinary or fecal continence, and
communicate in a meaningful way. It often serves as
a strong diagnostic aid for clinicians.
There are many tools available and various
versions have been adapted for use across clinical
settings. Historically, functional assessments focused
on disability. Functional assessment instruments
were initially created to measure the level of
disability in chronic conditions and were not
intended for use in dementia diagnostic testing.
Functional assessment instruments in current use in
research and clinical settings were developed for the
purpose of staging the illness and measuring inter-
vention outcomes. The additional burden of diag-
nostic applications and efficacy measures has led to
improved instruments with better sensitivity and that
include patient’s self-report, direct observation of
performance-based measures, and family member
reports.
In summary, the goals of functional assessment in
dementia care are to support a diagnosis, establish a
baseline function, develop therapeutic goals, identify
risk factors, adjust medicine dosages, and monitor
the clinical course of a patient. Functional depen-
dence, rather than cognitive impairment, is a better
predictor of caregiving needs and burden. With an
increase in awareness to assess the functional aspects
of a disease, there is a higher rate of successfully
assisting, managing, and treating illnesses. Lastly,
early detection of functional decline and subsequent
interventions are critical in maximizing the indepen-
dence of the patient and improving the quality of life
for both the patient and the caregiver.
—Rosalie Gearhart and Nisha N. Money
See also–Aging, Overview; Alzheimer’s Disease;
Cognitive Impairment; Dementia; Memory,
Overview
Further Reading
Brod, M., Stewart, A., Sands, L., et al. (1999). Conceptualiza-
tion and measurement of quality of life in dementia: The
Dementia Quality of Life instrument (DQoL). Gerontologist
39, 25–35.
ACUTE CONFUSIONAL STATE 31
Fleming, K., Evans, J., Weber, D., et al. (1995). Practical functional
assessment of elderly persons: A primary-care approach. Mayo
Clinic Proc. 70, 890–910.
Galasko, D., Bennett, D., Sano, M., et al. (1997). An inventory to
assess activities of daily living for clinical trials in Alzheimer’s
disease. The Alzheimer’s Disease Cooperative Study. Alzheimer
Dis. Assoc. Discord. 11, S33–S39.
Katz, S., Ford, A. B., Moskowisc, R. W., et al. (1963). Studies of
illness in the aged. The index of ADL: A standardized measure
of biological and psychosocial function. J. Am. Med. Assoc.
185, 914–919.
Lawton, M. P., and Brody, E. M. (1969). Assessment of older
people: Self maintaining and instrumental activities of daily
living. Gerontologist 9, 179–186.
Loewenstein, D. A., and Mogosky, B. (1999). Functional assess-
ment in the older adult patient. In Handbook of Assessment in
Clinical Gerontology (P. Lichtenberg, Ed.), pp. 268–281. Wiley,
New York.
Mahurin, R., and DeBettignies, B. (1991). Structured assessment
of independent living skills: Preliminary report of a perfor-
mance measure of functional abilities in dementia. J. Gerontol.
46, 58–66.
Morris, J. (1993). The Clinical Dementia Rating (CDR): Current
version and scoring rules. Neurology 43, 2412–2414.
Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H., et al. (1982).
Measurement of functional activities in older adults in the
community. J. Gerontol. 37, 323–329.
Reisberg, B. (1988). Functional Assessment Staging (FAST).
Psychopharmacol. Bull. 24, 653–659.
Spector, W. D. (1996). Functional Disability Scales. Quality of Life
and Pharmaeconomics in Clinical Trials, 2nd ed. Lippincott–
Raven Publishers, Philadelphia.
Acute Confusional State
(Delirium)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE Diagnostic and Statistical Manual of Mental
Disorders, fourth edition, defines delirium as an
acute ‘‘disturbance of consciousness with reduced
ability to focus, sustain, or shift attention.’’ As part
of the definition, Dementia, a more enduring and
usually progressive decline in cognitive function, is
excluded. Global cognitive impairment, a reduced
level of consciousness, increased or decreased psy-
chomotor activity, and a disordered wake–sleep cycle
are common accompaniments. Synonyms, some
inappropriate or vague, include acute brain syn-
drome, toxic psychosis, clouded state, global cogni-
tive impairment, pseudodementia, and twilight
states. Context-related synonyms are intensive care
unit psychosis, postoperative encephalopathy, and
postsurgery psychiatric syndrome. Although some

influence the ability to conduct activities in the areas
of memory, orientation, judgment and problem
solving, community affairs, home and hobbies, and
personal care. The FAST evaluates functional dete-
rioration in dementia patients throughout the entire
course of the illness. It evaluates the ability of an
individual to ambulate, dress and bathe without
assistance, retain urinary or fecal continence, and
communicate in a meaningful way. It often serves as
a strong diagnostic aid for clinicians.
There are many tools available and various
versions have been adapted for use across clinical
settings. Historically, functional assessments focused
on disability. Functional assessment instruments
were initially created to measure the level of
disability in chronic conditions and were not
intended for use in dementia diagnostic testing.
Functional assessment instruments in current use in
research and clinical settings were developed for the
purpose of staging the illness and measuring inter-
vention outcomes. The additional burden of diag-
nostic applications and efficacy measures has led to
improved instruments with better sensitivity and that
include patient’s self-report, direct observation of
performance-based measures, and family member
reports.
In summary, the goals of functional assessment in
dementia care are to support a diagnosis, establish a
baseline function, develop therapeutic goals, identify
risk factors, adjust medicine dosages, and monitor
the clinical course of a patient. Functional depen-
dence, rather than cognitive impairment, is a better
predictor of caregiving needs and burden. With an
increase in awareness to assess the functional aspects
of a disease, there is a higher rate of successfully
assisting, managing, and treating illnesses. Lastly,
early detection of functional decline and subsequent
interventions are critical in maximizing the indepen-
dence of the patient and improving the quality of life
for both the patient and the caregiver.
—Rosalie Gearhart and Nisha N. Money
See also–Aging, Overview; Alzheimer’s Disease;
Cognitive Impairment; Dementia; Memory,
Overview
Further Reading
Brod, M., Stewart, A., Sands, L., et al. (1999). Conceptualiza-
tion and measurement of quality of life in dementia: The
Dementia Quality of Life instrument (DQoL). Gerontologist
39, 25–35.
ACUTE CONFUSIONAL STATE 31
Fleming, K., Evans, J., Weber, D., et al. (1995). Practical functional
assessment of elderly persons: A primary-care approach. Mayo
Clinic Proc. 70, 890–910.
Galasko, D., Bennett, D., Sano, M., et al. (1997). An inventory to
assess activities of daily living for clinical trials in Alzheimer’s
disease. The Alzheimer’s Disease Cooperative Study. Alzheimer
Dis. Assoc. Discord. 11, S33–S39.
Katz, S., Ford, A. B., Moskowisc, R. W., et al. (1963). Studies of
illness in the aged. The index of ADL: A standardized measure
of biological and psychosocial function. J. Am. Med. Assoc.
185, 914–919.
Lawton, M. P., and Brody, E. M. (1969). Assessment of older
people: Self maintaining and instrumental activities of daily
living. Gerontologist 9, 179–186.
Loewenstein, D. A., and Mogosky, B. (1999). Functional assess-
ment in the older adult patient. In Handbook of Assessment in
Clinical Gerontology (P. Lichtenberg, Ed.), pp. 268–281. Wiley,
New York.
Mahurin, R., and DeBettignies, B. (1991). Structured assessment
of independent living skills: Preliminary report of a perfor-
mance measure of functional abilities in dementia. J. Gerontol.
46, 58–66.
Morris, J. (1993). The Clinical Dementia Rating (CDR): Current
version and scoring rules. Neurology 43, 2412–2414.
Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H., et al. (1982).
Measurement of functional activities in older adults in the
community. J. Gerontol. 37, 323–329.
Reisberg, B. (1988). Functional Assessment Staging (FAST).
Psychopharmacol. Bull. 24, 653–659.
Spector, W. D. (1996). Functional Disability Scales. Quality of Life
and Pharmaeconomics in Clinical Trials, 2nd ed. Lippincott–
Raven Publishers, Philadelphia.
Acute Confusional State
(Delirium)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE Diagnostic and Statistical Manual of Mental
Disorders, fourth edition, defines delirium as an
acute ‘‘disturbance of consciousness with reduced
ability to focus, sustain, or shift attention.’’ As part
of the definition, Dementia, a more enduring and
usually progressive decline in cognitive function, is
excluded. Global cognitive impairment, a reduced
level of consciousness, increased or decreased psy-
chomotor activity, and a disordered wake–sleep cycle
are common accompaniments. Synonyms, some
inappropriate or vague, include acute brain syn-
drome, toxic psychosis, clouded state, global cogni-
tive impairment, pseudodementia, and twilight
states. Context-related synonyms are intensive care
unit psychosis, postoperative encephalopathy, and
postsurgery psychiatric syndrome. Although some
32 ACUTE CONFUSIONAL STATE
authors refer to delirium as a florid state with
disorientation, fear, terrifying hallucinations, and
agitation (often with heightened sympathetic nervous
activity), there is a continuum ranging from a mild,
subacute beclouded condition (low type) to an
agitated, confusional state (raving type).
In confusional states, a variable number of
cognitive deficits are consistently superimposed on
a defect in attention. Attention comprises alertness
and the ability to select and focus on a given task or
stimulus. Patients show impaired concentration,
probably as a component of impaired attention.
Because of the difficulty in maintaining attention,
patients who are alert are often distractible. The
attention shifts to the loudest or most novel stimulus.
To elicit clinical evidence of subtly impaired atten-
tion, the following are useful: digit span (number of
digits repeated), serial 7 s (counting down from 100
by continually subtracting 7), spelling ‘‘world’’
backwards, or counting down from 20 to 1 within
10 sec with no more than one error.
Perception, thinking, and memory are usually all
impaired to variable extents. Perceptual difficulties
include difficulty in processing, discriminating, and
integrating stimuli with previously stored memories.
Hallucinations and delusions may intrude as intern-
ally created altered perceptions. Patients may mis-
perceive information. Hallucinations—auditory,
visual, or tactile (usually formication or a sense of
ants crawling on the skin)—may accompany agita-
tion, especially in withdrawal or toxic states, but
kinesthetic hallucinations are rare. Some delusions
are frightening (e.g., mistaking an intravenous line
for a snake), and others may be persecutory.
Patients are often disoriented in time and place but
never to person. Visuospatial problems and con-
structional apraxia are frequent.
Alertness often fluctuates between delirium with
agitation and lethargy with clouding of consciousness,
quiet perplexity, or mild stupor. Agitation may be
associated with apprehension, paranoia, and tremor.
Increased sympathetic nervous system activity fre-
quently accompanies the agitated form of delirium,
with facial flushing or pallor, dilated pupils, tachy-
cardia, sweating, and a postural-action tremor. Con-
fusion, agitation, and delusions may be more
prominent at night (sundowning), leading to poor
sleep. Emotional–behavioral disturbances that accom-
pany agitated delirium include rage, combativeness,
irritability, fear, and apprehension or euphoria. Con-
versely, depression or apathy may be found alternat-
ing with these or with the quiet confusional state.
Alterations in motivation, drive, or conation
probably derive from a number of the previously
mentioned alterations in mental functioning. A
reduction or deficiency of motivation is termed
abulia or hypobulia. Conversely, motor activity
may be increased with restlessness that is similar to
the hyperactivity inattention syndrome of children.
Akathisia, a state of restlessness with inability to be
still, may be found. Heightened emotionality, with
euphoria or irritability, sometimes accompanies the
increase in motor activity. Some aspects may be
combined: Restless patients may resist attempts of
the examiner to move or motivate the patient in a
certain direction.
Motor signs accompanying acute confusion may
occur singly or in combination: Psychomotor retar-
dation (decreased motor responsiveness without
paralysis or profound decrease in conscious level),
hyperactivity, asterixis, multifocal myoclonus, ge-
genhalten, and a postural-action tremor.
EPIDEMIOLOGY AND IMPORTANCE
Ten to 15% of patients admitted to acute medical
and surgical wards are acutely confused. Some
diagnostic groups have a high prevalence of confu-
sion: cardiac surgery (32%), surgery for hip fracture
(45–55%), and bacteremia (70%).
Delirium tremens (DTs), an acute organic psycho-
sis during alcohol withdrawal, currently accounts for
4.5% of inpatients in acute care hospitals. Such
patients are admitted for (i) an illness not directly
caused by alcohol, but DTs occur within 7 days after
admission; (ii) acute withdrawal symptoms other
than DTs, with later DTs; or (iii) acute DTs.
The elderly are more prone to acute confusion in
hospital: 15% of such patients are confused on
admission and probably an additional 20% develop
confusion during their hospitalization. Drug toxicity
features prominently among the most common
immediately identified, preventable, or treatable
causes of the acute confusional state in the elderly.
A differential diagnosis of etiologies of delirium is
presented in Table 1.
MANAGEMENT
The debilitated elderly are especially susceptible to
delirium. Drugs should be used only when necessary,
taking renal and hepatic function into account for
the dosage schedule. To prevent drug withdrawal
reactions, it is best to taper, rather than to withdraw
 ACUTE CONFUSIONAL STATE 33

Table 1 CAUSES OF ACUTE CONFUSIONAL STATEa

Systemic illnesses Withdrawal syndromes

Sepsis (septic encephalopathy) Alcohol
Acute uremia Drugs
Hepatic failure CNS infections
Cardiac failure Meningitis
Pulmonary disease (especially pneumonia Encephalitis
and pulmonary embolism) Intracranial lesions
Electrolyte disturbances Head trauma
Hypercalcemia Acute lesions (right parietal, bilateral occipital, or mesial frontal)
Porphyria Subdural hematoma
Carcinoid syndrome Hypertensive encephalopathy
Endocrinopathies Miscellaneous
Thyroid dysfunction Heat stroke
Parathyroid tumors Electrocution
Adrenal dysfunction Sleep deprivation
Pituitary dysfunction
Nutritional deficiencies
Thiamine (Wernicke’s)
Niacin
Vitamin B12
Folate
Intoxications
Drugs (especially anticholinergics in
elderly)
Alcohols
Metals
Industrial agents
Biocides
a
Modified with permission from Cummings, J. L. (1985). Clinical Neuropsychiatry, p. 69. Drune & Stratton, Orlando, FL.

abruptly, medications that have been used for some
time, especially monoamine oxidase inhibitors,
clonidine, narcotics, barbiturates, and antiepileptic
drugs.
Early recognition, prompt investigation, and man-
agement of the acute confusional state should lessen
morbidity and mortality that is associated with more
profound disturbances of consciousness. Supportive
therapy is also needed; basic fluid and electrolyte
balance, adequate nutrition, and vitamin supplemen-
tation must be initiated and maintained. All non-
essential drugs should be stopped. Agitation requires
nearly continuous nursing care, a well-lit room, a
regular routine, constant reorientation and reassur-
ance, and often pharmacological treatment. Halo-
peridol and short-acting benzodiazepines (e.g.,
lorazepam) are the safest and most useful drugs; in
general, barbiturates should be avoided. Agitation
and fear without psychotic features are best treated
with an anxiolytic, such as lorazepam. Restraints
may add to patients’ agitation and are best avoided
except when absolutely necessary. If pain is asso-
ciated with agitation, narcotics are usually necessary.
The brief use of neuromuscular blocking agents in
agitated, ventilated patients is sometimes necessary if
other measures have failed. Increased sympathetic
activity (perspiration, tachycardia, and hypertension)
can be treated with clonidine, a centrally acting a2-
adrenergic agonist.
—G. Bryan Young
See also–Alcohol-Related Neurotoxicity;
Alertness; Attention; Awareness; Delusions;
Dementia; Hallucinations
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed. American Psychiatric
Association, Washington, DC.
Berggren, D., Gustafson, Y., Erickson, B., et al. (1987). Post-
operative confusion after anesthesia in elderly patients with
femoral neck fractures. Anesth. Analg. 66, 497–504.
Francis, J. (1992). Delirium in older patients. J. Am. Geriatr. Soc.
40, 829–838.
Francis, J. (1999). Three millennia of delirium research: Moving
beyond echoes of the past. J. Am. Geriatr. Soc. 47, 1382.
Gibson, G. E., Blass, J. P., Huang, H. M., et al. (1991). The
cellular basis of delirium and its relevance to age-related
34 ACUTE DISSEMINATED ENCEPHALOMYELITIS
disorders including Alzheimer’s disease. Int. Psychogeriatr. 3,
373–395.
Komel, H. W. (1993). Visual illusions and hallucinations. Ballieres
Clin. Neurol. 2, 243.
Lipowski, Z. J. (1990). Delirium: Acute Confusional States.
Oxford Univ. Press, New York.
Ross, C. A. (1991). CNS arousal systems: Possible role in delirium.
Int. Psychogeriatr. 3, 353–371.
Schuchardt, V., and Bourke, D. L. (1994). Alcoholic delirium and
other withdrawal syndromes. In NeuroCritical Care (W. Hacke,
Ed.), pp. 846–855. Springer-Verlag, Berlin.
Smith, L. W., and Dimsdale, J. E. (1989). Postcardiotomy delirium:
Conclusions after 25 years. Am. J. Psychiatry 146, 452–458.
Thomas, R. I., Cameron, D. J., and Fahs, M. C. (1988). A
prospective study of delirium and prolonged hospital stay. Arch.
Gen. Psychiatry 45, 937.
Van der Mast, R. C., and Roest, F. H. (1992). Delirium after
cardiac surgery: A critical review. Psychosom. Med. 54,
240–245.
Acute Disseminated
Encephalomyelitis (ADEM)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACUTE disseminated encephalomyelitis (ADEM) is an
acute monophasic immune-mediated disorder affect-
ing the central nervous system (CNS) white matter. It
has a strong similarity to experimental allergic
encephalomyelitis that has been produced in mon-
keys by the sensitization to injected myelin or myelin
components (protein, proteolipid protein, and mye-
lin–oligodendocyte glycoprotein).
Neuropathological studies reveal perivenular de-
myelination with infiltration of lymphocytes and
macrophages and perivascular edema. There is
relative sparing of axons. The degree of vasogenic
edema can be extreme.
The pathogenesis is likely a T cell-mediated
disease mediated against a CNS myelin-associated
protein, especially myelin basic protein. This is based
on (i) the resemblance of ADEM to experimental
allergic encephalomyelitis, (ii) the occurrence of
cases of ADEM following immunization against
rabies when the vaccine was prepared from neural
tissue, and (iii) the fact that T cells from patients
with ADEM have increased reactivity against myelin
basic protein. It has been hypothesized that there
may be molecular mimicry between certain viruses
and myelin basic protein that sensitizes the host to its
own myelin. The lymphocytes cross the blood–brain
barrier and set up the reaction in CNS white matter,
causing increased permeability of the blood–brain
barrier and more lymphocytic invasion. Another
possibility is that there is a nonspecific immunologi-
cal activation that disrupts the blood–brain barrier
and the demyelination occurs due to myelinotoxic
effects of exposure to the blood cells and plasma.
Another variation on this theme is that the endothe-
lial cells are directly infected, allowing the blood–
brain barrier disruption.
ADEM typically follows infections such as measles
(about 1 in 1000 cases of natural measles), rubella
(German measles), varicella, and less commonly after
immunization against measles, rubella, diphtheria/
tetanus, and pertussis. Clinical symptoms typically
begin 1 or 2 weeks after a viral infection or
immunization. Patients become febrile, often accom-
panied by headache, nausea, and vomiting. Neuro-
logical symptoms and signs are variable and include
acute confusion, focal signs (including hemiparesis,
visual loss, paraparesis, ataxia, seizures, dystonia, or
chorea), and impaired alertness (ranging from
drowsiness to coma).
The differential diagnosis includes a severe form of
multiple sclerosis (e.g., Marburg variant), encepha-
litis due to direct viral invasion of the brain, cerebral
vein thrombosis, cerebral vasculitis, lymphomatoid
angiomatosis, systemic collagen vascular diseases,
and vitamin B12 deficiency.
The following can be of assistance in the detection
of ADEM:
1. Neuroimaging: Magnetic resonance imaging
(MRI) shows gray and white matter lesions on T2-
weighted images, with enhancement following gado-
linium injection on T1-weighted images. Determina-
tion of the degree of gray matter involvement is
helpful in differentiating ADEM from multiple
sclerosis (Fig. 1). Computed tomography is less
sensitive but can show white matter lucency in the
cerebral hemispheres, along with brain swelling.
2. Cerebrospinal fluid may show increased lym-
phocytes and increases in protein, but it may be
normal in one-third of patients.
3. Electrophysiological testing: Electroencephalo-
grams may show generalized or multifocal slowing in
the delta (r4 Hz) frequency. Evoked potential
studies (showing abnormalities in sensory pathways,
e.g., visual, auditory, or somatosensory) are not very
helpful, except in confirming a multifocal process.
Randomized controlled trials of therapeutic mea-
sures have not been performed. The disorder may
spontaneously improve, so reports of therapeutic
34 ACUTE DISSEMINATED ENCEPHALOMYELITIS
disorders including Alzheimer’s disease. Int. Psychogeriatr. 3,
373–395.
Komel, H. W. (1993). Visual illusions and hallucinations. Ballieres
Clin. Neurol. 2, 243.
Lipowski, Z. J. (1990). Delirium: Acute Confusional States.
Oxford Univ. Press, New York.
Ross, C. A. (1991). CNS arousal systems: Possible role in delirium.
Int. Psychogeriatr. 3, 353–371.
Schuchardt, V., and Bourke, D. L. (1994). Alcoholic delirium and
other withdrawal syndromes. In NeuroCritical Care (W. Hacke,
Ed.), pp. 846–855. Springer-Verlag, Berlin.
Smith, L. W., and Dimsdale, J. E. (1989). Postcardiotomy delirium:
Conclusions after 25 years. Am. J. Psychiatry 146, 452–458.
Thomas, R. I., Cameron, D. J., and Fahs, M. C. (1988). A
prospective study of delirium and prolonged hospital stay. Arch.
Gen. Psychiatry 45, 937.
Van der Mast, R. C., and Roest, F. H. (1992). Delirium after
cardiac surgery: A critical review. Psychosom. Med. 54,
240–245.
Acute Disseminated
Encephalomyelitis (ADEM)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACUTE disseminated encephalomyelitis (ADEM) is an
acute monophasic immune-mediated disorder affect-
ing the central nervous system (CNS) white matter. It
has a strong similarity to experimental allergic
encephalomyelitis that has been produced in mon-
keys by the sensitization to injected myelin or myelin
components (protein, proteolipid protein, and mye-
lin–oligodendocyte glycoprotein).
Neuropathological studies reveal perivenular de-
myelination with infiltration of lymphocytes and
macrophages and perivascular edema. There is
relative sparing of axons. The degree of vasogenic
edema can be extreme.
The pathogenesis is likely a T cell-mediated
disease mediated against a CNS myelin-associated
protein, especially myelin basic protein. This is based
on (i) the resemblance of ADEM to experimental
allergic encephalomyelitis, (ii) the occurrence of
cases of ADEM following immunization against
rabies when the vaccine was prepared from neural
tissue, and (iii) the fact that T cells from patients
with ADEM have increased reactivity against myelin
basic protein. It has been hypothesized that there
may be molecular mimicry between certain viruses
and myelin basic protein that sensitizes the host to its
own myelin. The lymphocytes cross the blood–brain
barrier and set up the reaction in CNS white matter,
causing increased permeability of the blood–brain
barrier and more lymphocytic invasion. Another
possibility is that there is a nonspecific immunologi-
cal activation that disrupts the blood–brain barrier
and the demyelination occurs due to myelinotoxic
effects of exposure to the blood cells and plasma.
Another variation on this theme is that the endothe-
lial cells are directly infected, allowing the blood–
brain barrier disruption.
ADEM typically follows infections such as measles
(about 1 in 1000 cases of natural measles), rubella
(German measles), varicella, and less commonly after
immunization against measles, rubella, diphtheria/
tetanus, and pertussis. Clinical symptoms typically
begin 1 or 2 weeks after a viral infection or
immunization. Patients become febrile, often accom-
panied by headache, nausea, and vomiting. Neuro-
logical symptoms and signs are variable and include
acute confusion, focal signs (including hemiparesis,
visual loss, paraparesis, ataxia, seizures, dystonia, or
chorea), and impaired alertness (ranging from
drowsiness to coma).
The differential diagnosis includes a severe form of
multiple sclerosis (e.g., Marburg variant), encepha-
litis due to direct viral invasion of the brain, cerebral
vein thrombosis, cerebral vasculitis, lymphomatoid
angiomatosis, systemic collagen vascular diseases,
and vitamin B12 deficiency.
The following can be of assistance in the detection
of ADEM:
1. Neuroimaging: Magnetic resonance imaging
(MRI) shows gray and white matter lesions on T2-
weighted images, with enhancement following gado-
linium injection on T1-weighted images. Determina-
tion of the degree of gray matter involvement is
helpful in differentiating ADEM from multiple
sclerosis (Fig. 1). Computed tomography is less
sensitive but can show white matter lucency in the
cerebral hemispheres, along with brain swelling.
2. Cerebrospinal fluid may show increased lym-
phocytes and increases in protein, but it may be
normal in one-third of patients.
3. Electrophysiological testing: Electroencephalo-
grams may show generalized or multifocal slowing in
the delta (r4 Hz) frequency. Evoked potential
studies (showing abnormalities in sensory pathways,
e.g., visual, auditory, or somatosensory) are not very
helpful, except in confirming a multifocal process.
Randomized controlled trials of therapeutic mea-
sures have not been performed. The disorder may
spontaneously improve, so reports of therapeutic

Figure 1
T2-weighted image of a patient with postinfectious, acute
disseminated encephalomyelitis (ADEM), illustrating multifocal
demyelination in the subcortical regions, with the largest in the
right posterior cerebrum and deep white matter. Note also the
considerable involvement of deep gray nuclei. This feature favors
ADEM over multiple sclerosis. The computed tomographic scan,
performed less than 24 hr earlier, did not reveal any definite
abnormality.
success are difficult to evaluate. Corticosteroids,
especially pulsed methylprednisolone (e.g.,
1000 mg/day for 5–7 days) with a slow taper of
prednisone or dexamethasone, are often effective
anecdotally. Plasmapheresis and intravenous immu-
noglobulin administration have been reported to be
of benefit in some patients who fail to respond to
corticosteroids.
—G. Bryan Young
See also–Acute Hemorrhagic Encephalitis;
Anoxic-Ischemic Encephalopathy;
Demyelinating Disease, Central; Sepsis-
Associated Encephalopathy; Toxic
Encephalopathy; Uremic Encephalopathy;
Wernicke’s Encephalopathy
Further Reading
Hart, M. N., and Earle, K. M. (1975). Hemorrhagic and
perivenous encephalitis: A clinical–pathological review of 38
cases. J. Neurol. Neurosurg. Psychiatry 38, 585–591.
Pasternak, J. F., Devivo, D. C., and Prensky, A. L. (1980). Steroid-
responsive encephalomyelitis in childhood. Neurology 30,
481–486.
Patel, S. P., and Friedman, R. S. (1997). Neuropsychiatric features
of acute disseminated encephalomyelitis: A review. J. Neuro-
psychiatry Clin. Neurosci. 9, 534–540.
Tselis, A. C., and Lisak, R. P. (1995). Acute disseminated
encephalomyelitis and isolated central nervous system demye-
linative symptoms. Curr. Opin. Neurol. 8, 227–229.
ACUTE HEMORRHAGIC ENCEPHALITIS 35
Acute Hemorrhagic
Encephalitis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACUTE hemorrhagic encephalitis [also known as
acute hemorrhagic leukoencephalitis (of Weston
Hurst), acute necrotizing hemorrhagic encephalitis,
and Strümpell–Leichtenstern syndrome] is a severe
form of an immune-mediated brain disease that
typically follows a viral illness in young adults or
children. The disorder is probably an extreme form
of acute disseminated encephalomyelitis (ADEM), as
evidenced by cases with hemorrhagic conversion
from initially typical ADEM on magnetic resonance
imaging (MRI) scanning. There are multifocal
hemorrhagic lesions in the white matter of the brain,
variable brain edema, and mixed red blood cells and
leukocytes with increased protein and normal glu-
cose in the cerebrospinal fluid. Brain biopsy shows
perivenous demyelination and hemorrhages of vari-
able size.
Patients become acutely ill within 2 weeks of an
upper respiratory infection with headache, stiff neck,
fever, and confusion. They then develop focal or
multifocal neurological signs related to disease in the
cerebral hemispheres and/or brainstem. The former
include focal seizures, hemiplegia, and pseudobulbar
palsy. Consciousness is almost always impaired, with
stupor and then coma. Occasionally, it less severe
and more focal; the spinal cord may be involved.
The differential diagnosis often includes herpes
simplex encephalitis, hematological disorders (such
as thrombotic thrombocytopenic purpura), cortical
vein thrombosis, acute toxic encephalopathy (Reye’s
syndrome in younger children), hypoxic–ischemic
encephalopathy, and status epilepticus from various
causes.
Because of the rarity of the syndrome, no treat-
ment trials have been conducted. Vigorous treatment
of raised intracranial pressure is usually instituted
with mannitol, hyperventilation, and corticosteroids.
The autoimmune/vascular component has been
treated with corticosteroids, plasmapheresis, and
cyclophosphamide.
—G. Bryan Young
See also–Acute Disseminated Encephalomyelitis
(ADEM); Anoxic-Ischemic Encephalopathy;

Figure 1
T2-weighted image of a patient with postinfectious, acute
disseminated encephalomyelitis (ADEM), illustrating multifocal
demyelination in the subcortical regions, with the largest in the
right posterior cerebrum and deep white matter. Note also the
considerable involvement of deep gray nuclei. This feature favors
ADEM over multiple sclerosis. The computed tomographic scan,
performed less than 24 hr earlier, did not reveal any definite
abnormality.
success are difficult to evaluate. Corticosteroids,
especially pulsed methylprednisolone (e.g.,
1000 mg/day for 5–7 days) with a slow taper of
prednisone or dexamethasone, are often effective
anecdotally. Plasmapheresis and intravenous immu-
noglobulin administration have been reported to be
of benefit in some patients who fail to respond to
corticosteroids.
—G. Bryan Young
See also–Acute Hemorrhagic Encephalitis;
Anoxic-Ischemic Encephalopathy;
Demyelinating Disease, Central; Sepsis-
Associated Encephalopathy; Toxic
Encephalopathy; Uremic Encephalopathy;
Wernicke’s Encephalopathy
Further Reading
Hart, M. N., and Earle, K. M. (1975). Hemorrhagic and
perivenous encephalitis: A clinical–pathological review of 38
cases. J. Neurol. Neurosurg. Psychiatry 38, 585–591.
Pasternak, J. F., Devivo, D. C., and Prensky, A. L. (1980). Steroid-
responsive encephalomyelitis in childhood. Neurology 30,
481–486.
Patel, S. P., and Friedman, R. S. (1997). Neuropsychiatric features
of acute disseminated encephalomyelitis: A review. J. Neuro-
psychiatry Clin. Neurosci. 9, 534–540.
Tselis, A. C., and Lisak, R. P. (1995). Acute disseminated
encephalomyelitis and isolated central nervous system demye-
linative symptoms. Curr. Opin. Neurol. 8, 227–229.
ACUTE HEMORRHAGIC ENCEPHALITIS 35
Acute Hemorrhagic
Encephalitis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACUTE hemorrhagic encephalitis [also known as
acute hemorrhagic leukoencephalitis (of Weston
Hurst), acute necrotizing hemorrhagic encephalitis,
and Strümpell–Leichtenstern syndrome] is a severe
form of an immune-mediated brain disease that
typically follows a viral illness in young adults or
children. The disorder is probably an extreme form
of acute disseminated encephalomyelitis (ADEM), as
evidenced by cases with hemorrhagic conversion
from initially typical ADEM on magnetic resonance
imaging (MRI) scanning. There are multifocal
hemorrhagic lesions in the white matter of the brain,
variable brain edema, and mixed red blood cells and
leukocytes with increased protein and normal glu-
cose in the cerebrospinal fluid. Brain biopsy shows
perivenous demyelination and hemorrhages of vari-
able size.
Patients become acutely ill within 2 weeks of an
upper respiratory infection with headache, stiff neck,
fever, and confusion. They then develop focal or
multifocal neurological signs related to disease in the
cerebral hemispheres and/or brainstem. The former
include focal seizures, hemiplegia, and pseudobulbar
palsy. Consciousness is almost always impaired, with
stupor and then coma. Occasionally, it less severe
and more focal; the spinal cord may be involved.
The differential diagnosis often includes herpes
simplex encephalitis, hematological disorders (such
as thrombotic thrombocytopenic purpura), cortical
vein thrombosis, acute toxic encephalopathy (Reye’s
syndrome in younger children), hypoxic–ischemic
encephalopathy, and status epilepticus from various
causes.
Because of the rarity of the syndrome, no treat-
ment trials have been conducted. Vigorous treatment
of raised intracranial pressure is usually instituted
with mannitol, hyperventilation, and corticosteroids.
The autoimmune/vascular component has been
treated with corticosteroids, plasmapheresis, and
cyclophosphamide.
—G. Bryan Young
See also–Acute Disseminated Encephalomyelitis
(ADEM); Anoxic-Ischemic Encephalopathy;
36 ACUTE MOTOR AND SENSORY AXONAL NEUROPATHY
Encephalitis, Viral; Sepsis-Associated
Encephalopathy; Toxic Encephalopathy; Uremic
Encephalopathy; Wernicke’s Encephalopathy
Further Reading
Atlas, S. W., Grossman, R. I., Goldberg, H. I., et al. (1986). MR
diagnosis of acute disseminated encephalomyelitis. J. Comput.
Assist. Tomogr. 10, 798–801.
Dangond, F., Lacomis, D., Schwartz, E. B., et al. (1981). Acute
disseminated encephalomyelitis progressing to hemorrhagic
encephalitis. Neurology 41, 1697–1698.
Hurst, E. W. (1941). Acute hemorrhagic leucoencephalitis: A
previously undefined entity. Med. J. Aust. 1, 1–6.
Seales, D., and Greer, M. (1991). Acute hemorrhagic leukoence-
phalitis. A successful recovery. Arch. Neurol. 48, 1086–1088.
Acute Motor and Sensory
Axonal Neuropathy (AMSAN)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACUTE motor and sensory axonal neuropathy
(AMSAN) is a subtype of Guillain–Barré syndrome
(GBS). It is an autoimmune disease in which the
immune system mistakenly attacks the axons of the
peripheral nerves and causes flaccid paralysis.
HISTORY
The concepts of GBS have evolved considerably since
it was first described. In 1859, Landry reported nine
cases of acute flaccid paralysis. Because of the
absence of central nervous system changes, he
attributed the paralysis to peripheral nerve disease.
By 1893, Bury and Ross were able to review 93
published cases, but a variety of causes of acute
flaccid paralysis were undoubtedly included. The
literature became easier to interpret after 1916, when
Guillain, Barré, and Strohl codified ‘‘their’’ syndrome
of relatively symmetrical, rapidly evolving flaccid
paralysis (areflexia) and the characteristic laboratory
finding (elevated spinal fluid protein without cells).
The hallmark study of GBS by Asbury and colleagues
30 years ago identified lymphocytic infiltration and
macrophage-mediated demyelination as characteris-
tic features of the early pathology. Thus, the clinical
term GBS came to be used interchangeably with the
pathologic term acute inflammatory demyelinating
polyneuropathy (AIDP). Based on the analogy with
experimental allergic neuritis, the pathogenesis of
GBS was presumed to be a cell-mediated immune
attack on intrinsic myelin proteins.
However, in 1986, Feasby et al. described five
patients with the clinical diagnosis of GBS. All five
patients had electrically inexcitable motor nerves and
were quadriplegic. One patient died and three of four
survivors showed poor recovery. Autopsy studies on
the fatal case showed severe axonal degeneration in
nerve roots and distal nerves without inflammation
or demyelination. Feasby et al. suggested that these
patients represented a separate clinicopathological
entity and constituted a variant of GBS characterized
by an acute axonal neuropathy. This notion was
challenged by many investigators since inexcitable
nerves can also be caused by primary demyelination
with severe secondary demyelination or distal con-
duction block and not by primary immune attack
against axons.
The notion that axons can be primary targets of
attack in GBS gained further support after a series of
reports by a team of Chinese and American
researchers led by Dr. Guy McKhann. Every summer,
hundreds of Chinese children from the rural region
of northern China developed a clinical syndrome
consistent with GBS. McKhann et al. discovered that
approximately two-thirds of the children had axonal
changes on electromyograph (EMG), whereas the
remaining one-third had demyelinating changes. Of
the children with the axonal pattern, the majority
showed a unique pattern in which motor axons were
strikingly abnormal, with relatively sparing of
sensory axons. Despite the axonal pattern on the
EMG, most patients recovered as in typical demye-
linating GBS. Pathologically, patients with axonal
changes on EMG had periaxonal macrophages
(Fig. 1) in the ventral roots and peripheral nerves
with limited lymphocytic inflammation. This disease
pattern was designated acute motor axonal neuro-
pathy (AMAN).
Although the majority of children had only motor
nerve involvement, a few children also had severe
sensory nerve involvement. These children were
more severely affected and were overrepresented in
the autopsy series. Pathologically, like the AMAN
cases, they also had characteristic periaxonal macro-
phages and little lymphocytic inflammation, suggest-
ing that the two patterns may be closely related. This
pattern was termed acute motor–sensory axonal
neuropathy and is thought to be related to the cases
described by Feasby et al. A scheme for categorizing
the various patterns of GBS is shown in Fig. 2.
36 ACUTE MOTOR AND SENSORY AXONAL NEUROPATHY
Encephalitis, Viral; Sepsis-Associated
Encephalopathy; Toxic Encephalopathy; Uremic
Encephalopathy; Wernicke’s Encephalopathy
Further Reading
Atlas, S. W., Grossman, R. I., Goldberg, H. I., et al. (1986). MR
diagnosis of acute disseminated encephalomyelitis. J. Comput.
Assist. Tomogr. 10, 798–801.
Dangond, F., Lacomis, D., Schwartz, E. B., et al. (1981). Acute
disseminated encephalomyelitis progressing to hemorrhagic
encephalitis. Neurology 41, 1697–1698.
Hurst, E. W. (1941). Acute hemorrhagic leucoencephalitis: A
previously undefined entity. Med. J. Aust. 1, 1–6.
Seales, D., and Greer, M. (1991). Acute hemorrhagic leukoence-
phalitis. A successful recovery. Arch. Neurol. 48, 1086–1088.
Acute Motor and Sensory
Axonal Neuropathy (AMSAN)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ACUTE motor and sensory axonal neuropathy
(AMSAN) is a subtype of Guillain–Barré syndrome
(GBS). It is an autoimmune disease in which the
immune system mistakenly attacks the axons of the
peripheral nerves and causes flaccid paralysis.
HISTORY
The concepts of GBS have evolved considerably since
it was first described. In 1859, Landry reported nine
cases of acute flaccid paralysis. Because of the
absence of central nervous system changes, he
attributed the paralysis to peripheral nerve disease.
By 1893, Bury and Ross were able to review 93
published cases, but a variety of causes of acute
flaccid paralysis were undoubtedly included. The
literature became easier to interpret after 1916, when
Guillain, Barré, and Strohl codified ‘‘their’’ syndrome
of relatively symmetrical, rapidly evolving flaccid
paralysis (areflexia) and the characteristic laboratory
finding (elevated spinal fluid protein without cells).
The hallmark study of GBS by Asbury and colleagues
30 years ago identified lymphocytic infiltration and
macrophage-mediated demyelination as characteris-
tic features of the early pathology. Thus, the clinical
term GBS came to be used interchangeably with the
pathologic term acute inflammatory demyelinating
polyneuropathy (AIDP). Based on the analogy with
experimental allergic neuritis, the pathogenesis of
GBS was presumed to be a cell-mediated immune
attack on intrinsic myelin proteins.
However, in 1986, Feasby et al. described five
patients with the clinical diagnosis of GBS. All five
patients had electrically inexcitable motor nerves and
were quadriplegic. One patient died and three of four
survivors showed poor recovery. Autopsy studies on
the fatal case showed severe axonal degeneration in
nerve roots and distal nerves without inflammation
or demyelination. Feasby et al. suggested that these
patients represented a separate clinicopathological
entity and constituted a variant of GBS characterized
by an acute axonal neuropathy. This notion was
challenged by many investigators since inexcitable
nerves can also be caused by primary demyelination
with severe secondary demyelination or distal con-
duction block and not by primary immune attack
against axons.
The notion that axons can be primary targets of
attack in GBS gained further support after a series of
reports by a team of Chinese and American
researchers led by Dr. Guy McKhann. Every summer,
hundreds of Chinese children from the rural region
of northern China developed a clinical syndrome
consistent with GBS. McKhann et al. discovered that
approximately two-thirds of the children had axonal
changes on electromyograph (EMG), whereas the
remaining one-third had demyelinating changes. Of
the children with the axonal pattern, the majority
showed a unique pattern in which motor axons were
strikingly abnormal, with relatively sparing of
sensory axons. Despite the axonal pattern on the
EMG, most patients recovered as in typical demye-
linating GBS. Pathologically, patients with axonal
changes on EMG had periaxonal macrophages
(Fig. 1) in the ventral roots and peripheral nerves
with limited lymphocytic inflammation. This disease
pattern was designated acute motor axonal neuro-
pathy (AMAN).
Although the majority of children had only motor
nerve involvement, a few children also had severe
sensory nerve involvement. These children were
more severely affected and were overrepresented in
the autopsy series. Pathologically, like the AMAN
cases, they also had characteristic periaxonal macro-
phages and little lymphocytic inflammation, suggest-
ing that the two patterns may be closely related. This
pattern was termed acute motor–sensory axonal
neuropathy and is thought to be related to the cases
described by Feasby et al. A scheme for categorizing
the various patterns of GBS is shown in Fig. 2.
 ACUTE MOTOR AND SENSORY AXONAL NEUROPATHY 37

elevation without an increase in cells, the hallmark

of AIDP, is also seen in both AMAN and AMSAN
variants of GBS. Cerebrospinal fluid protein begins
to increase after 7–14 days and is not a necessary
finding for initial diagnosis.
Additionally, many patients show elevation of
anti-ganglioside antibodies. Importantly, specific
anti-ganglioside antibodies have been associated
with different forms of GBS. For example, anti-
Gq1b antibody is seen most commonly in the Fisher
syndrome and anti-GD1a antibody in both AMAN
and AMSAN patterns. On the other hand, anti-GM1
antibody is commonly seen in both AIDP and
AMAN patterns.

Course
Weakness progresses in an unpredictable fashion,
Figure 1 occasionally with alarming rapidity. In approxi-
A macrophage (M) from an AMAN case is seen infiltrating the mately 50% of patients, progression halts by 2
node of Ranvier (N) and attacking the axon (arrowheads). Arrows weeks and a nadir is reached by 4 weeks in
indicate myelin.
approximately 90%. One should question the
diagnosis if nadir is not reached by this time or the
CLINICAL PRESENTATION course is waxing and waning. Recovery of both
AIDP and AMAN patients follows a similar course
The presentation of patients with GBS is described in over a 4-week to 6-month period. In AMSAN
the entry on GBS. Like typical AIDP patients, patients with inexcitable nerves, recovery is often
patients with the AMSAN pattern of GBS report slow and incomplete.
weakness of the legs and paresthesiae as their first
symptoms. These symptoms are often followed by
weakness of the arms and choking on fluids. DIAGNOSIS
However, any distribution, including cranial nerve In fully developed and typical GBS, the diagnosis is
involvement, may be present from the onset. rarely problematic. Using a combination of clinical
Common antecedent events include symptoms of and electrodiagnostic criteria, it is usually straight-
upper respiratory infection and diarrhea. Serological forward to distinguish among AIDP, AMAN, and
studies have shown that antecedent infection with the Fisher syndrome. Electrophysiologically, both
Campylobacter or Mycoplasma is common. AMAN and AMSAN patients show low compound
Loss of tendon reflexes is the hallmark of AMSAN;
even in mild cases, reflexes are typically lost. Muscle
wasting is a common sign of axonal degeneration.
This feature can be seen with either AMAN or AIDP
with secondary axonal degeneration. Sensory invol-
vement is typically mild in relation to motor
dysfunction. Paresthesiae or vague aching in the
back, calves, and feet may be described at the onset.
Unlike patients with AMAN, in whom little sensory
deficit can be found, patients with AMSAN are often
found to have loss of vibration and, less frequently,
proprioception. Many AMSAN patients require
ventilatory support because of respiratory muscle
weakness.
Laboratory abnormalities are restricted to the Figure 2
spinal fluid in most cases. The typical protein Classification of GBS.
38 ACUTE MOTOR AND SENSORY AXONAL NEUROPATHY
muscle action potentials without evidence of demye-
lination (such as excessive slowing of conduction
velocity, lengthening of the F-wave, or an increase
in distal latency). Sensory nerve conduction studies
are often abnormal in AMSAN cases but not in
AMAN cases. However, in severe AMSAN patients
who present with inexcitable nerve, it can be diffi-
cult to differentiate AMSAN from severe AIDP. An
inexcitable nerve can be due either to primary
immune attack to the axon or to secondary
degeneration of axons following immune-mediated
destruction of myelin. At the onset of AIDP, features
of demyelination may be demonstrable. However,
once compound muscle action potentials and sen-
sory nerve action potentials are severely reduced
or absent, the electrophysiological distinction be-
tween AIDP with nerve terminal demyelination,
AIDP with severe secondary axonal degeneration,
and AMSAN with primary immune attack on the
axon is not possible. Thus, in severe cases of GBS
early electrodiagnostic studies are often particularly
helpful.
DIFFERENTIAL DIAGNOSIS
The Fisher syndrome is readily diagnosed by its
distinctive clinical picture of ataxia, ophthalmopar-
esis, and areflexia, with relatively preserved or
normal strength. Nonneuropathic disorders, includ-
ing botulism, tick paralysis, and poliomyelitis,
should be excluded. In addition, other neuropathies
can produce similar pictures as those of the other
GBS variants. Acute intermittent porphyria can
produce an abrupt motor neuropathy, and increased
excretion of porphobilinogen in the urine is diag-
nostic during the acute phase of this disorder. The
diagnosis can be confirmed by quantitative porphyr-
ins and d-aminolevulinic acid determinations in the
urine. Diphtheritic neuropathy, due to pharyngeal or
wound infection, is a concern in unvaccinated
individuals. Occasionally, toxic neuropathies such
as lead exposure can produce clinical manifestations
resembling GBS. In particular, exposure to neuro-
toxic hexacarbons, either on an occupational basis or
because of chronic use as an intoxicant (glue or paint
sniffing), can produce a subacutely evolving poly-
neuropathy with marked reduction in conduction
velocity.
Diagnosis may be more difficult early in the
disease. The initial physician contact is often made
when symptoms are limited to paresthesiae, aching
pain in the extremities or back, and mild weakness.
At this stage, both lumbar puncture and nerve
conduction studies may be normal. Widespread
areflexia or hyporeflexia should suggest the possibi-
lity of GBS.
PATHOLOGY
In the axonal patterns of GBS, lymphocytic infiltra-
tion is typically absent or scanty. In general, both
AMAN and AMSAN share many pathological
features, with the difference that AMSAN cases
exhibit involvement of sensory nerves and roots. In
addition, autopsy cases of AMAN exhibit milder
pathology than that observed in AMSAN cases. The
earliest identifiable changes are in the nodes of
Ranvier of motor fibers; specifically, nodal gap
lengthens at time points when the fibers appear
otherwise normal. Immunopathologically, this
change correlates with the binding of IgG and the
activation of complement, as reflected by the
presence of the complement activation marker C3d
on the node of Ranvier. Early on, macrophages are
recruited to the node of Ranvier, perhaps because of
the attraction from C5a and other complement-
derived chemoattractants. These macrophages insert
processes into the nodal gap, penetrating the over-
lying basal lamina of the Schwann cell. The macro-
phages then encircle the node and frequently dissect
beneath the myelin sheath attachment sites of the
paranode to enter the periaxonal space of the
internode.
Many fibers express complement activation mar-
kers in the periaxonal space (the 11-nm space
between the axolemma and the adaxonal Schwann
cell plasmalemma). The periaxonal space is normally
extremely regular in its spacing, and it is sealed from
both ions and macromolecules of the endoneurial
fluid by junctional complexes between the myelin
terminal loops and the axolemma. The intrusion of
the macrophage probably opens the periaxonal space
to endoneurial constituents, allowing antibody and
complement to enter the internodal region. Immu-
nocytochemical studies have demonstrated that the
antigen to which IgG binds is on the axolemma (as it
is in the node of Ranvier). Once macrophages have
invaded the periaxonal space, the axon collapses
away from the Schwann cell, resulting in a marked
dilatation of the periaxonal space. However, the
axon appears to survive for some time, although it is
surrounded by macrophages. The end stage of this
process is widespread axonal degeneration of the
fibers.

TREATMENT
The care of AMSAN patients is like that of other
subtypes of GBS. Both plasmapheresis and intrave-
nous human immunoglobulin are beneficial in AIDP.
Whether these therapies are also effective in AMAN
or AMSAN has not been tested in large clinical trials.
However, from small series and anecdotal reports,
AMAN and AMSAN appear to be responsive to both
plasma exchange and immunoglobulin therapies.
PATHOPHYSIOLOGY
Several lines of evidence indicate that ‘‘molecular
mimicry’’ plays an important role in the pathogenesis
of GBS and its variants. Molecular mimicry occurs
when the immune response to specific antigens in
infectious organisms is directed against cross-reactive
epitopes in the host. As noted previously, many GBS
patients develop anti-ganglioside antibodies. Anti-
GD1a antibody has been linked to both AMAN and
AMSAN. Anti-GQ1b antibody has been linked to
the Fisher variant of GBS. Careful localization
showed that GD1a epitopes are enriched in motor
axons and that GQ1b is enriched in oculomotor
nerves. These localization studies gave satisfying
correspondence to the clinical features of different
variants of GBS. In addition, specific antecedent
infections, dominated by Campylobacter, Mycoplas-
ma, and Cytomegalovirus, precede GBS. Detailed
analysis of the surface antigens of Campylobacter
has shown evidence of ganglioside-like epitopes, such
as GM1, GQ1b, and GD1a, on the lipopolysacchar-
ide (LPS) of the bacteria. Thus, the following is a
possible pathophysiological mechanism:
1. Infection with a strain of Campylobacter jejuni,
which has specific carbohydrate antigens on the
inner core portion of the LPS.
2. Development, by the host, of antibodies to this
carbohydrate moiety.
3. Antibody binding and complement activation
on shared antigens located on the nodal
axolemma.
4. Lengthening of the node and opening of the
paranodal space, with entry of antibody and
complement into the periaxonal space of some
fibers.
5. Recruitment of macrophages to the node and
the internodal periaxonal spaces.
6. In severe cases, axonal degeneration results.
—Tony Ho
ADDISON’S DISEASE 39
See also–CIDP (Chronic Inflammatory
Demyelinating Polyradiculoneuropathy);
Guillain-Barré Syndrome, Clinical Aspects;
Guillain-Barré Syndrome, Neuroimmunology of
Further Reading
Asbury, A. K. (2000). New concepts of Guillain–Barré syndrome.
J. Child Neurol. 15, 183–191.
Ho, T., and Griffin, (1999). Guillain–Barré syndrome. Curr. Opin.
Neurol. 12, 389–394.
Ho, T. W., McKhann, G. M., and Griffin, J. W. (1998). Human
autoimmune neuropathies. Annu. Rev. Neurosci. 21, 187–226.
Hughes, R. A., Hadden, R. D., Gregson, N. A., et al. (1999).
Pathogenesis of Guillain–Barré syndrome. J. Neuroimmunol.
100, 74–97.
Addison’s Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THOMAS ADDISON described patients with skin
bronzing, asthenia, and hypotension who at autopsy
had enlarged adrenal glands infected with tubercu-
losis. He published his classic book, On the
Constitutional and Local Effects of Disease of the
Supra Renal Capsules, in 1855. Today, Addison’s
disease (AD) is synonymous with primary adrenal
insufficiency of any etiology; consequently, this entry
does not discuss secondary adrenal insufficiency or
adrenal axis suppression.
Adrenal insufficiency can result from congenital
defects in adrenal development or steroidogenesis,
adrenal destruction from infections or (very rarely)
cancer metastases, or, most commonly in developed
societies, from autoimmune disease (Table 1). The
diagnosis of adrenal insufficiency relies on a peak
plasma cortisol o18 mg/dl after stimulation with 250
mg ACTH (cosyntropin or tetracosactin). It is also
useful to measure plasma renin and aldosterone
because defects in mineralocorticoid production can
occur asynchronously with glucocorticoid deficiency
or not at all, aiding in the differential diagnosis.
Depending on the age of the patient, evaluation may
require measurement of other steroid hormones to
identify enzyme defects or other diagnostic tests to
tailor treatment. For example, elevated very long-
chain fatty acyl-CoA esters are diagnostic of X-
linked adrenoleukodystrophy syndromes, which
should always be considered in any young male with
AD, particularly when a family history in maternal
uncles or brothers exists.

TREATMENT
The care of AMSAN patients is like that of other
subtypes of GBS. Both plasmapheresis and intrave-
nous human immunoglobulin are beneficial in AIDP.
Whether these therapies are also effective in AMAN
or AMSAN has not been tested in large clinical trials.
However, from small series and anecdotal reports,
AMAN and AMSAN appear to be responsive to both
plasma exchange and immunoglobulin therapies.
PATHOPHYSIOLOGY
Several lines of evidence indicate that ‘‘molecular
mimicry’’ plays an important role in the pathogenesis
of GBS and its variants. Molecular mimicry occurs
when the immune response to specific antigens in
infectious organisms is directed against cross-reactive
epitopes in the host. As noted previously, many GBS
patients develop anti-ganglioside antibodies. Anti-
GD1a antibody has been linked to both AMAN and
AMSAN. Anti-GQ1b antibody has been linked to
the Fisher variant of GBS. Careful localization
showed that GD1a epitopes are enriched in motor
axons and that GQ1b is enriched in oculomotor
nerves. These localization studies gave satisfying
correspondence to the clinical features of different
variants of GBS. In addition, specific antecedent
infections, dominated by Campylobacter, Mycoplas-
ma, and Cytomegalovirus, precede GBS. Detailed
analysis of the surface antigens of Campylobacter
has shown evidence of ganglioside-like epitopes, such
as GM1, GQ1b, and GD1a, on the lipopolysacchar-
ide (LPS) of the bacteria. Thus, the following is a
possible pathophysiological mechanism:
1. Infection with a strain of Campylobacter jejuni,
which has specific carbohydrate antigens on the
inner core portion of the LPS.
2. Development, by the host, of antibodies to this
carbohydrate moiety.
3. Antibody binding and complement activation
on shared antigens located on the nodal
axolemma.
4. Lengthening of the node and opening of the
paranodal space, with entry of antibody and
complement into the periaxonal space of some
fibers.
5. Recruitment of macrophages to the node and
the internodal periaxonal spaces.
6. In severe cases, axonal degeneration results.
—Tony Ho
ADDISON’S DISEASE 39
See also–CIDP (Chronic Inflammatory
Demyelinating Polyradiculoneuropathy);
Guillain-Barré Syndrome, Clinical Aspects;
Guillain-Barré Syndrome, Neuroimmunology of
Further Reading
Asbury, A. K. (2000). New concepts of Guillain–Barré syndrome.
J. Child Neurol. 15, 183–191.
Ho, T., and Griffin, (1999). Guillain–Barré syndrome. Curr. Opin.
Neurol. 12, 389–394.
Ho, T. W., McKhann, G. M., and Griffin, J. W. (1998). Human
autoimmune neuropathies. Annu. Rev. Neurosci. 21, 187–226.
Hughes, R. A., Hadden, R. D., Gregson, N. A., et al. (1999).
Pathogenesis of Guillain–Barré syndrome. J. Neuroimmunol.
100, 74–97.
Addison’s Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THOMAS ADDISON described patients with skin
bronzing, asthenia, and hypotension who at autopsy
had enlarged adrenal glands infected with tubercu-
losis. He published his classic book, On the
Constitutional and Local Effects of Disease of the
Supra Renal Capsules, in 1855. Today, Addison’s
disease (AD) is synonymous with primary adrenal
insufficiency of any etiology; consequently, this entry
does not discuss secondary adrenal insufficiency or
adrenal axis suppression.
Adrenal insufficiency can result from congenital
defects in adrenal development or steroidogenesis,
adrenal destruction from infections or (very rarely)
cancer metastases, or, most commonly in developed
societies, from autoimmune disease (Table 1). The
diagnosis of adrenal insufficiency relies on a peak
plasma cortisol o18 mg/dl after stimulation with 250
mg ACTH (cosyntropin or tetracosactin). It is also
useful to measure plasma renin and aldosterone
because defects in mineralocorticoid production can
occur asynchronously with glucocorticoid deficiency
or not at all, aiding in the differential diagnosis.
Depending on the age of the patient, evaluation may
require measurement of other steroid hormones to
identify enzyme defects or other diagnostic tests to
tailor treatment. For example, elevated very long-
chain fatty acyl-CoA esters are diagnostic of X-
linked adrenoleukodystrophy syndromes, which
should always be considered in any young male with
AD, particularly when a family history in maternal
uncles or brothers exists.
40 ADENOVIRUSES

Table 1 CAUSES OF ADRENAL INSUFFICIENCYa See also–Adrenal Gland; Cushing Syndrome;

Myopathy, Endocrine
Adrenal Adrenal hypoplasia congenita, ACTH receptor
development mutation, triple A syndrome,b SF-1
deficiency Further Reading
Enzyme 21-Hydroxylase, 11-hydroxylase, 3-b- Ten, S., New, M., and Maclaren, N. (2001). Clinical review 130:
deficiencies hydroxysteroid dehydrogenase/isomerase, Addison’s disease 2001. J. Clin. Endocrinol. Metab. 86, 2909–
lipoid CAH 2922.
Infection Tuberculosis, fungal, viral (CMV, HIV-1)
Autoimmune Isolated, APS-1, APS-2
Destruction/ Metastatic cancer, hemochromatosis,
toxic insult hemorrhage or thrombosis,
adrenoleukodystrophy
Adenoviruses
a
Abbreviations used: APS, autoimmune polyglandular syn- Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
drome; CAH, congenital adrenal hyperplasia; CMV, cytomegalo-
virus.
b
Alacrima, achalasia, and Addison’s disease. ROWE and colleagues first isolated adenoviruses
(AdVs) in 1953 from human adenoidal tissue. There
are now more than 90 isolated strains, of which
approximately 50 are of human origin. Human AdVs
In general, treatment centers on glucocorticoid
have been classified into six groups, A–F, based on
replacement, usually hydrocortisone or prednisone,
their similarity with respect to oncogenic and
supplemented with liberal salt intake and sometimes
hemagglutination properties, DNA sequence, and
9-a-fludrocortisone as mineralocorticoid. The corti-
electrophoretic mobility patterns of their polypep-
sol production rate is 8–10 mg/m2/day in human
tides. Because one of the serotypes, AdV 12, was
beings, which means that the average individual
shown to cause tumors in rodents, and because
produces approximately 12–15 mg of cortisol daily.
almost all the serotypes have been shown to trans-
Oral administration of 20–25 mg of cortisol (hydro-
form rodent cells, AdVs were classified as tumor
cortisone) per day is usually sufficient to compensate
viruses. However, none of these viruses have been
for losses due to incomplete absorption and first-pass
shown to be associated with malignancies in humans.
hepatic metabolism. Doses are divided to give 15–20
For many years, AdVs have been a model system to
mg in the morning and 5–10 mg in the early
study eukaryotic gene expression and virus–host
afternoon (not evening) to resemble the diurnal
interactions, and this has led to a better under-
rhythm. An exception is in treatment of 21-hydro-
standing of viral and cellular gene expression and
xylase deficiency, whose treatment nuances are
regulation, DNA replication, cell cycle control, and
beyond the scope of this entry. The mineralocorticoid
cellular growth regulation and clarification of a
activity of hydrocortisone can allow monotherapy in
variety of molecular processes. AdVs are an infre-
many patients, particularly if salt intake is generous,
quent cause of infections of the central nervous
but some patients require 0.05–0.2 mg/day 9-a-
system (CNS). Recently, they have become of interest
fludrocortisone to eliminate orthostasis and to
to clinical and basic neuroscientists because of their
normalize plasma renin.
use as virus vectors for gene delivery to neural cells.
Patients are instructed to increase their hydro-
cortisone dose in times of physiological stress. I ask
patients to double their dose for minor illnesses (viral
VIRUS STRUCTURE AND
syndromes) only if fever and vomiting, diarrhea, or
GENOME ORGANIZATION
poor oral intake occur. More severe illnesses, such as
pneumonia, require tripling the dose and usually AdVs are nonenveloped, icosahedral in shape, and
require hospitalization or at least direct physician 70–100 nm in diameter. The virion has 20 triangular
evaluation. Hydrocortisone dosing should not be surfaces and 12 vertices, with a fiber-shaped struc-
routinely increased for trivial illnesses because ture projecting from each of these vertices. The viral
chronic overreplacement can lead to compromised coat consists of 252 subunits, of which 240 are
bone density, thin skin, and other manifestations of hexon proteins and 12 are penton proteins. The viral
Cushing syndrome. genome is a linear DNA of approximately 36,000
—Richard J. Auchus base pairs (bp) that is divided into 100 map units,
40 ADENOVIRUSES

Table 1 CAUSES OF ADRENAL INSUFFICIENCYa See also–Adrenal Gland; Cushing Syndrome;

Myopathy, Endocrine
Adrenal Adrenal hypoplasia congenita, ACTH receptor
development mutation, triple A syndrome,b SF-1
deficiency Further Reading
Enzyme 21-Hydroxylase, 11-hydroxylase, 3-b- Ten, S., New, M., and Maclaren, N. (2001). Clinical review 130:
deficiencies hydroxysteroid dehydrogenase/isomerase, Addison’s disease 2001. J. Clin. Endocrinol. Metab. 86, 2909–
lipoid CAH 2922.
Infection Tuberculosis, fungal, viral (CMV, HIV-1)
Autoimmune Isolated, APS-1, APS-2
Destruction/ Metastatic cancer, hemochromatosis,
toxic insult hemorrhage or thrombosis,
adrenoleukodystrophy
Adenoviruses
a
Abbreviations used: APS, autoimmune polyglandular syn- Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
drome; CAH, congenital adrenal hyperplasia; CMV, cytomegalo-
virus.
b
Alacrima, achalasia, and Addison’s disease. ROWE and colleagues first isolated adenoviruses
(AdVs) in 1953 from human adenoidal tissue. There
are now more than 90 isolated strains, of which
approximately 50 are of human origin. Human AdVs
In general, treatment centers on glucocorticoid
have been classified into six groups, A–F, based on
replacement, usually hydrocortisone or prednisone,
their similarity with respect to oncogenic and
supplemented with liberal salt intake and sometimes
hemagglutination properties, DNA sequence, and
9-a-fludrocortisone as mineralocorticoid. The corti-
electrophoretic mobility patterns of their polypep-
sol production rate is 8–10 mg/m2/day in human
tides. Because one of the serotypes, AdV 12, was
beings, which means that the average individual
shown to cause tumors in rodents, and because
produces approximately 12–15 mg of cortisol daily.
almost all the serotypes have been shown to trans-
Oral administration of 20–25 mg of cortisol (hydro-
form rodent cells, AdVs were classified as tumor
cortisone) per day is usually sufficient to compensate
viruses. However, none of these viruses have been
for losses due to incomplete absorption and first-pass
shown to be associated with malignancies in humans.
hepatic metabolism. Doses are divided to give 15–20
For many years, AdVs have been a model system to
mg in the morning and 5–10 mg in the early
study eukaryotic gene expression and virus–host
afternoon (not evening) to resemble the diurnal
interactions, and this has led to a better under-
rhythm. An exception is in treatment of 21-hydro-
standing of viral and cellular gene expression and
xylase deficiency, whose treatment nuances are
regulation, DNA replication, cell cycle control, and
beyond the scope of this entry. The mineralocorticoid
cellular growth regulation and clarification of a
activity of hydrocortisone can allow monotherapy in
variety of molecular processes. AdVs are an infre-
many patients, particularly if salt intake is generous,
quent cause of infections of the central nervous
but some patients require 0.05–0.2 mg/day 9-a-
system (CNS). Recently, they have become of interest
fludrocortisone to eliminate orthostasis and to
to clinical and basic neuroscientists because of their
normalize plasma renin.
use as virus vectors for gene delivery to neural cells.
Patients are instructed to increase their hydro-
cortisone dose in times of physiological stress. I ask
patients to double their dose for minor illnesses (viral
VIRUS STRUCTURE AND
syndromes) only if fever and vomiting, diarrhea, or
GENOME ORGANIZATION
poor oral intake occur. More severe illnesses, such as
pneumonia, require tripling the dose and usually AdVs are nonenveloped, icosahedral in shape, and
require hospitalization or at least direct physician 70–100 nm in diameter. The virion has 20 triangular
evaluation. Hydrocortisone dosing should not be surfaces and 12 vertices, with a fiber-shaped struc-
routinely increased for trivial illnesses because ture projecting from each of these vertices. The viral
chronic overreplacement can lead to compromised coat consists of 252 subunits, of which 240 are
bone density, thin skin, and other manifestations of hexon proteins and 12 are penton proteins. The viral
Cushing syndrome. genome is a linear DNA of approximately 36,000
—Richard J. Auchus base pairs (bp) that is divided into 100 map units,

with each map unit representing 360 bp. The DNA
contains inverted terminal repeat sequences ranging
in length from approximately 100 to 140 bp
depending on the serotype, which play an important
role in the replication of the viral genome. Both
strands of the viral genome are transcribed during an
early and late phase of infection that are separated by
the onset of viral DNA replication. The early genes
that are transcribed include E1A, E1B, E2A, E2B,
E3, and E4. The late genes are transcribed from a
major late promoter into a long primary transcript
that undergoes extensive splicing and polyadenyla-
tion.
VIRUS INFECTION AND
DISEASE PATHOGENESIS
The AdV serotypes from subgroups A, C, D, E, and F
bind to a cell surface receptor called coxsackievirus
and adenovirus receptor. The virus then enters the
cell by endocytosis following interaction between the
viral capsid penton base with cell surface integrins
aVb3 and aVb5. The acidification of the endosome
causes a conformational change and dissociation of
capsid proteins with the release of an unstable virion
into the cytoplasm. The virion is then transported to
the nucleus of the cell, where the viral genome is
released and undergoes transcription. The AdV life
cycle is divided into early and late phases by the
onset of viral DNA replication.
AdVs can cause varied diseases. Infection of the
upper respiratory tract can result in acute febrile
pharyngitis, accounting for 5–15% of cases of the
common cold. Other illnesses include keratoconjuc-
tivitis, gastroenteritis, pneumonia, bronchitis, hepa-
titis, and acute hemorrhagic cystitis. Most of these
infections lead to self-limited illness or a latent
persistent asymptomatic infection. Some AdV sero-
types manifest a particular tissue tropism and disease
association; for example, AdV serotypes 8, 19, and
37 are associated with virulent disease of the
conjunctiva.
ADENOVIRUS CENTRAL NERVOUS
SYSTEM INFECTIONS
A number of AdV serotypes (including 1–3, 5–7, 12,
and 32) have been isolated from the cerebrospinal
fluid of patients with meningitis and encephalitis,
suggesting a role for this virus in the pathogenesis of
CNS disease. Most of these cases have involved
children between ages 1 and 12 years, with few
ADENOVIRUSES 41
fatalities; for example, the presence of AdV type 11
was reported in the brain of a newborn infant with
pneumonia associated with encephalitis. AdV infec-
tion has also been associated with Reye’s syndrome,
although not as frequently as it is associated with
influenza and varicella-zoster viruses. Some AdV
CNS infections have been opportunistic, occurring in
immunocompromised states, such as lymphoma,
agammaglobulinemia, thymic alymphopenia, renal
transplant, and acquired immune deficiency syn-
drome (AIDS). Serotypes 1, 2, 4–6, and 11 have been
implicated in non-AIDS opportunistic infections,
whereas infections in AIDS patients have mostly
involved serotypes 34, 35, and, in a few cases, types
7, 31, and 49. The AdVs have been isolated from the
cerebrospinal fluid and CNS tissue of AIDS patients
with encephalitis. Intranuclear inclusions have been
detected in the subependymal regions, and viral
hexon protein has been detected in neurons.
Although AdV has not been linked to CNS tumor
formation in humans, inoculation of AdV type 12
intraperitoneally, intravitreously, or intracerebrally
into newborn hamsters or rats produces tumors in
the CNS.
Most AdVs are species specific for replication,
although there is some cross-infectivity between
closely related species. Although species specificity
affects replication of the virus, it does not affect virus
adsorption, penetration, and synthesis of early
proteins.
Mouse AdV-1 (MAV-1) has been shown to induce
acute fatal hemorrhagic encephalitis following in-
traperitoneal inoculation of the virus. Acute CNS
disease symptoms include tremors, seizures, ataxia,
and paralysis in C57BL/6 mice. Petechial hemor-
rhages, edema, neovascularization, and mild inflam-
mation in the brain and spinal cord are seen. Electron
microscope analysis shows evidence of inflammation,
such as activated microglia, as well as swollen
astrocytic endfeet and perivascular lipid deposition
indicative of blood–brain barrier dysfunction. In-
fectious virus was present in the brain and spinal
cord but not in other organs, indicating a tropism for
the CNS that is mouse strain dependent.
ADV AS A VECTOR FOR GENE THERAPY OF
CNS DISEASES
Recombinant replication-deficient AdVs have a
number of desirable properties as virus vectors for
gene delivery: (i) There is a large amount of
molecular biological information on the virus,
42 ADENOVIRUSES
enabling manipulation of the genome with relative
ease; (ii) AdV has a long history of use as a safe and
effective vaccinating agent; (iii) the oncogenic risk
can be virtually eliminated by deleting E1 genes; (iv)
the virus can be grown to high titers; (v) high levels
of gene expression can be achieved; (vi) AdVs remain
extrachromosomal; and (vii) AdVs have a broad host
range and can infect quiescent or terminally differ-
entiated cells such as neurons. This latter property
has made the replication-defective AdVs especially
attractive vectors for the in vitro and in vivo
expression of foreign genes within neurons. It should
also be noted that AdV vectors have been used as a
neurobiological tool to deliver and express trans-
genes in primary neuronal cells, a cell type that is not
efficiently transfected using conventional means.
Recombinant AdV vectors are generally based on
group C serotypes 2 and 5 since these serotypes have
not been associated with severe illnesses and do not
cause tumors in animals. The general strategy to
express proteins using AdV as a vector involves
deletions in the E1 and possibly the E3 regions of the
AdV genome and the insertion of cDNA of the
transgene of interest in E1, E3, near E4, or down-
stream of the major late promoter. Deletion of the E1
gene virtually eliminates viral replication, whereas
the additional deletion of E3 allows more space for
gene insertion. The AdV vectors are grown in
cultured cells that constitutively express the neces-
sary AdV genes in trans that are missing from the
vector’s genome and are important in viral replica-
tion.
Several studies have reported AdV-mediated deliv-
ery of genes into the CNS via varied routes, including
delivery into the parenchyma and ventricular space.
Direct injection of recombinant AdV into the rodent
CNS leads to expression of the transgene in
oligodendrocytes, astrocytes, neurons, and ependy-
ma. In highly myelinated areas with a compact
cellular structure (e.g., the cortex and olfactory
bulb), expression is limited to the region close to
the injection needle, whereas more widespread
transgene expression is observed in areas with a
laminar structure (e.g., the hippocampus).
Transport of AdV vectors from the periphery to
the CNS may serve as an attractive route for gene
delivery to motor neurons. Studies have demon-
strated efficient reporter gene transfer into CNS
motor and sensory neurons that innervate the
inoculated muscles following intramuscular injection
of AdV. Inoculation of the tongue of a mouse with
AdV expressing the Escherichia coli lacZ gene led to
robust b-galactosidase (b-gal) activity of the hypo-
glossal motor nerve nuclei, whereas b-gal staining
was detected in the anterior horn cells in the spinal
cord following injection of the lower extremity
muscle. Similar results were seen following intra-
muscular inoculation of AdV of a mouse that carried
a mutant superoxide dismutase type 1 gene asso-
ciated with familial amyotrophic lateral sclerosis. b-
gal activity was observed in both sensory and motor
nerve roots in the brain stem and spinal cord,
demonstrating anterograde and retrograde axonal
flow. The presence of b-gal in second-order sensory
neurons (trigeminal spinal nucleus and nucleus
solitarius) suggested that transsynaptic spread had
occurred following the inoculation (and after passage
through the neuromuscular junction and into the
peripheral nerve). Studies demonstrated that the
expression of the transgene was a result of the
delivery of genes rather than, or in addition to, a
retrograde axonal flow of b-gal enzyme. In other
experiments that suggested transsynaptic spread,
nasal instillation of AdV resulted in gene expression
in mitral cells from the olfactory bulb, locus
coeruleus, area postrema, and neurons from the
anterior olfactory nucleus.
Recombinant AdVs have been studied with respect
to their potential use in cerebrovascular diseases,
specifically in the relief of vasospasm following
subarachnoid hemorrhage. The feasibility of using
AdVs in gene transfer into the cerebral blood vessels,
perivascular tissue, and subarachnoid space of
experimental animals has been explored. Some
studies have involved AdV expressing nitric oxide
synthase, thereby leading to nitric oxide formation
with subsequent augmentation of nitric oxide-in-
duced vasodilation. The relatively limited duration of
transgene expression following AdV delivery is taken
advantage of by this approach since vasospasm is a
transient problem.
Recombinant AdVs in the CNS have also been
investigated in the treatment of brain tumors. In
some cases, AdV expressing herpes simplex virus
thymidine kinase gene has been injected directly into
the CNS of an animal followed by administration of
ganciclovir. AdV has also been injected intraarterially
following opening of the blood–brain barrier with
osmotic shock.
ROLE OF HOST IMMUNE SYSTEM
Three coat proteins—hexon, penton, and fiber—
are antigenic and contain epitopes recognized by

neutralizing antibodies. The hexon and fiber proteins
contain virus group- and type-specific epitopes. The
type-specific anti-hexon neutralizing antibodies from
humans inhibit viral replication; however, they do
not block attachment or internalization of the virus.
In addition, as is the case with many other viruses,
AdVs have a number of genes and gene products that
interfere with the host immune response. For
example, E1A, VA RNA, and E3 antagonize a and
b interferons; E1A, VA RNA inhibit the cytolytic T
cell response; and E3 inhibits the effect of tumor
necrosis factor.
The role of the cellular and humoral immune
system in limiting AdV-mediated gene transfer
systemically and in the CNS has been under study.
A host immune response directed against the virion
capsid proteins in the inoculum, as well as against
products of the viral genes (and transgene), can limit
the duration of transgene expression and prevent
efficient gene expression following repeated admin-
istration of the vector. The duration of transgene
expression varies in AdV-transduced neural cells and
depends on the age of the host, the specific transgene,
and the route of vector delivery. Some studies have
reported CNS expression for at least 2 months after
infection, although the number of expressing cells
declines over time. The decline in expressing cells
may be due to a number of reasons, including the
presence of the immune response, promoter inactiva-
tion, or viral DNA degradation. The immunosup-
pressant drug FK506 (tacrolimus), which readily
crosses the blood–brain barrier, can extend the
duration of gene expression in the CNS of mice
following injection of the recombinant AdV; this
result emphasizes the importance of the immune
response in the limited duration of transgene expres-
sion. Interestingly, AdV vectors can elicit an inflam-
matory response both at the site of vector delivery in
the CNS and at more remote sites that are
synaptically linked. In addition, the vector can
remain a potential target for a destructive immune
response that induces local demyelination.
—Ghanashyam D. Ghadge and Raymond P. Roos
See also–Arboviruses, Encephalitis Caused by;
Enteroviruses; Viral Vaccines and Antiviral
Therapy
Further Reading
Charles, P. C., Guida, J. D., Brosnan, C. F., et al. (1998). Mouse
adenovirus type-1 replication is restricted to vascular endothe-
ADRENAL GLAND 43
lium in the CNS of susceptible strains of mice. Virology 245,
216–228.
Ghadge, G. D., Roos, R. P., Kang, U. J., et al. (1995). CNS gene
delivery by retrograde transport of recombinant replication-
defective adenoviruses. Gene Ther. 2, 132–137.
Osamura, T., Mizuta, R., Yoshioka, H., et al. (1993). Isolation of
adenovirus type 11 from the brain of a neonate with pneumonia
and encephalitis. Eur. J. Pediatr. 152, 496–499.
Pillay, D., Lipman, M. C., Lee, C. A., et al. (1993). A clinico-
pathological audit of opportunistic viral infections in HIV-
infected patients. AIDS 7, 969–974.
Roos, R. P. (1989). Adenovirus. In Handbook of Clinical
Neurology (R. R. McKendall, Ed.), pp. 281–293. Elsevier
Science, New York.
Rowe, W. C., Huebner, R. J., Gilmore, L. K., et al. (1953).
Isolation of a cytopathic agent from human adenoid undergoing
spontaneous degeneration in tissue culture. Proc. Soc. Exp.
Biol. Med. 84, 570–573.
Schnurr, D., Bollen, A., Crawford-Miksza, L., et al. (1995).
Adenovirus mixture isolated from the brain of an AIDS patient
with encephalitis. J. Med. Virol. 47, 168–171.
Stoodley, M., Weihl, C. C., Zhang, Z. D., et al. (2000). Effect of
adenovirus-mediated nitric oxide synthase gene transfer on
vasospasm after experimental subarachnoid hemorrhage. Neu-
rosurgery 46, 1193–1202.
Wood, M. J., Charlton, H. M., Wood, K. J., et al. (1996). Immune
responses to adenovirus vectors in the nervous system. Trends
Neurosci. 19, 497–501.
Zahradnik, J. M., Spencer, M. J., and Porter, D. D. (1980).
Adenovirus infection in the immunocompromised patient. Am.
J. Med. 68, 725–732.
Adrenal Gland
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SPECIALIZED CELLS from near the gonadal ridge form
the precursors of steroidogenic cells of the adrenal
glands and gonads. Cells destined to become the
adrenal cortex migrate to the suprarenal area and are
invaded by neuroendocrine cells to become the
adrenal medulla. The fetal adrenal cortex rapidly
acquires robust ability to make C19 steroids, the
precursors for high estrogen production in pregnancy.
At birth, the fetal adrenal involutes, replaced by the
definitive adrenal cortex. The outer rim of cells form
the zona glomerulosa, where aldosterone is produced,
and the inner zone forms the zona fasciculata, where
cortisol is made. The innermost region that touches
the medulla, the zona reticularis, is not well devel-
oped in infancy. With the onset of adrenarche at
approximately age 8, the reticularis expands and
produces large amounts of dehydroepiandrosterone
sulfate (DHEA-S). After age 30, the reticularis begins

neutralizing antibodies. The hexon and fiber proteins
contain virus group- and type-specific epitopes. The
type-specific anti-hexon neutralizing antibodies from
humans inhibit viral replication; however, they do
not block attachment or internalization of the virus.
In addition, as is the case with many other viruses,
AdVs have a number of genes and gene products that
interfere with the host immune response. For
example, E1A, VA RNA, and E3 antagonize a and
b interferons; E1A, VA RNA inhibit the cytolytic T
cell response; and E3 inhibits the effect of tumor
necrosis factor.
The role of the cellular and humoral immune
system in limiting AdV-mediated gene transfer
systemically and in the CNS has been under study.
A host immune response directed against the virion
capsid proteins in the inoculum, as well as against
products of the viral genes (and transgene), can limit
the duration of transgene expression and prevent
efficient gene expression following repeated admin-
istration of the vector. The duration of transgene
expression varies in AdV-transduced neural cells and
depends on the age of the host, the specific transgene,
and the route of vector delivery. Some studies have
reported CNS expression for at least 2 months after
infection, although the number of expressing cells
declines over time. The decline in expressing cells
may be due to a number of reasons, including the
presence of the immune response, promoter inactiva-
tion, or viral DNA degradation. The immunosup-
pressant drug FK506 (tacrolimus), which readily
crosses the blood–brain barrier, can extend the
duration of gene expression in the CNS of mice
following injection of the recombinant AdV; this
result emphasizes the importance of the immune
response in the limited duration of transgene expres-
sion. Interestingly, AdV vectors can elicit an inflam-
matory response both at the site of vector delivery in
the CNS and at more remote sites that are
synaptically linked. In addition, the vector can
remain a potential target for a destructive immune
response that induces local demyelination.
—Ghanashyam D. Ghadge and Raymond P. Roos
See also–Arboviruses, Encephalitis Caused by;
Enteroviruses; Viral Vaccines and Antiviral
Therapy
Further Reading
Charles, P. C., Guida, J. D., Brosnan, C. F., et al. (1998). Mouse
adenovirus type-1 replication is restricted to vascular endothe-
ADRENAL GLAND 43
lium in the CNS of susceptible strains of mice. Virology 245,
216–228.
Ghadge, G. D., Roos, R. P., Kang, U. J., et al. (1995). CNS gene
delivery by retrograde transport of recombinant replication-
defective adenoviruses. Gene Ther. 2, 132–137.
Osamura, T., Mizuta, R., Yoshioka, H., et al. (1993). Isolation of
adenovirus type 11 from the brain of a neonate with pneumonia
and encephalitis. Eur. J. Pediatr. 152, 496–499.
Pillay, D., Lipman, M. C., Lee, C. A., et al. (1993). A clinico-
pathological audit of opportunistic viral infections in HIV-
infected patients. AIDS 7, 969–974.
Roos, R. P. (1989). Adenovirus. In Handbook of Clinical
Neurology (R. R. McKendall, Ed.), pp. 281–293. Elsevier
Science, New York.
Rowe, W. C., Huebner, R. J., Gilmore, L. K., et al. (1953).
Isolation of a cytopathic agent from human adenoid undergoing
spontaneous degeneration in tissue culture. Proc. Soc. Exp.
Biol. Med. 84, 570–573.
Schnurr, D., Bollen, A., Crawford-Miksza, L., et al. (1995).
Adenovirus mixture isolated from the brain of an AIDS patient
with encephalitis. J. Med. Virol. 47, 168–171.
Stoodley, M., Weihl, C. C., Zhang, Z. D., et al. (2000). Effect of
adenovirus-mediated nitric oxide synthase gene transfer on
vasospasm after experimental subarachnoid hemorrhage. Neu-
rosurgery 46, 1193–1202.
Wood, M. J., Charlton, H. M., Wood, K. J., et al. (1996). Immune
responses to adenovirus vectors in the nervous system. Trends
Neurosci. 19, 497–501.
Zahradnik, J. M., Spencer, M. J., and Porter, D. D. (1980).
Adenovirus infection in the immunocompromised patient. Am.
J. Med. 68, 725–732.
Adrenal Gland
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SPECIALIZED CELLS from near the gonadal ridge form
the precursors of steroidogenic cells of the adrenal
glands and gonads. Cells destined to become the
adrenal cortex migrate to the suprarenal area and are
invaded by neuroendocrine cells to become the
adrenal medulla. The fetal adrenal cortex rapidly
acquires robust ability to make C19 steroids, the
precursors for high estrogen production in pregnancy.
At birth, the fetal adrenal involutes, replaced by the
definitive adrenal cortex. The outer rim of cells form
the zona glomerulosa, where aldosterone is produced,
and the inner zone forms the zona fasciculata, where
cortisol is made. The innermost region that touches
the medulla, the zona reticularis, is not well devel-
oped in infancy. With the onset of adrenarche at
approximately age 8, the reticularis expands and
produces large amounts of dehydroepiandrosterone
sulfate (DHEA-S). After age 30, the reticularis begins
44 ADRENAL GLAND

to slowly atrophy, such that DHEA-S production and

reticularis mass decline with age, decreasing to
childhood levels by the eighth decade.
Steroid hormone production by the adrenal cortex
begins with the conversion of cholesterol to pregne-
nolone in the mitochondria by the cholesterol side
chain cleavage enzyme (CYP11A1 or P450scc). This
step is regulated acutely by the steroidogenic acute
regulatory protein (StAR) and chronically by main-
tenance of key adrenal transcription factors, includ-
ing cAMP- and calcium-responsive proteins as well Figure 1
Schematic diagram of adrenal zonation. The adrenal cortex is
as steroidogenic factor-1 (SF-1). The specific enzymes zonated, from outside to inside, as the zonas glomerulosa (ZG),
present beyond P450scc determine which steroids are fasciculata (ZF), and reticularis (ZR). The adrenal medulla fills the
produced by a given cell or zone of the adrenal cortex center of the gland.
(Figs. 1 and 2).
Diseases of the adrenal cortex can reflect under-
production of some or all steroids or over- steroids as occurs in adrenal carcinomas. Steroid
production of steroids. Deficiency of all hormones overproduction can also be driven by tumors that
occurs from defects in adrenal development, defi- secrete ACTH.
ciencies in early steps of steroidogenesis (such as The adrenal medulla is an extension of the
StAR), and destructive diseases of the gland. sympathetic nervous system (SNS), producing epi-
Selective deficiency of groups of hormones occurs nephrine in response to stress or other stimuli for
with deficiencies of specific downstream steroido- SNS activation. Cortisol percolating down from the
genic enzymes. Tumors of the adrenal gland can adrenal cortex induces the enzyme phenylethylamine
overproduce mainly one hormone, such as aldoster- N-methyl transferase, allowing conversion of nor-
one in Conn’s syndrome, or can make a plethora of epinephrine to epinephrine.

Figure 2
Abbreviated steroidogenic pathways of the human adrenal glands. Whereas all zones contain CYP11A1 (P450scc), which converts
cholesterol to pregnenolone, other zones contain specific repertoires of enzymes to yield the characteristic products of those zones. The zona
glomerulosa is deficient in CYP17 (17a-hydroxylase/17,20-lyase) but contains CYP21 (21-hydroxylase) and CYP11B2 (aldosterone
synthase) as well as 3-b-HSD (3-b-hydroxysteroid dehydrogenase/D5/4-isomerase), limiting steroidogenesis to aldosterone. The zona
fasciculata does not contain CYP11B2 and thus does not make aldosterone, but the presence of CYP17 and CYP11B1 (11-b-hydroxylase)
enables cortisol production. The zona reticularis has abundant CYP17 and DHEA sulfotransferase as well as cytochrome b5 (cyt b5), the
cofactor protein for the 17,20-lyase reaction; however, it is relatively deficient in 3-b-HSD, allowing vigorous production of only DHEA and
DHEA-S.

Atrophy of the adrenal medulla can accompany
adrenal cortex destruction, and loss of adrenal
medullary function can occur with degeneration of
the autonomic nervous system. Pheochromocytomas,
which are tumors of the adrenal medulla, are a rare
cause of catecholamine-mediated hypertension, oc-
curring in approximately 0.5% of all patients with
hypertension.
—Richard J. Auchus
See also–Addison’s Disease; Cushing’s Disease;
Cushing Syndrome; Myopathy, Endocrine
Further Reading
Auchus, R. J., and Miller, W. L. (2001). The principles, pathways,
and enzymes of human steroidogenesis. In Endocrinology (L. J.
DeGroot and J. L. Jameson, Eds.), 4th ed. Saunders, Philadel-
phia.
Adrenocortical Steroids
see Steroids
Adrenomyleukodystrophy
see Leukodystrophy
Adrian, Edgar Douglas
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SIR EDGAR DOUGLAS ADRIAN (1889–1977) was one
of the most influential neuroscientists of the 20th
century. He shared the 1932 Nobel Prize in medicine
ADRIAN, EDGAR DOUGLAS 45
and physiology with Sir Charles Sherrington; they
were honored ‘‘for their discoveries regarding the
functions of neurons.’’
Adrian was born in London, where his father was
a legal adviser to the British government. After
studying at Westminster School in London, Adrian
attended Trinity College in Cambridge. He began his
research career under the famous neurophysiologist
Keith Lucas, who had already shown that following a
stimulation-induced contraction, the skeletal muscle
remained refractory to subsequent stimulations over
a brief period. Continuing work on this line, Adrian
and Lucas discovered the ‘‘all-or-none’’ phenomenon,
for which Adrian won a scholarship in science.
Adrian enrolled in medicine at Bartholomew’s
Hospital in London and returned to Cambridge in
1919, where he pursued Lucas’s research (Lucas
tragically died in 1917 during World War I). In 1937,
Adrian succeeded Sir Joseph Barcroft as Professor of
Physiology, a post he was to hold until 1951.
Adrian’s initial work involved developing the
capillary electrometer that enabled him to measure
minute signals from the nerve fibers. He used
cathode-ray tubes for recording purposes. With
these, he amplified the nerve impulses more than
5000 times and recorded the electrical discharges in
single nerve fibers produced by tension on the
muscles, pressure and touch on them, or the move-
ment of a hair and pricking the nerve with a needle.
Adrian’s general experimental setup was decep-
tively simple: a single end-organ from the frog muscles
attached to a single nerve fiber related to the muscle.
By stimulating the end-organ, Adrian discovered that
the nerve fiber showed regular impulses, the frequen-
cies of which varied with time. A stimulus of constant
intensity applied to the skin immediately excited the
end-organ, but the excitation decreased with time
even though the stimulus intensity had not changed.
He concluded that such diminishing intensities
paralleled the decreasing sensation in the brain. Using
similar methods and precise recording techniques, he
discovered additional insights into the nature of
coding of the motor and sensory impulses in afferent
and efferent fibers of nerves.
Regarding the brain’s role in sensory perception,
Adrian concluded (as had Sir Henry Head from his
clinical studies) that the nerve impulses from the
afferent fibers ended in the thalamus, and by
mapping the cortex, one can gauge the distribution
of brain representation. He believed that such
distributions varied in animals based on their specific
functional needs. In human and monkey, for

Atrophy of the adrenal medulla can accompany
adrenal cortex destruction, and loss of adrenal
medullary function can occur with degeneration of
the autonomic nervous system. Pheochromocytomas,
which are tumors of the adrenal medulla, are a rare
cause of catecholamine-mediated hypertension, oc-
curring in approximately 0.5% of all patients with
hypertension.
—Richard J. Auchus
See also–Addison’s Disease; Cushing’s Disease;
Cushing Syndrome; Myopathy, Endocrine
Further Reading
Auchus, R. J., and Miller, W. L. (2001). The principles, pathways,
and enzymes of human steroidogenesis. In Endocrinology (L. J.
DeGroot and J. L. Jameson, Eds.), 4th ed. Saunders, Philadel-
phia.
Adrenocortical Steroids
see Steroids
Adrenomyleukodystrophy
see Leukodystrophy
Adrian, Edgar Douglas
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
SIR EDGAR DOUGLAS ADRIAN (1889–1977) was one
of the most influential neuroscientists of the 20th
century. He shared the 1932 Nobel Prize in medicine
ADRIAN, EDGAR DOUGLAS 45
and physiology with Sir Charles Sherrington; they
were honored ‘‘for their discoveries regarding the
functions of neurons.’’
Adrian was born in London, where his father was
a legal adviser to the British government. After
studying at Westminster School in London, Adrian
attended Trinity College in Cambridge. He began his
research career under the famous neurophysiologist
Keith Lucas, who had already shown that following a
stimulation-induced contraction, the skeletal muscle
remained refractory to subsequent stimulations over
a brief period. Continuing work on this line, Adrian
and Lucas discovered the ‘‘all-or-none’’ phenomenon,
for which Adrian won a scholarship in science.
Adrian enrolled in medicine at Bartholomew’s
Hospital in London and returned to Cambridge in
1919, where he pursued Lucas’s research (Lucas
tragically died in 1917 during World War I). In 1937,
Adrian succeeded Sir Joseph Barcroft as Professor of
Physiology, a post he was to hold until 1951.
Adrian’s initial work involved developing the
capillary electrometer that enabled him to measure
minute signals from the nerve fibers. He used
cathode-ray tubes for recording purposes. With
these, he amplified the nerve impulses more than
5000 times and recorded the electrical discharges in
single nerve fibers produced by tension on the
muscles, pressure and touch on them, or the move-
ment of a hair and pricking the nerve with a needle.
Adrian’s general experimental setup was decep-
tively simple: a single end-organ from the frog muscles
attached to a single nerve fiber related to the muscle.
By stimulating the end-organ, Adrian discovered that
the nerve fiber showed regular impulses, the frequen-
cies of which varied with time. A stimulus of constant
intensity applied to the skin immediately excited the
end-organ, but the excitation decreased with time
even though the stimulus intensity had not changed.
He concluded that such diminishing intensities
paralleled the decreasing sensation in the brain. Using
similar methods and precise recording techniques, he
discovered additional insights into the nature of
coding of the motor and sensory impulses in afferent
and efferent fibers of nerves.
Regarding the brain’s role in sensory perception,
Adrian concluded (as had Sir Henry Head from his
clinical studies) that the nerve impulses from the
afferent fibers ended in the thalamus, and by
mapping the cortex, one can gauge the distribution
of brain representation. He believed that such
distributions varied in animals based on their specific
functional needs. In human and monkey, for
46 AGEUSIA
example, large areas of the sensory cortex are
devoted to the face and hands, relative to those
devoted to the trunk. In contrast, in the pony, the
areas devoted to the nostrils are large relative to
those of the rest of the body, and in the pig the areas
devoted to the snout are large in comparison to those
of the trunk, which enables the pig to explore its
environment effectively.
In 1929, the German scientist Hans Berger
developed the electroencephalogram (EEG); Adrian
immediately began studying the role and clinical
utility of this new instrument. Recording the
electrical waves from human brain, he classified
numerous variations in normal and abnormal sub-
jects. Because of these and similar studies, Adrian
played a key role in advancing the clinical value of
the EEG, particularly in epilepsy research and in the
study of other brain lesions.
In addition to numerous scientific articles in
prestigious scientific journals, Adrian wrote many
books, three of which remain classics: The Basis of
Sensation (1927), The Mechanism of Nervous Action
(1932), and The Physical Basis of Perception (1947).
He served as president of the Royal Society (1950–
1955) and of the Royal Society of Medicine (1960–
1962). In 1954, he was president of the British
Association for the Advancement of Science. He was
made the Chevalier of the French Legion of Honor
and a trustee of the Rockefeller Institute. He was
knighted Baron of Cambridge in 1955.
A man of tireless energy and industry, Adrian
exerted a great influence on his pupils and on the
development of neurophysiology research. The citi-
zens of Cambridge viewed him as an icon: His lean
figure, thrusting forward, threading along the
crowded, curvy roads of the city on his bicycle at
high speeds was an endearing sight to behold.
Adrian was an expert fencer and an enthusiastic
mountaineer—a recreation he shared with Lady
Adrian, who was a justice of the peace, performing
much social work in Cambridge. Among Lord
Adrian’s other recreations were sailing and his great
interest in the arts. Just as he was a great teacher, he
was a legendary after-dinner speaker. Like his mentor
and colaureate, Charles Sherrington, Lord Adrian was
also deeply admired and respected throughout his life.
—Tonse N. K. Raju
See also–Electroencephalogram (EEG); Neurons,
Overview; Sherrington, Charles Scott (see Index
entry Biography for complete list of
biographical entries)
Further Reading
Adrian, E. D. (1926). The impulses produced by sensory nerve-
endings: Part IV. Impulses from pain receptors. J. Physiol. 62,
33–51.
Adrian, E. D. (1930). The activity of injury on mammalian nerve
fibers. Proc. R. Soc. Ser. B 106, 596.
Barlow, H. B., and Mollen, J. D. (Eds.) (1982). The Senses.
Cambridge Univ. Press, New York.
Brazier, M. A. B. (1988). A History of Neurophysiology in the
Nineteenth Century. Raven Press, Baltimore.
Affective Disorders
see Mood Disorders
Ageusia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
TASTE is one of the five senses (hearing, smell, taste,
touch, and vision) that is used to perceive the
environment. Taste belongs to the group of senses
collectively termed chemical senses, which are the
sensory modalities used to detect chemical sub-
stances in the environment. These chemicals are
minute molecules present in the air and the
substances that come in contact with the mucosal
surfaces of the eyes, nose, and mouth. Receptors in
the nose and mouth detect these molecules and
generate signals to which the brain assigns a meaning
that is interpreted as smells, tastes, and flavors. Taste
is the result of the interaction of food and drink
molecules with oral surface receptor cells. When
sensory perception becomes impaired, disorders of
taste and smell occur.
Ageusia is defined as the lack of taste. A person
with ageusia cannot detect any ‘‘taste’’ from things
put in the mouth. True ageusia, lack of ability to taste
all taste modalities, is rare. Partial taste loss or taste
alterations are much more common. Interestingly,
people who complain of loss of taste almost always
have an actual loss of smell. The two sensory
functions are closely related.
A comprehensive list of taste disorders includes
ageusia, which is the complete loss of taste;
hypogeusia, the decreased perception of taste mole-
cules; dysgeusia, the altered or abnormal perception
of taste molecules; and hypergeusia, the heightened
perception of taste molecules. Three disorders that
46 AGEUSIA
example, large areas of the sensory cortex are
devoted to the face and hands, relative to those
devoted to the trunk. In contrast, in the pony, the
areas devoted to the nostrils are large relative to
those of the rest of the body, and in the pig the areas
devoted to the snout are large in comparison to those
of the trunk, which enables the pig to explore its
environment effectively.
In 1929, the German scientist Hans Berger
developed the electroencephalogram (EEG); Adrian
immediately began studying the role and clinical
utility of this new instrument. Recording the
electrical waves from human brain, he classified
numerous variations in normal and abnormal sub-
jects. Because of these and similar studies, Adrian
played a key role in advancing the clinical value of
the EEG, particularly in epilepsy research and in the
study of other brain lesions.
In addition to numerous scientific articles in
prestigious scientific journals, Adrian wrote many
books, three of which remain classics: The Basis of
Sensation (1927), The Mechanism of Nervous Action
(1932), and The Physical Basis of Perception (1947).
He served as president of the Royal Society (1950–
1955) and of the Royal Society of Medicine (1960–
1962). In 1954, he was president of the British
Association for the Advancement of Science. He was
made the Chevalier of the French Legion of Honor
and a trustee of the Rockefeller Institute. He was
knighted Baron of Cambridge in 1955.
A man of tireless energy and industry, Adrian
exerted a great influence on his pupils and on the
development of neurophysiology research. The citi-
zens of Cambridge viewed him as an icon: His lean
figure, thrusting forward, threading along the
crowded, curvy roads of the city on his bicycle at
high speeds was an endearing sight to behold.
Adrian was an expert fencer and an enthusiastic
mountaineer—a recreation he shared with Lady
Adrian, who was a justice of the peace, performing
much social work in Cambridge. Among Lord
Adrian’s other recreations were sailing and his great
interest in the arts. Just as he was a great teacher, he
was a legendary after-dinner speaker. Like his mentor
and colaureate, Charles Sherrington, Lord Adrian was
also deeply admired and respected throughout his life.
—Tonse N. K. Raju
See also–Electroencephalogram (EEG); Neurons,
Overview; Sherrington, Charles Scott (see Index
entry Biography for complete list of
biographical entries)
Further Reading
Adrian, E. D. (1926). The impulses produced by sensory nerve-
endings: Part IV. Impulses from pain receptors. J. Physiol. 62,
33–51.
Adrian, E. D. (1930). The activity of injury on mammalian nerve
fibers. Proc. R. Soc. Ser. B 106, 596.
Barlow, H. B., and Mollen, J. D. (Eds.) (1982). The Senses.
Cambridge Univ. Press, New York.
Brazier, M. A. B. (1988). A History of Neurophysiology in the
Nineteenth Century. Raven Press, Baltimore.
Affective Disorders
see Mood Disorders
Ageusia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
TASTE is one of the five senses (hearing, smell, taste,
touch, and vision) that is used to perceive the
environment. Taste belongs to the group of senses
collectively termed chemical senses, which are the
sensory modalities used to detect chemical sub-
stances in the environment. These chemicals are
minute molecules present in the air and the
substances that come in contact with the mucosal
surfaces of the eyes, nose, and mouth. Receptors in
the nose and mouth detect these molecules and
generate signals to which the brain assigns a meaning
that is interpreted as smells, tastes, and flavors. Taste
is the result of the interaction of food and drink
molecules with oral surface receptor cells. When
sensory perception becomes impaired, disorders of
taste and smell occur.
Ageusia is defined as the lack of taste. A person
with ageusia cannot detect any ‘‘taste’’ from things
put in the mouth. True ageusia, lack of ability to taste
all taste modalities, is rare. Partial taste loss or taste
alterations are much more common. Interestingly,
people who complain of loss of taste almost always
have an actual loss of smell. The two sensory
functions are closely related.
A comprehensive list of taste disorders includes
ageusia, which is the complete loss of taste;
hypogeusia, the decreased perception of taste mole-
cules; dysgeusia, the altered or abnormal perception
of taste molecules; and hypergeusia, the heightened
perception of taste molecules. Three disorders that
 AGEUSIA 47

are not malfunctions of the taste system directly but EPIDEMIOLOGY

still produce altered taste perception are gustatory
Although true ageusia is rare, several studies indicate
agnosia (the inability to detect shape of objects in the
that chemosensory disorders encompassing both
mouth), the disordered oral sensation of the burning
taste and smell are not uncommon. Approximately
mouth syndrome, and xerostomia (dry mouth).
2–4 million Americans suffer from chemosensory
Contributing to the sensation of taste is the common
disorders. As described in the National Institutes of
chemical sense. This sense is responsible for percep-
Health/National Institute on Deafness and Other
tion of coolness, astringence, and irritation or ‘‘chili
Communication Disorders Health Information bul-
pepper’’ hot. This entry focuses on the abnormalities
letin, approximately 200,000 people visit a doctor
of direct taste perception.
each year for chemosensory disorders. More than
Ageusia, hypogeusia (which is more common
90% of individuals who see a doctor because they
that hypergeusia), and dysgeusia can be further
have experienced a loss of what they perceive as taste
quantified as being complete (involving all taste
actually have a disordered sense of smell. (Most taste
qualities), partial (involving only some taste quali-
is perceived through smell.) There is some loss of
ties), or localized (involving only a portion of the oral
chemosensory function related to increasing age,
cavity).
mostly due to loss of smell. Approximately 75% of
people older than age 80 report some degree of taste
WHY IS TASTE LOSS A PROBLEM? or smell loss. A study by the National Geographic
Society indicates that this age-related loss is universal
Humans do not rely on taste as the primary mode of
across all cultures.
interacting with the environment. Thus, taste dis-
The National Ambulatory Medical Care survey
orders have not received as much attention as
indicates that 68% of patients experiencing a taste
disorders of other sensory systems (e.g., vision).
problem believe it affects their quality of life. Forty-
However, abnormalities of taste are relatively com-
six percent report a change in appetite or body
mon and occur in conjunction with many common
weight, and 56% report alterations in their daily
health disorders and stages of life (e.g., pregnancy).
living or psychological well-being. Of all systemic
Taste disorders can be quite serious. They are not life
illnesses, depression is most often associated with
threatening but can be the major cause of day-to-day
chemosensory disorders. In some studies, up to one-
discomfort and decreased health because they
third of patients report chemosensory dysfunction.
directly affect many quality-of-life issues.
Because of compensatory taste mechanisms, regional
Taste is used to sample the chemical environment
or localized taste loss that can be diagnosed by
intended for consumption (i.e., food). The interac-
specialized testing goes unnoticed and unreported by
tion of molecules with taste buds signals the
patients.
pleasantness of food molecules and the noxious or
The list of conditions or illnesses associated with
bitter sensation of spoiled food and poisons. Spoiled
taste loss is extensive. Taste loss occurs most
foods and liquids have a bitter or sour taste that is
commonly with physiological alterations, such as
often perceived as being strong. Natural (plant)
during pregnancy, treatments involving numerous
poisons, which are alkaloids and anticholinergic
medications, chemotherapy or radiation therapy, and
agents, are usually bitter. The bitter sensation
certain illnesses.
stimulates expulsion and prevents ingestion of these
dangerous substances.
Of particular importance in the elderly is the
CAUSES
potential role of laryngeal taste buds in protection of
the airway. Stimulation of taste buds in the orophar- Rarely, ageusia can be inherited, such as in familial
ynx not only produces a qualitative taste but also dysautonomia. Genetic alterations in taste percep-
activates reflexes, which prevents aspiration. The risk tion are common, such as sensitivity to phenylthio-
of aspiration due to systemic illnesses is compounded carbamide or the sweetness imparted to water by
if a person cannot taste. People who lose their sense artichokes. Taste alterations can be acquired via
of taste are at risk of developing depression. This can injury or illness. Accidental injuries such as head
be either due to or in addition to a significantly trauma rarely cause taste alterations. Illnesses, on the
reduced desire to eat, which can, in turn, lead to other hand, frequently cause taste alterations,
worse health problems. although usually they are not as severe as ageusia.
48 AGEUSIA
Acute illnesses such as upper respiratory infections
and even otitis media can temporarily alter taste.
Exposure to chemicals can cause taste alterations.
Medications comprise the largest group in this cate-
gory, but chemicals in insecticides or chemicals in the
workplace may also cause alterations. Various as-
pects of oral health may alter taste, including poor oral
hygiene, dental caries, smoking, or dental appliances.
Molecules carried in the blood, such as those of medi-
cations or hormones, can be perceived via saliva.
Nerves innervating taste buds can be inadvertently
damaged during local surgical procedures, such as
molar extractions or middle ear surgeries, or during
regional surgeries such as tumor removal.
Lastly, various treatment regimens can alter taste.
This probably comprises the largest group of taste-
altering etiologies. Radiation therapy for head and
neck cancer and chemotherapeutic agents commonly
alter taste. In addition, many medicinal drugs alter
taste.
Liver disease, diabetes mellitus, hypothyroidism,
depression, and nutritional deficiencies are fre-
quently associated with taste loss. Other conditions
associated with taste loss include Bell’s palsy,
Wallenburg’s syndrome, tumors on the cranial nerves
or brain regions involved in taste, obesity, and
hypertension. The most common drugs associated
with ageusia include cyclobenzaprine HCl, vincris-
tine, amitryptyline, terbinafine, clopidogrel, pheny-
toin, acarbose, losartan, rifabutin, lovastatin,
captopril, and penicillamine. Many other drugs are
associated with taste alterations.
DIAGNOSIS AND EVALUATION
A person who presents with the complaint of taste
loss is evaluated in standard medical fashion. A
thorough history is taken to determine the length of
time of the sensory loss, the qualities involved, any
associated conditions that may be the cause, and any
potential exposure, and also to obtain a survey of the
patient’s general health. The history should provide
an anatomical diagnosis and indications of the
possible source of the taste loss.
A physical examination is used to assess the
information provided during the history and to
further refine possible sources of the taste loss.
Specific to chemosensory loss is psychophysical
testing, which is done by a specialist to determine
the quality, intensity, and location of the taste loss.
Measurements are made of threshold, suprathres-
hold, magnitude, and absolute perceived intensity.
These tests are done for the four basic taste qualities:
sweet, sour, bitter, and salty. Finally, imaging of the
head and neck may reveal or rule out lesions such as
tumors, focal lesions, and other injuries to taste-
associated structures.
TREATMENT
Once the etiology of the ageusia or alteration in taste
has been made, the treatment is usually straightfor-
ward. Treatment is based on treating the cause in
most cases. Enhancement of the taste system directly
is more difficult. If a drug is the cause of the ageusia,
stopping or altering the drug will alleviate the
symptoms. If the ageusia is secondary to a systemic
illness, treatment of the illness will often alleviate the
symptoms. In cases of trauma, taste may resume as
the nerve heals. A similar approach is taken when
certain medications or treatments cannot be easily
altered. Regarding chemotherapeutic agents, radia-
tion, and other drug regimens, working with a
nutritionist or dietician who has experience in
dealing with people who have alterations in taste in
order to enhance the diet, making the flavors more
appealing or stronger, may help make eating more
appealing. Occasionally, alterations in taste may
spontaneously resolve. Strategies aimed at directly
repairing the taste system are under investigation.
—Gina M. Nelson
See also–Olfactory Nerve (Cranial Nerve I);
Sensation, Assessment of; Sensory System,
Overview; Smell; Taste
Further Reading
Bartoshuk, L. M. (1989). The functions of taste and olfaction.
Ann. N. Y. Acad. Sci. 575, 353–362.
Getchell, T. V., Bartoshuk, L., Doty, R., et al. (Eds.) (1991). Smell
and Taste in Health and Disease. Raven Press, New York.
Gilbert, A. N., and Wysocki, C. J. (1987). The National
Geographic Smell Survey Results. National Geographic Society,
Washington, DC.
Monell Chemical Senses Center (2002). http://www.monell.org.
National Ambulatory Medical Care Survey (1979). In Report of
the Panel on Communicative Disorders to the National
Advisory Neurological and Communicative Disorders and
Stroke Council. NIH publ. No. 79-1914. National Advisory
Neurological and Communicative Disorders and Stroke Coun-
cil, Washington, DC.
National Institute on Deafness and Other Communication
Disorders (2002). Taste and taste disorders. http://www.nidcd.
nih.gov/textonly/health/pubs st/taste.htm.
Smith, D. V., and Margolskee, R. F. (2001). Making sense of taste.
Sci. Am. 284, 32–39.

Aggression
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGGRESSIVE BEHAVIOR has been subtyped into a
variety of categories, including offensive vs defensive
aggression, affective vs predatory aggression, mater-
nal vs male-to-male aggression, and fear-induced,
territorial, and instrumental aggression.
For the purpose of this entry, aggression is
categorized into three types. The first category, not
discussed here, is the purely defensive form, such as
that of a mother defending her offspring from attack.
The second type is frequently defined as affective
aggression because it involves a high level of emotion
and physiological arousal (e.g., angry barroom
brawl). The third category, predatory aggression, is
characterized by low levels of arousal, as seen in cats
that calmly stalk their prey. Frequently, affective and
predatory aggression are conflated as a single form of
offensive aggression, although one can conceptualize
the affective type as a defensive response to perceived
threat. In support of this differentiation, the two types
originate from unique neural substrates and serve
different purposes. The societal cost of aggression is
high, and by identifying the major brain structures
and neurotransmitters involved, more effective pre-
vention and treatment programs can be developed.
Knowledge about aggression derives from three
sources: animal experiments, studies of normal
humans, and studies of humans with pathological
violent behavior. The sources of pathological popu-
lations include violent offenders, impulsive psychia-
tric patients, patients with a history of psychopathy,
fire setters, impulsive individuals with a history of
alcohol abuse, and juvenile offenders. In human
studies, behavior is correlated with some biological
property, such as direct volumetric measurement of
the brain, functional anatomy, and metabolic studies.
ANATOMY OF AGGRESSIVE BEHAVIOR
The complex phenomenon of aggression involves a
circuitry of nerve cells linking two major brain areas:
the limbic lobe and the prefrontal cortex (PFC). The
PFC is located in the rostral portion of the dorsal and
lateral (forward, top, and side) surfaces of the frontal
lobe (Fig. 1). The PFC is involved in higher cognitive
functioning, and, with its extensive connections
throughout the brain, it plays a critical role in inhibiting
behaviors that are controlled by other parts of the brain.
AGGRESSION 49
Figure 1
The prefrontal cortex (A) receives strong serotonergic input from
the raphe nucleus (B).
Emotional reactions to the environment originate
in the amygdala, within the limbic lobe. From the
amygdala, these signals are sent to the other limbic
structures, including the hippocampus, parahippo-
campal gyri, hypothalamus, thalamus, and cingulate
cortex. These limbic messages are then interpreted
and filtered by the PFC, which acts in this capacity as
a braking system that regulates or halts the signals
that modify aggression. The PFC thus normally
modulates the emotional content generated by the
limbic system. In the case of impulsive aggression,
this modulation can be severely reduced. Although
lesions to any part of this system can result in forms
of aggressive behavior, this entry focuses on damage
affecting the inhibitory role of the PFC.
Lesions to the PFC have long been linked to
impulsive aggression. In the most famous case of
PFC damage, the previously amicable railroad worker
Phineas Gage became impulsively violent, unpredict-
able, and irresponsible after a metal rod penetrated his
PFC (particularly the anterior and mesial section of
his orbital frontal cortex and anterior sections of his
cingulate gyrus). Other less dramatic cases corrobo-
rate this observation. Structural magnetic resonance
imaging studies of aggressive epilepsy patients showed
decreased gray matter in the left PFC. Other
aggressive populations (including murderers, hospita-
lized psychiatric patients, and alcoholic criminal
offenders) all show reduced activity in the PFC.
Evidence from normal individuals also supports
the connection between the PFC and aggressive
behavior. Recalling angry events in one’s life leads
to activation of areas of the PFC (the left orbito-
frontal cortex and the right cingulate cortex). Among
individuals from the general population, those with
50 AGGRESSION
antisocial personality traits have reduced gray matter
in the PFC. Head trauma and tumors that damage
the PFC consistently result in an increase in
aggressive and violent attitudes and behaviors.
Reduced brain activity and lesions to the PFC have
been associated with risk taking, rule breaking,
argumentativeness, and defective moral reasoning,
further illustrating the PFC’s role in inhibiting
behavior.
INADEQUATE INHIBITION OF
THE LIMBIC LOBE
The most likely mechanism of the PFC’s role in
aggression is its inability to effectively inhibit the
limbic structures that generate the aggressive affect.
Insufficient PFC activation may prevent inhibition of
brain structures located in the limbic lobe. The
amygdala, a key structure in the limbic system, has
numerous axonal connections to the PFC, and
without proper inhibition messages from the PFC,
this structure can drive behavior in an unchecked,
unregulated manner.
Raine’s work with impulsive murderers illustrates
a second potential mechanism for aggressive beha-
vior: Murderers in his sample showed not only
reduced activity in the PFC but also abnormally high
levels of metabolism in the right hemisphere struc-
tures of the limbic lobe (i.e., amygdala, thalamus,
and hippocampus). This result suggests that excessive
levels of limbic activity may disrupt the circuit by
causing too much input for the PFC to inhibit.
TWO UNIQUE SUBTYPES: EMOTIONALLY
CHARGED AGGRESSION VS
PREMEDITATED AGGRESSION
Animal brain stimulation studies and human posi-
tron emission tomography studies suggest that there
are two subtypes of aggression with distinct neural
pathways. The defensive rage pathway appears to be
designed to protect the organism from attack,
generating a high level of arousal. The offensive or
predatory system, in contrast, is activated when the
organism is calmly, carefully stalking prey. Animal
stimulation studies suggest that distinct systems may
have evolved: one to generate arousal when fear-
producing predators threaten (type 1 aggression) and
the second to minimize arousal to help focus on
tracking prey (type 2 aggression). Studies of cat and
rat brains indicate that the type 1 defensive rage
pathway arises from the medial hypothalamus and
the dorsal area of the periaqueductal gray, receiving
input from the medial, basal, and cortical nuclei of
the amygdala. The type 2 predatory pathway
originates in the ventral (bottom) half of the
periaqueductal gray, linking the lateral hypothalamus
and central and lateral nuclei of the amygdala,
connecting to the bed nucleus of the stria terminalis
and the autonomic nuclei of the caudal medulla.
Animal stimulation studies corroborate the finding
that the medial hypothalamus (involved in defensive
rage) generates an excited/aggressive behavior,
whereas the lateral hypothalamus (involved in pre-
datory aggression) is involved in the production of
anger. Interestingly, when the defensive rage system is
activated, the predatory system is suppressed. Con-
versely, the defensive system is suppressed while the
predatory system is active (Table 1).
The two-factor theory of neural systems for
aggression is supported by the human literature.
Aggressive behavior in humans has also been
classified as predatory vs defensive (or predatory vs
affective). Studies of psychopathic vs nonpsycho-
pathic criminals provide a compelling link with the
animal literature described above. Psychopathic
criminals, who comprise approximately 15% of
prison inmates, behave differently from nonpsycho-
pathic individuals. Psychopaths commit predatory,
callous crimes that tend to lack strong emotional
arousal. They typically victimize strangers and they
later show little remorse or empathy for the victim,
simulating a form of type 2 behavior seen in animals
coolly stalking prey. In contrast, most violent crimes
committed by nonpsychopaths involve an emotion-
ally charged argument with a family member or
dating partner (e.g., impulsive attack on an unfaith-
ful spouse). These nonpsychopathic individuals have
strong, angry, emotionally charged reactions that
suggest they feel threatened either physically or by a
loss in status (as seen in type 1 aggression).
Psychopathic and nonpsychopathic individuals differ
on biological traits, such as electrical patterns of the
brain (event-related potential studies), cognitive
processing (information-processing skills), and ser-
otonin levels.
The two-factor theory is also supported by studies
of murderers classified as impulsive, emotional
murderers vs premeditated ones. The affectively
driven, impulsive men showed reductions in both
left and right lateral PFC metabolism, whereas the
predatory group did not. The impulsive group also
showed an increased metabolic rate in right hemi-
sphere subcortical regions, lending evidence to the
 AGGRESSION 51

Table 1 DISTINCT NEURAL SUBSTRATES FOR AGGRESSION

Type 1: Defensive rage Type 2: Predatory aggression

Individual perceives imminent attack, becomes fearful Individual motivated by hunger, desire for power, resources, access to mates
k k
Activation of medial nucleus of amygdala Activation of central and lateral nuclei of amygdala
k k
Stimulation of medial hypothalamus Stimulation of lateral hypothalamus, bed nucleus of stria terminalis, ventral
k periaqueductal gray, autonomic nuclei of caudal medulla
Stimulation of dorsal periaqueductal grey k
k Activation of predatory attack
Activation of defensive rage behaviors >
> Suppression of defensive rage system
Suppression of predatory attack system

idea that impulsive criminals may be less able to
regulate or inhibit the excessive activity of the limbic
area of the brain.
SEROTONIN AND AGGRESSION
Serotonin is the most important and extensively
studied of the neurotransmitters involved in aggres-
sion. In practice, serotonin concentrations cannot be
measured directly, so related compounds must be
measured, such as the serotonin precursor trypto-
phan and the serotonin metabolite 5-HIAA. Con-
centrations of these compounds can also be
manipulated to alter the density of the neurotrans-
mitter. Such experiments are useful because inferred
serotonin concentrations are typically inverse to
aggressive behavior.
Serotonin is widely distributed in the brain and
also found in blood platelets. There are approxi-
mately 16 different types of serotonin. Nine unique
subtypes of serotonin cell groups have been identified
in two systems in the brain, one caudal and one
rostral. In the rostral system, cell bodies in the raphe
nuclei send axons throughout the frontal cortex, with
particularly dense projections to the prefrontal
cortex (Fig. 1).
The link between serotonin depletion and aggres-
sion has been well documented during the past four
decades. In studies in which cerebrospinal fluid levels
of serotonin metabolites are measured, individuals
with aggression and impulsivity have shown low
levels of the serotonin metabolite 5-HIAA. For
example, those with a history of making impulsive
suicide attempts, naval recruits with aggressive
behavior, violent criminals, fire setters, aggressive
alcoholics, behaviorally disruptive children and
adolescents, and aggressive psychiatric inpatients all
have been shown to possess abnormally low levels of
serotonin metabolites in their systems. Platelet
studies show a decrease in serotonin transporter sites
in aggressive children and aggressive psychiatric
patients, suggesting that serotonin levels are low in
these groups, even in the bloodstream.
It is believed that faulty impulse control is the
mechanism for the relationship between aggression
and serotonin. Impulsive but not premeditative
murderers are prone to low 5-HIAA levels, suggest-
ing that serotonin concentration may be a stronger
marker for impulsivity than for aggression per se.
Administration of serotonergic (serotonin-enhancing)
drugs appears to decrease aggressive impulsivity in
adult males with a history of behavior problems, and
studies of nonhuman primates replicate these find-
ings. Among normal volunteers, lower concentra-
tions of 5-HIAA were correlated with higher self-
ratings on an ‘‘urge to act out hostility’’ scale.
Fenfluramine challenge studies (in which serotonin
is enhanced) also demonstrate a correlation with
lifetime history of aggression and impulsivity among
normal men by documenting how these men do not
process serotonin in the same manner as normal
controls process it. It is noteworthy that serotonin
production is under substantial genetic control, and it
has also been associated with childhood abuse in
humans and lack of maternal attention in nonhuman
primates. This is important because it suggests that a
deprived or abusive upbringing may set in motion
biological traits that cause impulsive aggression.
Pharmacological challenge studies in which neuro-
transmitter (NT) levels are experimentally manipu-
52 AGGRESSION
lated by increasing or blocking production with
other chemicals elucidate the mechanism for aggres-
sion. Serotonin levels are subject to a number of
regulatory processes, including the availability of the
serotonin precursor tryptophan, the production of
prolactin, and the dietary effects of cholesterol and
tryptophan on serotonin production. Prolactin levels
naturally fluctuate in response to serotonin levels,
and prolactin production is attenuated in antisocial,
personality disordered patients. Patients with the
lowest levels of prolactin production are most prone
to be assaultive, impulsive, and irritable. Thus, even
when serotonin levels are adequate, prolactin may
not be generated properly, preventing inhibition of
aggressive behavior.
SEROTONIN, DIET, AND AGGRESSION
Serotonin levels are so closely linked to aggressive
behavior that dietary factors affecting concentrations
can significantly alter the degree of aggressive
behavior. The immediate precursor to serotonin is
the common amino acid hydroxytryptamine, or
tryptophan, and this amino acid is known to have
a direct effect on inhibiting aggression in human and
nonhuman primates. By introducing or limiting
tryptophan in the diet, normal men and nonhuman
primates have been shown to decrease or increase
laboratory-induced aggression, and the gene that
controls the production of tryptophan is associated
with levels of aggression, expression of anger, and
extreme impulsive behavior. A polymorphism in the
gene that controls the synthesis of tryptophan has
been associated with individual differences in aggres-
sion and angry personality traits. Dietary restriction
of cholesterol has also been shown to reduce central
serotonergic activity and increase levels of aggression
in primates.
NONSEROTONERGIC
NEUROTRANSMITTERS INVOLVED
IN AGGRESSION
There is evidence that a number of other neuro-
chemical agents play a role in aggressive behavior.
The hormonal catecholamines epinephrine and nor-
epinephrine are associated with central nervous
system activation to prepare for fighting, and
clozapine, an atypical antipsychotic, has been shown
to reduce aggression. Despite decades of research, the
role of testosterone in aggression remains unclear. It
appears that rather than simply correlating with
aggression, testosterone is instead related to more
socially acceptable outlets, such as assertiveness,
competitiveness, and social dominance. Testosterone
does interact with serotonin production, which may
affect aggressive behavior indirectly. For example,
high levels of plasma testosterone combined with low
levels of 5-HIAA have been associated with high
levels of aggression among rhesus monkeys.
COMBINING THE ANATOMICAL AND
CHEMICAL CORRELATES OF AGGRESSION
The PFC has a high density of receptors for serotonin
(type 2 in particular), and activation of the PFC is
pronounced in individuals given serotonin. When
administered the serotonergic agent fenfluramine,
impulsive–aggressive psychiatric patients did not
show the expected activation of the PFC and anterior
cingulate, suggesting that aggressive individuals may
not be producing normal levels of serotonin in these
areas of the brain. The cingulate cortex, also part of
the frontal lobe, is also innervated by the serotoner-
gic system, and these two regions are closely
connected by axons. Normal individuals show left
PFC and left anterior cingulate activation when given
serotonin-enhancing drugs, suggesting a selective
involvement of the left hemisphere of the PFC in
serotonin uptake and possibly aggression. This
supports a mechanism by which the PFC normally
acts to modulate aggression by becoming activated
by its primary NT, serotonin.
—Jennifer M. Murphy
See also–Amygdala; Behavior, Neural Basis of;
Behavior, Neuropathology of; Emotions; Frontal
Lobes; Neuropsychology, Overview; Serotonin
Further Reading
Anderson, S. W., Bechara, A., and Damasio, H. (1999). Impair-
ment of social and moral behavior related to early damage in
human prefrontal cortex. Nat. Neurosci. 2, 1032–1036.
Davidson, R., Putnam, K., and Larson, C. (2000). Dysfunction in
the neural circuitry of emotion regulation—A possible prelude
to violence. Science 289, 591–594.
Feldman, R., Meyer, J., and Quenzer, L. (1997). Principles of
Neuropsychopharmacology. Sinauer, Sunderland, MA.
Raine, A., Meloy, R., and Birle, S. (1998). Reduced prefrontal and
increased subcortical brain functioning assessed using positron
emission tomography in predatory and affective murderers.
Behav. Sci. Law 16, 319–332.
Siegel, A., Roeling, T., Gregg, T., et al. (1999). Neuropharmacol-
ogy of brain-stimulation-evoked aggression. Neurosci. Biobe-
hav. Rev. 23, 359–389.

Virkkunen, M., De Jong, J., and Bartko, J. (1989). Relationship of
psychological variables to recidivism in violent offenders and
impulsive fire setters. Arch. Gen. Psychiatry 46, 600–603.
Aging, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGING is clearly associated with deteriorating per-
formance on a number of cognitive measures. Age
effects are observed across multiple domains. They
are observed in both cross-sectional and longitudinal
study designs and generally resist adjustment for
education, gender, and sensorimotor handicap.
In fact, age-related cognitive decline is so common
that we risk losing sight of it as a clinical entity. It
may be statistically ‘‘normal’’ in the trivial sense that
it affects the majority of elderly persons tested.
However, like hypertension, adult-onset diabetes
mellitus (AODM), and prostate cancer, normal age-
related cognitive decline is a problem worthy of
clinical attention because it may be associated with
changes in behavior or functional status (e.g., relative
to young adults) that place elderly persons at risk; it
may offer insights into aging processes that are
increasingly coming under scientific scrutiny; and the
advent of potential treatment for age-associated
disease states, such as Alzheimer’s disease (AD), has
made it increasingly important to specifically identify
dementing illnesses in their ‘‘preclinical’’ stages and
distinguish them from normal age effects. In this
entry, we review the clinical features and possible
biological substrates of normal cognitive decline and
highlight the differences between normal aging and
the specific pattern of cognitive effects associated
with preclinical AD.
CHARACTERISTICS OF
AGE-RELATED EFFECTS
One of the most striking and reproducible findings in
gerontological research is the age-related increase in
reaction time. Reaction time is measured as the
latency, in milliseconds, between stimulus presenta-
tion and subject reaction. This increases linearly with
age and nonlinearly as a function of the complexity
of the task. This may explain the disproportionate
vulnerability of the elderly to timed tasks.
Moreover, the age-related increase in reaction time
is relatively independent of the domain being tested.
AGING, OVERVIEW 53
Memory, language, and visuospatial tasks are all
affected. This is in sharp contrast to AD, in which
cognitive skills are lost in a relatively fixed hierarch-
ical sequence (beginning essentially with memory
encoding) that reflects a similarly hierarchically
arranged sequence of brain structures affected by
AD pathology.
Unlike AD, which primarily affects heteromodal
association cortices in the frontal, temporal, and
parietal lobes, the pattern of cognitive decline
associated with normal aging shares many features
with that associated with isolated frontal lobe brain
injury. First, the effects of normal aging are
metamodal (e.g., they affect multiple cognitive
domains equally). Second, normal aging dispropor-
tionately affects complex tasks, particularly those
that activate anterior attentional systems responsible
for selective attention and inhibition of competing
stimuli.
These characteristics of age-related cognitive
decline suggest impaired executive control functions
(ECF). The executive functions are cybernetic pro-
cesses that govern the orchestration of simple
behaviors into complex, goal-directed action. Exam-
ples include selective attention, motor planning,
sequence initiation, the monitoring of ongoing
behavior, and the inhibition of context-irrelevant
behaviors or affects. A growing literature suggests
that the cognitive deficits associated with aging are
more consistent with a frontal system disorder than
an AD-like temporolimbic process.
CENTRAL NERVOUS SYSTEM SUBSTRATES
OF AGE-RELATED COGNITIVE DECLINE
The cognitive changes associated with normal aging
may reflect age-related structural/biochemical
changes in the brain, including changes in specific
neurotransmitter cerebral blood flow, diminished
brain volumes (atrophy), loss of synaptic density,
and diminished neuronal plasticity.
Changes in Biochemistry and Cortical
Blood Flow
Neurodegenerative disorders, such as AD and
Parkinson’s disease (PD), have been associated with
selective impairments in neurotransmitter functions.
Age-related changes resemble those of PD more than
AD. Volkow et al. demonstrated age-related de-
creases in D1 and D2 (dopamine) receptor binding
activity in the frontal cortex, anterior cingulate,
temporal cortex, and caudate. These age-related

Virkkunen, M., De Jong, J., and Bartko, J. (1989). Relationship of
psychological variables to recidivism in violent offenders and
impulsive fire setters. Arch. Gen. Psychiatry 46, 600–603.
Aging, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGING is clearly associated with deteriorating per-
formance on a number of cognitive measures. Age
effects are observed across multiple domains. They
are observed in both cross-sectional and longitudinal
study designs and generally resist adjustment for
education, gender, and sensorimotor handicap.
In fact, age-related cognitive decline is so common
that we risk losing sight of it as a clinical entity. It
may be statistically ‘‘normal’’ in the trivial sense that
it affects the majority of elderly persons tested.
However, like hypertension, adult-onset diabetes
mellitus (AODM), and prostate cancer, normal age-
related cognitive decline is a problem worthy of
clinical attention because it may be associated with
changes in behavior or functional status (e.g., relative
to young adults) that place elderly persons at risk; it
may offer insights into aging processes that are
increasingly coming under scientific scrutiny; and the
advent of potential treatment for age-associated
disease states, such as Alzheimer’s disease (AD), has
made it increasingly important to specifically identify
dementing illnesses in their ‘‘preclinical’’ stages and
distinguish them from normal age effects. In this
entry, we review the clinical features and possible
biological substrates of normal cognitive decline and
highlight the differences between normal aging and
the specific pattern of cognitive effects associated
with preclinical AD.
CHARACTERISTICS OF
AGE-RELATED EFFECTS
One of the most striking and reproducible findings in
gerontological research is the age-related increase in
reaction time. Reaction time is measured as the
latency, in milliseconds, between stimulus presenta-
tion and subject reaction. This increases linearly with
age and nonlinearly as a function of the complexity
of the task. This may explain the disproportionate
vulnerability of the elderly to timed tasks.
Moreover, the age-related increase in reaction time
is relatively independent of the domain being tested.
AGING, OVERVIEW 53
Memory, language, and visuospatial tasks are all
affected. This is in sharp contrast to AD, in which
cognitive skills are lost in a relatively fixed hierarch-
ical sequence (beginning essentially with memory
encoding) that reflects a similarly hierarchically
arranged sequence of brain structures affected by
AD pathology.
Unlike AD, which primarily affects heteromodal
association cortices in the frontal, temporal, and
parietal lobes, the pattern of cognitive decline
associated with normal aging shares many features
with that associated with isolated frontal lobe brain
injury. First, the effects of normal aging are
metamodal (e.g., they affect multiple cognitive
domains equally). Second, normal aging dispropor-
tionately affects complex tasks, particularly those
that activate anterior attentional systems responsible
for selective attention and inhibition of competing
stimuli.
These characteristics of age-related cognitive
decline suggest impaired executive control functions
(ECF). The executive functions are cybernetic pro-
cesses that govern the orchestration of simple
behaviors into complex, goal-directed action. Exam-
ples include selective attention, motor planning,
sequence initiation, the monitoring of ongoing
behavior, and the inhibition of context-irrelevant
behaviors or affects. A growing literature suggests
that the cognitive deficits associated with aging are
more consistent with a frontal system disorder than
an AD-like temporolimbic process.
CENTRAL NERVOUS SYSTEM SUBSTRATES
OF AGE-RELATED COGNITIVE DECLINE
The cognitive changes associated with normal aging
may reflect age-related structural/biochemical
changes in the brain, including changes in specific
neurotransmitter cerebral blood flow, diminished
brain volumes (atrophy), loss of synaptic density,
and diminished neuronal plasticity.
Changes in Biochemistry and Cortical
Blood Flow
Neurodegenerative disorders, such as AD and
Parkinson’s disease (PD), have been associated with
selective impairments in neurotransmitter functions.
Age-related changes resemble those of PD more than
AD. Volkow et al. demonstrated age-related de-
creases in D1 and D2 (dopamine) receptor binding
activity in the frontal cortex, anterior cingulate,
temporal cortex, and caudate. These age-related
54 AGING, OVERVIEW
declines are significantly associated with declines in
motor function and impaired performance on frontal
tasks. Similarly, Camicioli et al. report that incident
cognitive impairment among well elderly persons is
associated with clinical signs of dopaminergic
hypofunction, including slower finger tapping and
gait. A significant association between decreased D2
receptor binding by positron emission tomography
and age-related differences in perceptual speed and
episodic memory has also been observed by Backman
et al. The absence of impaired motor function can
help discriminate AD from normal aging. Normal
aging has also been associated with diminished
frontal cerebral blood flow by single photon emission
tomography. Age effects are most apparent under
stressful conditions, when effective blood supply for
the task at hand may be diminished.
Diminished Brain Volumes
Cortical and total brain volume declines linearly with
age in cross-sectional studies. However, the frontal
lobes are disproportionately affected. Age-related
losses in frontal cortical volume are relatively greater
in mesiofrontal (partial r ¼
0.71) and dorsofrontal
(r ¼
0.57) relative to orbitofrontal (r ¼
0.32)
regions. Longitudinal studies also confirm dispropor-
tionate frontal atrophy over time (0.55% per year) in
healthy adults.
Synaptic Density
The cognitive impairments of AD are strongly
associated with neuronal degeneration and neuronal
dropout. Although similar degenerative changes
occur in normal aging, neuronal dropout alone does
not account for the reduction in brain volume
associated with normal aging. Cortical atrophy in
normal aging is more closely related to neuronal
shrinkage (e.g., the loss of neuronal diameter) and
the loss of dendritic arborization (e.g., decreased
synaptic density). It is not strongly related to
neuronal cytoskeleton changes such as intraneuronal
neurofibrillary changes that are associated to AD.
Interestingly, Cerella hypothesizes that a loss of
connectivity in neural networks may explain the
change in cognitive latencies observed during normal
aging. Random nodal dropout in mathematical
neural network models of cognitive task perfor-
mance seems sufficient to explain the age-associated
variance in cognitive task performance over a wide
variety of tasks and task complexities.
Decrease in Neuronal Plasticity
Normal aging has been associated with a loss of what
is broadly referred to as synaptic plasticity. This
reflects the dynamic interaction between processes
that promote synaptogenesis and those that hinder it.
Plasticity is most evident in young animals, notably
in the hippocampus’ response to learning and
memory tasks. Loss of plasticity can also be
demonstrated in older animals.
Interestingly, the apolipoprotein E gene (APOE),
which has been associated with AD risk, is upregu-
lated by neuronal injury and also may be relevant to
neuronal plasticity in normal aging. ApoE is the
major lipid transport protein expressed in brain, and
it may be important for repair and maintenance of
synaptic connections. ApoE is synthesized by astro-
cytes. It has recently been demonstrated that astro-
cyte activity is critical to the development of
neuronal synaptic networks. Healthy neurons raised
in the absence of astrocytes do not spontaneously
develop functional neuronal connections. Since the
transport of cholesterol and other lipoproteins plays
a central role in synaptogenesis, it is possible that
persons differing in their apoE phenotype also differ
in their capacities of synaptogenesis. Recent in vitro
data have shown that the synaptogenic response to
estradiol does not occur in apoE-deficient knockout
mice. ApoE e3 enhances and apoE e4 inhibits neurite
outgrowth in neuronal cell cultures.
Effects of Superimposed Diseases
Increasingly, physical illnesses have been shown to
influence cognition in old age. Among the chronic
conditions most studied, systolic hypertension is a
predictor of cognitive function, as are depression and
stroke. AODM has been associated with poorer
performance on some memory-related tests com-
pared to that of nondiabetics and may aggravate the
usual changes that occur with aging. Diabetic
patients do not have increased AD pathology
compared with age-matched controls. Preliminary
data suggest that some benefit to cognition can be
gained by improved glycemic control.
Longitudinal studies such as the Framingham and
Honolulu Heart Program cohorts have reported a
modest inverse association between mean blood
pressure over 5 years and cognitive function mea-
sured 12–15 years later. In the Framingham study,
this association was most apparent in those who
were untreated. Cervilla et al. found that a reduction
in systolic blood pressure, among hypertensives,

could protect against cognitive decline. Recently,
researchers reported on improvement in executive
function and glucose metabolism after 12 weeks of
therapy in previously uncontrolled hypertension.
DISTINGUISHING BETWEEN PRECLINICAL
AD AND NORMAL AGING
Pathological Substrates of Preclinical AD
To distinguish between normal age effects and
preclinical AD, one must examine the distribution
of AD pathology in its preclinical stages. Braak and
Braak published an autopsy series comprising 2661
unselected cases that is particularly relevant. They
confirmed earlier studies suggesting that AD pathol-
ogy spreads along a hierarchical sequence of brain
structures. The hippocampus and entorhinal cortex
are affected early. Although less than 10% of cases
older than the age of 70 escaped AD pathology
entirely, the majority had AD pathology limited to
the transentorhinal cortex (e.g., Braak stages I and
II). Geddes et al. have shown that only memory is
affected at this stage, and metabolic changes in these
regions may precede the clinical detection of
dementia by many years. A relatively small minority
of Braak’s cases had pathology beyond Braak stage V
(the point at which dementia is usually detected by
clinicians). The age-specific prevalence of this stage
in the pathology closely matches the published
estimates of AD prevalence in community samples.
These findings have several important implica-
tions. First, they imply that the vast majority of
nondemented older persons do have at least some
preclinical AD pathology. Any age-related finding
must be interpreted in this context. For the most
part, AD pathology in nondemented elders will be
limited to transentorhinal cortex. This might explain
the frequent finding of impaired memory task
performance in nondemented older persons. How-
ever, preclinical AD should be associated with the
unique pattern of memory task performance that is
associated with hippocampal lesions. In contrast,
age-related frontal system changes may produce a
different pattern of memory deficit. These can be
distinguished psychometrically.
On the other hand, Braak’s results also suggest that
AD pathology in nondemented elders is not sufficient
to explain the more metamodal aspects of age-related
cognitive decline, which would be more consistent
with a frontal system disruption. AD pathology does
not affect the frontal lobes until at least Braak stage
AGING, OVERVIEW 55
IV and higher. This level of Braak pathology is
present in a minority of older persons and is
coincident with clinical dementia.
Is AD Dementia Inevitable?
Given that hippocampal AD pathology is widespread
after age 65, is it inevitable that mildly cognitively
impaired persons with AD-like memory impairment
will progress to frank AD? The answer is probably
not. Even relatively advanced entorhinal AD pathol-
ogy does not guarantee a clinical diagnosis of
dementia. Moreover, it is increasingly clear that the
clinical diagnosis of AD may not be accurate after
age 80 (e.g., in the majority of AD cases according to
epidemiological studies). For example, Mayeux et al.
compared the accuracy of a clinical diagnosis of
‘‘probable AD’’ made by experienced clinicians using
NINCDS–ADRDA criteria against autopsy in 1833
Alzheimer’s Disease Research Centers subjects.
Among the subset of cases aged 79 years and older,
the specificity of a clinical diagnosis of AD was only
23%. Other recent studies also fail to confirm AD at
autopsy in a significant fraction of demented non-
agenarians.
Similarly, some epidemiological studies have not
shown that their preclinical AD groups progress to
frank cortical dementia over longitudinal follow-up.
Breitner et al. lowered their estimate of the pre-
valence of AD in the NAS–NRC registry of aging
twin veterans from 2.0 to 0.5% after longitudinal
follow-up failed to confirm progression to frank
dementia in 90% of cases who had been diagnosed
with ‘‘mild/ambiguous changes suggestive of incident
AD’’ at baseline. Moreover, there is evidence that
many demented nursing home residents diagnosed
cross-sectionally with AD fail to progress to end-
stage cortical dementia when followed longitudinally.
The failure of highly selected well elderly groups to
develop AD is exemplified in two studies. Rubin et al.
reported the results of a 15-year longitudinal
examination of clinical and psychometric perfor-
mance of a group of older healthy adults aged 64–83
years. Braak and Braak’s study suggests that almost
all these cases could be expected to have low-grade
AD pathology. Nonetheless, a minority (40%)
experienced cognitive decline within 12 years of
enrollment. On average, there was no longitudinal
decline in psychometric performance. Similarly,
Howieson et al. found that substantial cognitive
decline is not inevitable in highly selected well elderly
persons. In a population-based community sample
(N ¼ 2.537), Jacquim-Gadda et al. reported very
56 AGING, OVERVIEW
little change in MMSE scores (0.02 points overall,
and 0.57 points after age 85) during 5 years of
follow-up.
It is more likely that memory losses due to
subclinical AD pathology are converted to dementia
by the addition of incident ECF impairment due to
non-AD processes, including normal aging. When
cognitive impairments are limited to temporal lobe
functions or there is only hippocampal atrophy by
magnetic resonance imaging (MRI), slower rates of
change in cognition are observed.
In fact, unrecognized frontal lobe dysfunction may
commonly antedate the clinical diagnosis of AD.
Hanninen et al. compared 43 individuals with age-
associated memory impairments according to Na-
tional Institute of Mental Health criteria to 47 age-
matched healthy controls. Four neuropsychological
tests and MRIs were performed on all subjects.
Investigators found that in subjects thought to be
normal except for memory problems, there was
impairment in three of the four tests assessing frontal
lobe function. This implies that age-related ECF
impairments may account for much of the incident
dementia among cases with mild cognitive impair-
ment (MCI).
CONCLUSION
Normal aging is associated with both cross-sectional
and longitudinal declines in cognitive function. These
disproportionately affect ECF and are associated
with age-related changes in frontal lobe structure and
function. The pattern of cognitive decline in normal
aging is distinct from that expected in AD, and there
is reason to suspect that many cases of dementia
among the oldest elderly patients may be misattrib-
uted to that disorder. The clinical discrimination
between normal aging and preclinical AD is made
difficult by the high prevalence of low-grade AD
pathology in nondemented elderly persons. MCI case
definitions should be careful to distinguish between
hippocampal and frontal system-related patterns of
memory function. Incident ECF impairment may not
necessarily imply conversion to AD dementia, and
longitudinal follow-up may be required to confi-
dently distinguish AD- from non-AD-related demen-
tia in the oldest elderly patients.
—Donald R. Royall and Belinda Vicioso
See also–Activities of Daily Living (ADL);
Alzheimer’s Disease; Cognitive Impairment;
Dementia; Depression; Executive Function;
Memory, Overview; Memory, Working
Further Reading
Backman, L., Ginovart, N., Dixon, R. A., et al. (2000). Age-
related cognitive deficits mediated by changes in the striatal
dopamine system. Am. J. Psychiatry 157, 635–637.
Braak, H., and Braak, E. (1998). Evolution of neuronal changes in
the course of Alzheimer’s disease. J. Neural Transm. 53, 127–
140.
Breitner, J. C., Welsh, K. A., Robinette, C. D., et al. (1994).
Alzheimer’s disease in the NAS-NRC registry of aging twin
veterans. II. Longitudinal findings in a pilot series. Dementia 5,
99–105.
Camicioli, R., Howieson, D., Oken, B., et al. (1998). Motor
slowing precedes cognitive impairment in the oldest old.
Neurology 50, 1496–1498.
Cerella, J. (1990). Aging and information processing rate. In
Handbook of the Psychology of Aging (J. E. Birren, R. B.
Sloane, and G. B. Cohen, Eds.), 3rd ed., pp. 201–221.
Academic Press, New York.
Cervilla, J. A., Prince, M., Lovestone, S., et al. (2000). Long-term
predictors of cognitive outcome in a cohort of older people with
hypertension. Br. J. Psychiatry 177, 66–71.
Crystal, H. A., Dickson, D., Davies, P., et al. (2000). The relative
frequency of ‘‘dementia of unknown etiology’’ increases with
age and is nearly 50% in nonagenarians. Arch. Neurol. 57,
713–719.
Geddes, J. W., Snowdon, D. A., Soultanian, N. S., et al. (1996).
Stages III–IV of Alzheimer’s related neuropathology are
associated with mild memory loss. Stages V–VI are associated
with dementia: Findings from the nun study. J. Neuropathol.
Exp. Neurol. 55, 617.
Hanninen, T., Hallikainen, M., Koivisto, K., et al. (1997). Decline
in frontal lobe functions in subjects with age-associated
memory impairment. Neurology 48, 148–153.
Howieson, D. B., Dame, A., Camicoli, R., et al. (1997). Cognitive
markers preceding Alzheimer’s dementia in the healthy oldest
old. J. Am. Geriatr. Soc. 45, 584–589.
Mayeux, R., Saunders, A. M., Shea, S., et al. (1998). Utility of the
apolipoprotein E genotype in the diagnosis of Alzheimer’s
disease. N. Engl. J. Med. 338, 506–511.
Polvikoski, T., Sulkava, R., Myllykangas, L., et al. (2001).
Prevalence of Alzheimer’s disease in very elderly people: A
prospective neuropathological study. Neurology 56, 1690–
1696.
Reed, B. R., Eberling, J. L., Mungas, D., et al. (2000). Memory
failure has different mechanisms in subcortical stroke and
Alzheimer’s disease. Ann. Neurol. 48, 275–284.
Royall, D. R., and Mahurin, R. K. (1996). Executive cognitive
functions: Neuroanatomy, measurement and clinical signifi-
cance. In Review of Psychiatry (L. J. Dickstein, J. M. Oldham,
and M. B. Riba, Eds.), pp. 175–204. American Psychiatric
Press, Washington, DC.
Royall, D. R., Palmer, R., Mulroy, A. R., et al. (2002). Pathological
determinants of the transition to clinical dementia in Alzhei-
mer’s disease. Exp. Aging Res. 28, 143–162.
Rubin, E. H., Storandt, M., Miller, J. P., et al. (1998). A
prospective study of cognitive function and onset of dementia
in cognitively healthy elders. Arch. Neurol. 55, 395–401.
Salthouse, T. A. (1996). The processing-speed theory of adult age
differences in cognition. Psychol. Rev. 103, 403–428.

Tariot, P. N., Ogden, M. A., Cox, C., et al. (1999). Diabetes and
dementia in long-term care. J. Am. Geriatr. Soc. 47, 423–429.
Ullian, E. M., Sapperstein, S. K., Christopherson, K. S., et al.
(2001). Control of synapse number by glia. Science 291, 657–
661.
Volkow, N. D., Logan, J., Fowler, J. S., et al. (2000). Association
between age-related decline in brain dopamine activity and
impairment in frontal and cingulate metabolism. Am. J.
Psychiatry 157, 75–80.
Zorumski, C. F., and Izumi, Y. (1998). Modulation of LTP
induction by NMDA receptor activation and nitric oxide
release. In Nitric Oxide in Brain Development, Plasticity
and Disease Progress in Brain Research (R. R. Mize, T. M.
Dawson, V. L. Dawso, et al., Eds.), pp. 173–182. Elsevier,
Amsterdam.
Agnosia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
FREUD (1891) coined the derivative Greek term
agnosia to describe what Teuber later engraved as a
‘‘percept stripped of its meaning.’’ In essence, an
agnosia is an acquired disturbance in recognizing a
sensory stimulus that was previously known. It is
generally used in reference to a specific sensory
modality (e.g., visual and auditory) and is distin-
guished from primary disturbances in sensory,
perceptual, or language processes, on the one hand,
and more global defects in cognition, on the other
hand. Although circumscribing the boundaries of
what an agnosia is not may appear facile, affirming
what an agnosia is has fueled ongoing debate for
more than a century. Munk (1881) provided the first
salient description of an agnosia-like syndrome. He
observed that dogs with bilateral occipital lobe
lesions reacted indifferently to previously learned
fear-evoking visual stimuli (‘‘mindblindness’’) but
retained the ability to navigate obstacles in their
path. Lissauer (1890) offered a widely influential
classification of agnosic phenomena into ‘‘appercep-
tive’’ and ‘‘associative’’ types. In this scheme,
recognition fails because either modality-specific
perceptual processing of the stimulus is compromised
(apperceptive) or there is an inability to access
semantic knowledge about the stimulus (associative).
In the latter case, a stimulus fails to evoke a
meaningful representation or sense of familiarity;
the subject is unable to name, demonstrate the use, or
make any relevant associations between the stimulus
and past experience. Although some modern authors
AGNOSIA 57
suggest that a degree of altered perception is present
in most cases of agnosia, other authorities have
argued for a more restricted view that agnosia is
fundamentally a defect in the ability to elicit a
memory representation pertinent to the stimulus.
Traversing this issue is the critical observation by
Geschwind that recognition, the crux of agnosia, is
not a singular phenomenon. Object recognition, for
example, may be inferred from three levels of
analysis: (i) overt identification, (ii) sorting or
grouping based on semantic relationship, and (iii)
nonverbal discriminatory responses. Recent theore-
tical perspectives of recognition emerging from
cognitive neuropsychology and computational neu-
roscience impute multiple, parallel streams of in-
formation processing, in contrast to the linear
apperceptive–associative model. In this context,
recognition in its varied forms accrues from the
integrated output of ‘‘modular’’ cortical and sub-
cortical processing systems in which perceptual and
memory components are inextricably linked. Not-
withstanding a contemporary trend to moot the
apperceptive–associative dialectic of agnosia, this
classification remains a historically important, if
dated, heuristic scheme.
Lissauer’s classification of visual agnosia into
apperceptive and associative types is based on the
severity of perceptual impairment. In apperceptive
visual agnosia, simple pictures, letters, and geometric
shapes typically cannot be identified by sight, copied,
or visually matched to sample. Such subjects may
appear to be almost functionally blind but will have
relatively preserved visual acuity, color vision,
brightness discrimination, and other elementary
visual capabilities. Visual apperceptive agnosia is
associated with cerebral insults such as carbon
monoxide poisoning, cardiac arrest, and bilateral
posterior cortical atrophy, and it rarely occurs as an
isolated syndrome. Cortical blindness is distin-
guished by defective visual acuity in the setting of
bilateral occipital lesions, and it is often accompa-
nied by denial of blindness (Anton’s syndrome).
Simultanagnosia is a syndrome of disordered visual
attention (‘‘sticky fixation’’), which may occur in
isolation or as a feature of Balint’s syndrome,
accompanied in the latter case by optic ataxia
(impaired visually guided reaching) and oculomotor
apraxia (inability to volitionally divert gaze). It is
generally characterized by the inability to shift the
perceptual focus of vision to more than one feature at
a time in a multielement scene, as opposed to
representing a primary defect in recognition. In

Tariot, P. N., Ogden, M. A., Cox, C., et al. (1999). Diabetes and
dementia in long-term care. J. Am. Geriatr. Soc. 47, 423–429.
Ullian, E. M., Sapperstein, S. K., Christopherson, K. S., et al.
(2001). Control of synapse number by glia. Science 291, 657–
661.
Volkow, N. D., Logan, J., Fowler, J. S., et al. (2000). Association
between age-related decline in brain dopamine activity and
impairment in frontal and cingulate metabolism. Am. J.
Psychiatry 157, 75–80.
Zorumski, C. F., and Izumi, Y. (1998). Modulation of LTP
induction by NMDA receptor activation and nitric oxide
release. In Nitric Oxide in Brain Development, Plasticity
and Disease Progress in Brain Research (R. R. Mize, T. M.
Dawson, V. L. Dawso, et al., Eds.), pp. 173–182. Elsevier,
Amsterdam.
Agnosia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
FREUD (1891) coined the derivative Greek term
agnosia to describe what Teuber later engraved as a
‘‘percept stripped of its meaning.’’ In essence, an
agnosia is an acquired disturbance in recognizing a
sensory stimulus that was previously known. It is
generally used in reference to a specific sensory
modality (e.g., visual and auditory) and is distin-
guished from primary disturbances in sensory,
perceptual, or language processes, on the one hand,
and more global defects in cognition, on the other
hand. Although circumscribing the boundaries of
what an agnosia is not may appear facile, affirming
what an agnosia is has fueled ongoing debate for
more than a century. Munk (1881) provided the first
salient description of an agnosia-like syndrome. He
observed that dogs with bilateral occipital lobe
lesions reacted indifferently to previously learned
fear-evoking visual stimuli (‘‘mindblindness’’) but
retained the ability to navigate obstacles in their
path. Lissauer (1890) offered a widely influential
classification of agnosic phenomena into ‘‘appercep-
tive’’ and ‘‘associative’’ types. In this scheme,
recognition fails because either modality-specific
perceptual processing of the stimulus is compromised
(apperceptive) or there is an inability to access
semantic knowledge about the stimulus (associative).
In the latter case, a stimulus fails to evoke a
meaningful representation or sense of familiarity;
the subject is unable to name, demonstrate the use, or
make any relevant associations between the stimulus
and past experience. Although some modern authors
AGNOSIA 57
suggest that a degree of altered perception is present
in most cases of agnosia, other authorities have
argued for a more restricted view that agnosia is
fundamentally a defect in the ability to elicit a
memory representation pertinent to the stimulus.
Traversing this issue is the critical observation by
Geschwind that recognition, the crux of agnosia, is
not a singular phenomenon. Object recognition, for
example, may be inferred from three levels of
analysis: (i) overt identification, (ii) sorting or
grouping based on semantic relationship, and (iii)
nonverbal discriminatory responses. Recent theore-
tical perspectives of recognition emerging from
cognitive neuropsychology and computational neu-
roscience impute multiple, parallel streams of in-
formation processing, in contrast to the linear
apperceptive–associative model. In this context,
recognition in its varied forms accrues from the
integrated output of ‘‘modular’’ cortical and sub-
cortical processing systems in which perceptual and
memory components are inextricably linked. Not-
withstanding a contemporary trend to moot the
apperceptive–associative dialectic of agnosia, this
classification remains a historically important, if
dated, heuristic scheme.
Lissauer’s classification of visual agnosia into
apperceptive and associative types is based on the
severity of perceptual impairment. In apperceptive
visual agnosia, simple pictures, letters, and geometric
shapes typically cannot be identified by sight, copied,
or visually matched to sample. Such subjects may
appear to be almost functionally blind but will have
relatively preserved visual acuity, color vision,
brightness discrimination, and other elementary
visual capabilities. Visual apperceptive agnosia is
associated with cerebral insults such as carbon
monoxide poisoning, cardiac arrest, and bilateral
posterior cortical atrophy, and it rarely occurs as an
isolated syndrome. Cortical blindness is distin-
guished by defective visual acuity in the setting of
bilateral occipital lesions, and it is often accompa-
nied by denial of blindness (Anton’s syndrome).
Simultanagnosia is a syndrome of disordered visual
attention (‘‘sticky fixation’’), which may occur in
isolation or as a feature of Balint’s syndrome,
accompanied in the latter case by optic ataxia
(impaired visually guided reaching) and oculomotor
apraxia (inability to volitionally divert gaze). It is
generally characterized by the inability to shift the
perceptual focus of vision to more than one feature at
a time in a multielement scene, as opposed to
representing a primary defect in recognition. In
58 AGNOSIA
visual associative agnosia, elementary visual percep-
tion is relatively intact, as evidenced by the ability to
match visual tokens or copy a drawing. However,
copying is often slavishly executed in a line-by-line
manner, lacking an appreciation of the whole.
Subjects can identify an object by touch or by a
verbal definition but are unable to name or demon-
strate recognition by nonverbal means, such as
pantomime or by grouping semantically related
objects (e.g., tools). Farah and Feinberg encapsulate
visual associative agnosia as ‘‘the loss of high-level
visual perceptual representations that are shaped by,
and embody the memory of, visual experience.’’
Visual associative agnosia has also been classified
according to specific categories of recognition deficits
(e.g., objects, words, and faces). In visual object
agnosia, recognition of everyday objects tends to be
more impaired for line drawings than for pictures,
which in turn is often worse relative to recognizing
the actual object. Optic aphasia, as with visual object
agnosia, is characterized by the selective inability to
identify an object on visual confrontation, but it is
thought to involve a modality-specific defect in
semantic access. The ability to point to or indicate
the use of an object on command demonstrates intact
semantic knowledge (recognition), and the ability to
name the object via tactile or auditory stimulation
distinguishes optic aphasia from an anomia. Visual
object agnosia is typically associated with bilateral
lesions in the occipitotemporal lobes, and it may be
accompanied by impaired recognition of words or
faces or both. The inability to recognize familiar
faces, prosopagnosia, is typically associated with
bilateral or right hemispheric occipitotemporal le-
sions and represents a special class of agnosic
phenomena. Subjects with prosopagnosia recognize
a face as a face (c.f., simultanagnosia), and even parts
of a face as such, but are unable to identify the face,
at times even their own, as being familiar. It is
distinguished from Capgras syndrome, in which a
spouse or close relative is viewed as an imposter. In
some cases of prosopagnosia, there may be addi-
tional deficits in recognizing specific exemplars of
other categories, such as automobiles or dogs, where
individual recognition depends on subtle visual
discrimination. Damasio and colleagues suggest that
the basic defect in prosopagnosia (and visual agnosia
in general) is a failure of the ‘‘visual trigger’’ to evoke
the relevant context for recognizing a familiar
stimulus. ‘‘Covert’’ recognition, in which subjects
exhibit autonomic arousal when viewing an osten-
sibly unrecognized familiar face, is variably present
in prosopagnosia. This phenomenon highlights the
dissociation between ‘‘explicit’’ (conscious) and
‘‘implicit’’ (unconscious) memory processes and
offers fertile ground for exploring mechanisms
underlying conscious awareness.
Auditory agnosia refers to the impaired ability to
recognize sounds despite adequate hearing as de-
monstrated by pure tone audiometry. In the late 19th
century, Freud first used the term agnosia to describe
a selective auditory recognition deficit as distinct
from a primary disturbance in language faculties.
Clinically, intact spontaneous speech, reading, and
writing skills distinguish an auditory agnosia from
aphasia. The term auditory agnosia has been used in
reference to impaired recognition of nonverbal
sounds only (e.g., a baby crying) or more broadly
to include both verbal and nonverbal auditory
recognition deficits. Pure word deafness and non-
verbal auditory agnosia are preferred terms for
indicating auditory recognition impairment of speech
and sounds, respectively. Cortical deafness is a
syndrome of profound impairment in the perception,
discrimination, and recognition of all auditory
stimuli. It is typically associated with bilateral
cerebrovascular lesions involving primary auditory
cortex (Heschl’s gyrus) and adjacent radiations, and
it is often accompanied by electrophysiological
evidence of impaired auditory perceptual acuity.
Pure word deafness involves the selective inability
to recognize speech, with relatively preserved appre-
ciation of nonverbal sounds and the absence of other
aphasic signs (e.g., paraphasic errors and reading or
writing impairment). Subjects may report that words
‘‘sound like a foreign language’’ or as ‘‘leaves rustling
in the wind.’’ Functionally, this syndrome represents
the disconnection of Wernicke’s area from bilateral
auditory input and is most commonly associated
with bilateral, symmetric cerebrovascular lesions
disrupting cortical and subcortical auditory path-
ways in the superior temporal gyrus. Subjects with
pure word deafness may exhibit difficulties with
phonemic discrimination and/or temporal resolution
of auditory stimuli, both implicated as left hemi-
sphere-dominant functions. Other cases may have a
more elementary ‘‘prephonemic’’ disturbance in
auditory perceptual acuity involving bilateral tem-
poral lobe lesions. Nonverbal auditory agnosia is a
rare syndrome with selective impairment in recogniz-
ing meaningful nonlinguistic sounds. Two forms
have been suggested: (i) a perceptual-discriminative
type characterized by acoustic recognition errors
(e.g., ‘‘crickets chirping’’ for ambulance siren) and

right hemisphere dysfunction and (ii) a semantic-
associative type arising from left hemisphere lesions
in which faulty recognition is semantically related
(e.g., ‘‘doorbell’’ for telephone ringer). Sensory
amusia refers to the inability to appreciate various
aspects of music. It is a frequent accompaniment of
pure word deafness, aphasia, and virtually all cases
of nonverbal auditory agnosia, but isolated cases
have been reported. Two suggested ‘‘paralinguistic’’
agnosia syndromes are auditory affective agnosia, a
deficit in being able to discern affective intonation in
speech, and phonagnosia, the inability to recognize
familiar voices. Both disorders are associated with
right hemisphere lesions, and the latter may represent
to some extent the auditory analog of prosopagnosia.
In comparison to visual and auditory agnosia
syndromes, primary disturbances in somatosensory
recognition are more steeply trenched in controversy
regarding their status as true agnosias. A major
branch of this controversy stems from difficulties
inherent in disentangling the integrated basic soma-
tosensory (kinesthetic and proprioceptive) and motor
processes utilized in tactual exploration of an object
in the service of recognition. Astereognosis has been
used to describe both the inability to make tactile
discriminations of shape and size and the inability to
recognize objects by touch. These two meanings of
the term roughly map to apperceptive and associative
types of agnosic phenomena, respectively. Tactile
agnosia is synonymous with the latter. Discrimina-
tion deficits in tactile recognition are most commonly
seen with lesions in the primary somatosensory area
and its connections in proximity to the somatotopic
‘‘hand’’ area. Lesions in related parietotemporal
somatosensory association areas are most strongly
implicated to underlie tactile agnosia.
The most common etiologies of agnosia syndromes
include cerebrovascular insults; toxic, metabolic, or
hypoxic injury; and degenerative brain disorders
(e.g., Alzheimer’s disease and corticobasal degenera-
tion). A specific type of epilepsy in children is associ-
ated with intermittent auditory agnosia (Landau–
Kleffner syndrome).
—Daniel I. Kaufer
See also–Agraphia; Alexia; Aphasia; Language
Disorders, Overview; Memory, Semantic;
Prosopagnosia; Visual Loss, Overview
Further Reading
Bauer, Russell M. (1993). Agnosia. In Clinical Neuropsychology
(K. M. Heilman and E. Valenstein, Eds.), 3rd ed. Oxford Univ.
Press, New York.
AGRAMMATISM 59
Damasio, A. R., Damasio, H., and Van Hoesen, G. W. (1982).
Prosopagnosia: Anatomic basis and behavioral mechanisms.
Neurology 32, 331–341.
Farah, M. J. (1990). Visual Agnosia: Disorders of Object
Recognition and What They Tell Us about Normal Vision.
MIT Press, Cambridge, MA.
Farah, M. J., and Feinberg, T. E. (1997). Visual object agnosia. In
Behavioral Neurology and Neuropsychology (T. E. Feinberg
and M. J. Farah, Eds.). McGraw-Hill, New York.
Geschwind, N. (1965). Disconnexion syndromes in animals and
man. Brain 88, 237–294.
Agrammatism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGRAMMATISM is an aphasic disorder characterized
by violations of grammatical rules in the subject’s
speech. Its most prominent feature is the difficulty
using ‘‘function’’ words (freestanding grammatical
morphemes, such as articles, prepositions, auxiliary
verbs, and clitic pronouns; bound grammatical
morphemes, such as verb and noun inflections,
etc.), in the presence of relative sparing of ‘‘content’’
words (nouns, adjectives, and verbs). It frequently
appears in the context of the nonfluent, dysarthric,
and dysprosodic speech characteristic of Broca’s
aphasia. In its mildest form, it is characterized by
fairly complex sentences with occasional omissions
of function words (e.g., ‘‘Then admitted againybe-
cause pain always feel. Take pills but no sleep.y
Then neurologist give sleeping pill, but I not sleep’’).
In more severe cases, speech consists of simple
sentences lacking function words (e.g., ‘‘In the
morning wear skirtythen bathythen washythen
exerciseyalways; then my daughterygo work). In
the most severe cases, it is reduced to one-word
utterances, often without recoverable grammatical
structure (e.g., ‘‘Meyhomeyheadacheydead!’’).
The features of agrammatic speech were first
studied in German-speaking subjects in the early
1900s. However, the characterization of the disorder
was critically influenced by later analyses conducted
on English-speaking aphasics. Thus, for a long time
the hallmark of agrammatism was deemed to be the
omission of function words, both freestanding and
bound to word roots. Studies conducted in the early
1980s on languages other than English (e.g., Italian,
Hebrew, and German) forced the reconsideration of
this view. They confirmed the widespread omission
of freestanding grammatical words but documented

right hemisphere dysfunction and (ii) a semantic-
associative type arising from left hemisphere lesions
in which faulty recognition is semantically related
(e.g., ‘‘doorbell’’ for telephone ringer). Sensory
amusia refers to the inability to appreciate various
aspects of music. It is a frequent accompaniment of
pure word deafness, aphasia, and virtually all cases
of nonverbal auditory agnosia, but isolated cases
have been reported. Two suggested ‘‘paralinguistic’’
agnosia syndromes are auditory affective agnosia, a
deficit in being able to discern affective intonation in
speech, and phonagnosia, the inability to recognize
familiar voices. Both disorders are associated with
right hemisphere lesions, and the latter may represent
to some extent the auditory analog of prosopagnosia.
In comparison to visual and auditory agnosia
syndromes, primary disturbances in somatosensory
recognition are more steeply trenched in controversy
regarding their status as true agnosias. A major
branch of this controversy stems from difficulties
inherent in disentangling the integrated basic soma-
tosensory (kinesthetic and proprioceptive) and motor
processes utilized in tactual exploration of an object
in the service of recognition. Astereognosis has been
used to describe both the inability to make tactile
discriminations of shape and size and the inability to
recognize objects by touch. These two meanings of
the term roughly map to apperceptive and associative
types of agnosic phenomena, respectively. Tactile
agnosia is synonymous with the latter. Discrimina-
tion deficits in tactile recognition are most commonly
seen with lesions in the primary somatosensory area
and its connections in proximity to the somatotopic
‘‘hand’’ area. Lesions in related parietotemporal
somatosensory association areas are most strongly
implicated to underlie tactile agnosia.
The most common etiologies of agnosia syndromes
include cerebrovascular insults; toxic, metabolic, or
hypoxic injury; and degenerative brain disorders
(e.g., Alzheimer’s disease and corticobasal degenera-
tion). A specific type of epilepsy in children is associ-
ated with intermittent auditory agnosia (Landau–
Kleffner syndrome).
—Daniel I. Kaufer
See also–Agraphia; Alexia; Aphasia; Language
Disorders, Overview; Memory, Semantic;
Prosopagnosia; Visual Loss, Overview
Further Reading
Bauer, Russell M. (1993). Agnosia. In Clinical Neuropsychology
(K. M. Heilman and E. Valenstein, Eds.), 3rd ed. Oxford Univ.
Press, New York.
AGRAMMATISM 59
Damasio, A. R., Damasio, H., and Van Hoesen, G. W. (1982).
Prosopagnosia: Anatomic basis and behavioral mechanisms.
Neurology 32, 331–341.
Farah, M. J. (1990). Visual Agnosia: Disorders of Object
Recognition and What They Tell Us about Normal Vision.
MIT Press, Cambridge, MA.
Farah, M. J., and Feinberg, T. E. (1997). Visual object agnosia. In
Behavioral Neurology and Neuropsychology (T. E. Feinberg
and M. J. Farah, Eds.). McGraw-Hill, New York.
Geschwind, N. (1965). Disconnexion syndromes in animals and
man. Brain 88, 237–294.
Agrammatism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGRAMMATISM is an aphasic disorder characterized
by violations of grammatical rules in the subject’s
speech. Its most prominent feature is the difficulty
using ‘‘function’’ words (freestanding grammatical
morphemes, such as articles, prepositions, auxiliary
verbs, and clitic pronouns; bound grammatical
morphemes, such as verb and noun inflections,
etc.), in the presence of relative sparing of ‘‘content’’
words (nouns, adjectives, and verbs). It frequently
appears in the context of the nonfluent, dysarthric,
and dysprosodic speech characteristic of Broca’s
aphasia. In its mildest form, it is characterized by
fairly complex sentences with occasional omissions
of function words (e.g., ‘‘Then admitted againybe-
cause pain always feel. Take pills but no sleep.y
Then neurologist give sleeping pill, but I not sleep’’).
In more severe cases, speech consists of simple
sentences lacking function words (e.g., ‘‘In the
morning wear skirtythen bathythen washythen
exerciseyalways; then my daughterygo work). In
the most severe cases, it is reduced to one-word
utterances, often without recoverable grammatical
structure (e.g., ‘‘Meyhomeyheadacheydead!’’).
The features of agrammatic speech were first
studied in German-speaking subjects in the early
1900s. However, the characterization of the disorder
was critically influenced by later analyses conducted
on English-speaking aphasics. Thus, for a long time
the hallmark of agrammatism was deemed to be the
omission of function words, both freestanding and
bound to word roots. Studies conducted in the early
1980s on languages other than English (e.g., Italian,
Hebrew, and German) forced the reconsideration of
this view. They confirmed the widespread omission
of freestanding grammatical words but documented
60 AGRAMMATISM
substitutions (rather than omissions) of bound
grammatical words. In these languages, which do
not allow the production of uninflected roots (in
Italian, vol- is the root of the verb volare, to fly, but is
not a real word, whereas talk- is the root of the verb
to talk but is also a real English word), inflected
words usually occur in one of the infinitival or
default forms. Additional deficits documented in
agrammatic speech are omissions of main verbs and
difficulties with word order or with case (in case-
marked languages such as German).
The frequent association of agrammatic speech
with Broca’s aphasia influenced attempts to distin-
guish this disorder from paragrammatic speech,
which would be characterized by substitutions
(rather than omissions) of function words and by
syntactically complex sentences, in the context of
fluent spoken output. However, analyses of sponta-
neous speech consistently failed to demonstrate
significantly different patterns of performance on
function words in the two disorders. Thus, the
apparent contrast between agrammatism and para-
grammatism seems to result from associated symp-
toms (nonfluent speech in the former, and fluent
speech in the latter) more than from theoretically
meaningful distinctions.
Subjects who speak agrammatically usually also
write ungrammatical sentences. Although detailed
analyses of writing are far less numerous than similar
analyses of speech, it has been suggested that in
writing agrammatism is generally milder and gram-
matical words are more prone to substitutions (as
opposed to omissions) than in speech. The co-
occurrence of agrammatism in speech and in writing
is not systematic, however, because there are reports
of agrammatic speech associated with normal writ-
ing and of agrammatic writing associated with
normal production of grammatical words in the
context of neologistic jargonaphasia.
Subjects with agrammatic production frequently
also present with agrammatic comprehension. It was
claimed for a long time that agrammatic subjects
have ‘‘good’’ comprehension of conversational
speech, but this view was reconsidered when
researchers started to evaluate comprehension by
means of semantically reversible sentences. A sen-
tence is semantically reversible when more than one
of the noun arguments can be agent, theme, or
beneficiary of the action denoted by the predicate
verb. Thus, ‘‘The boy was kissed by the girl’’ is a
semantically reversible sentence because in real life
both boy and girl can perform the act of kissing,
whereas ‘‘The apple was eaten by the boy’’ is
semantically irreversible because the act of eating
can only be performed by the boy. For the purpose of
studies on agrammatism, reversible sentences have
one crucial feature: Contrary to irreversible sen-
tences, which can be interpreted correctly merely on
the basis of encyclopedic knowledge (boy can eat
apple, but the reverse is impossible), they can be
comprehended only if grammatical rules are spared
(word order and the morphology of the sentence).
Thus, boy can kiss girl, and girl can kiss boy, but in
the sentence ‘‘The boy was kissed by the girl’’ word
order and passive morphology establish that it is the
girl who is doing the kissing. Experimental investiga-
tions on groups of subjects proved that aphasics who
produce ungrammatical sentences also fail to com-
prehend reversible sentences and other complex
syntactic structures that require, among other things,
a normal ability to process function words (e.g.,
those realizing the passive voice of a sentence). When
presented with the sentence ‘‘The horse is chased by
the cow,’’ an agrammatic speaker might decide that
horse, not cow, is doing the chasing, or he or she
might assign an identical meaning to the sentences
‘‘The boy that the girl is chasing is fat’’ and ‘‘The boy
that is chasing the girl is fat.’’ As in the case of
agrammatic speech and writing, the co-occurrence of
agrammatic production and comprehension, how-
ever frequent, is by no means the rule. Several reports
of subjects with flawless comprehension and agram-
matic output unequivocally demonstrate that agram-
matism can be restricted to production tasks.
INTERPRETATIONS
Early accounts of agrammatism (and some recent
proposals) focused on the production deficit. Deeply
influenced by the co-occurrence of the disorder with
the slow and effortful speech characteristic of Broca’s
aphasia, they invoked the notion of ‘‘economy of
effort.’’ In this view, the need to minimize articu-
latory effort leads the agrammatic speaker to plan
very simple and agrammatic sentences or to produce
simplified versions of sentences that at the planning
stage are complex and grammatically correct. This
results in utterances containing only the words that
are essential in order to convey the message; after all,
saying ‘‘Yesterdayywifeymovie’’ is not much less
informative than ‘‘Yesterday I went to see a movie
with my wife.’’ A distinct but somewhat related
hypothesis assumes that in agrammatic subjects only
words characterized by high values of stress and

saliency (as defined by phonological, emotional, and
motivational parameters) reach threshold for pro-
duction.
Faced with the frequent association of agrammatic
production and comprehension, later theories
struggled to find a unitary account of the disorder.
Agrammatism has been considered in turn the
consequence of a phonological deficit, of a syntactic
deficit, and of a lexical–semantic deficit. The
phonological deficit hypothesis attributes agramma-
tism to a failure to process unstressed words (the so-
called phonological nonwords) that do not alter the
assignment of sentential stress and in most languages
largely correspond to function words. In the presence
of such deficit, producing or comprehending a
sentence such as ‘‘The tiger is chased by the lion,’’
in which ‘‘the,’’ ‘‘is,’’ ‘‘-ed,’’ and ‘‘the’’ are phonolo-
gical nonwords, is impossible. According to syntactic
deficit theories, agrammatism results from the
inability to process various aspects of grammar.
Numerous proposals were made from this perspec-
tive. According to some authors, agrammatic sub-
jects manage to construct partial representations of a
sentence but cannot construct a global representation
due to a syntactic disorder (or, in some cases, to a
memory limitation). In a view inspired by Chomsky’s
government and binding theory, agrammatic subjects
are unable to produce grammatical sentences and fail
to comprehend complex grammatical structures
because they cannot process phonological traces.
According to others, agrammatism results from a
difficulty in processing word order, which obviously
results in failure to produce and comprehend
reversible sentences such as ‘‘The man is kissed by
the woman.’’ In another view, the disorder under-
lying agrammatism affects a ‘‘central syntactic
processor’’ responsible for processing function words
in comprehension and production. A different theory
proposes that agrammatism does not result from a
deficit affecting function words but from the inability
to map syntactic roles into semantic roles (in
comprehension) and vice versa (in production). In a
sentence such as ‘‘The man is kissed by the woman,’’
‘‘man’’ has the syntactic role of subject but the
semantic role of theme. Erroneous mapping of
syntactic into semantic roles (or vice versa) results
in incorrectly assigning to ‘‘man’’ the role of agent
instead of theme.
Each of these hypotheses focuses on a relevant
aspect of agrammatism and provides a reasonable
explanation for the performance observed in some
subjects. However, and without exception, these
AGRAMMATISM 61
theories fall short of a viable and comprehensive
account. The reason is that agrammatism is a
cognitively heterogeneous disorder: An agrammatic
speaker may or may not be an agrammatic writer,
and a subject with agrammatic production may or
may not present with agrammatic comprehension.
Furthermore, the functional deficits resulting in
agrammatic production and in agrammatic compre-
hension differ across subjects. In-depth analyses of
individual cases, based on extant theories of speech
production and comprehension, have begun to
document in further detail the range of distinct
cognitive deficits that can result in agrammatic
behavior. Agrammatic speech might result from one
or more of the following (or perhaps other, not yet
described, deficits): the inability to map semantic
roles into syntactic roles, omission or substitution of
function words as a consequence of selective damage
to the mental vocabulary, the inability to insert
grammatical words in the sentence frame even in the
presence of spared function word vocabulary, or
failure to retrieve the main verb. Similarly, agram-
matic comprehension might result from reduced
memory, from loss of syntactic abilities (both of
which, albeit by different mechanisms, impair the
construction of a complete structure for the stimulus
sentence), from the inability to map syntactic roles
into semantic roles, from the inability to understand
the meaning of the main verb or of the inflectional
endings of nouns or verbs, and so on. Also, in the
presence of a subject with agrammatic comprehen-
sion and production, it is impossible to establish a
priori whether the disorder results from damage to
one and the same mechanism, is shared by both
tasks, or results from separate impairments of
production and of comprehension.
The implications of these observations are
straightforward: Across-subject differences of the
types previously mentioned cannot reflect random
variation of performance across otherwise identical
subjects, and they result from damage to distinct
mechanisms. Thus, in order to understand gramma-
tical disorders of language and their neural corre-
lates, the most promising approach is to consider
‘‘agrammatism’’ as no more than a clinical label for a
set of cognitively heterogeneous disorders and to
concentrate on detailed studies of individual subjects.
Analyses of aphasic performance based on computa-
tional theories of language production and compre-
hension will allow us to understand the functional
mechanisms normally involved in speech processing,
the types of damage to these mechanisms that result
62 AGRAMMATISM
in the various forms of aphasic behavior, and their
representation in the brain.
CAUSES AND ANATOMICAL CORRELATES
The most frequent cause of agrammatism is a
cerebrovascular accident in the superior division of
the left middle cerebral artery supplying the frontal
and rolandic structures (Fig. 1). Less frequent causes
include brain tumors, traumatic head injuries, and
focal degenerative diseases such as the nonfluent
forms of primary progressive aphasia.
As expected on the basis of the co-occurrence of
agrammatism and nonfluent aphasia, brain damage
in these subjects often involves Broca’s area and
extends into adjacent cortical and subcortical struc-
tures of the frontal, superior temporal, and anterior
parietal lobes and into the insula. Involvement of the
left inferior frontal convolution in processing gram-
matical information is also suggested by recent
neuroimaging studies showing activation of this area
during tasks requiring syntactic processing. How-
ever, it is unclear which aspects of sentence proces-
sing are represented in these structures. For example,
damage to the left frontal structures involved in
agrammatism is also observed in subjects who are
unable to name verbs in isolation, and damage to the
Figure 1
CT scan displaying the brain regions typically damaged in
agrammatic aphasia.
perisylvian region without a prevalence of anterior
lesions was documented in a large sample of subjects
with agrammatic comprehension. In the two largest
samples of agrammatic speakers reported so far, the
largest lesion overlap was in the insula, and as many
as 20% of the subjects had lesions outside Broca’s
area and located posteriorly. Also, neuroimaging
data must be interpreted very cautiously because the
structures in or adjacent to Broca’s area (areas 44–
46) activated by syntactic tasks also show activation
during tasks that require processing of semantics,
lexicon, phonology, and working memory. Currently,
the most promising approach for the identification of
the brain structures underlying language comprehen-
sion and production is to combine the neuroanato-
mical evidence collected in subjects suffering from
damage to specific cognitive/linguistic mechanisms
with the activation results obtained in normal
subjects engaged in neuroimaging experiments.
—Gabriele Miceli
See also–Agraphia; Alexia; Anomia; Aphasia;
Language Disorders, Overview; Speech
Disorders, Overview
Further Reading
Badecker, W., and Caramazza, A. (1985). On considerations of
method and theory governing the use of clinical categories in
neurolinguistics and cognitive neuropsychology: The case
against agrammatism. Cognition 20, 97–125.
Caplan, D., Hildebrandt, N., and Makris, N. (1996). Location of
lesions in stroke patients with deficits in syntactic processing in
sentence comprehension. Brain 119, 933–949.
Caplan, D., Alpert, N., Waters, G., et al. (2000). Activation of
Broca’s area by syntactic processing under conditions of
concurrent articulation. Hum. Brain Mapp. 9, 65–71.
Caramazza, A., Capitani, E., Rey, A., et al. (2001). Agrammatic
Broca’s aphasia is not associated with a single pattern of
comprehension performance. Brain Lang. 76, 158–184.
Grodzinsky, Y., Pinango, M. M., Zurif, E. B., et al. (1999). The
critical role of group studies in neuropsychology: Comprehen-
sion regularities in Broca’s aphasia. Brain Lang. 67,
134–147.
Kean, M. L. (Ed.) (1983). Agrammatism. Academic Press, New
York.
Menn, L., and Obler, L. K. (Eds.) (1991). Agrammatic Aphasia. A
Narrative Sourcebook. Benjamins, Philadelphia.
Miceli, G. (1998). Grammatical disorders in aphasia. In
Handbook of Clinical and Experimental Neuropsychology (G.
Denes and L. Pizzamiglio, Eds.). Hove, Taylor & Francis,
London.
Miceli, G., Silveri, M. C., Romani, C., et al. (1989). Variation in
the pattern of omissions and substitutions of grammatical
morphemes in the spontaneous speech of so-called agrammatic
patients. Brain Lang. 36, 447–492.

Agraphia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGRAPHIA is a disorder of writing resulting from
damage to the brain. The terms agraphia and
dysgraphia are used interchangeably. Typically ex-
cluded from this definition are problems in writing,
spelling, and reading that emerge during childhood,
which is a condition referred to as developmental
dyslexia. Writing is a complex process involving the
integration of language skills, motor control, muscle
and joint sensation, and visual–spatial processing;
agraphia is a complex symptom with various
manifestations. Writing is readily disrupted by a
variety of specific and nonspecific brain injuries.
There is no systematic classification scheme for
agraphic disorders. Different varieties are usually
designated according to symptoms that accompany
the writing disorder, the presumptive underlying
mechanism of the writing disorder, or the patterns
of agraphic errors (Table 1). Although the following
discussion distinguishes writing disorders attributed
to a disturbance in language from those attributed to
other cognitive and neurological disorders, some-
times the distinction is uncertain, and occasionally
both linguistic and nonlinguistic processes are
simultaneously implicated.
ASSESSMENT
It should first be verified that the patient with
suspected agraphia was previously able to write
Table 1 WRITING DISORDERSa
Agraphia associated with a language disturbance
Aphasic agraphia
Alexia with agraphia
Lexical agraphia
Phonological agraphia
Deep agraphia
Semantic agraphia
Agraphia not associated with a language disturbance
Micrographia
Hypergraphia
Apraxic agraphia
Spatial agraphia
Other writing disorders
Agraphia in Gerstmann’s syndrome
Agraphia in confusional states
a
This agraphia classification scheme is neither systematic nor
comprehensive.
AGRAPHIA 63
and that the patient’s vision, sensation, and basic
motor functions are adequate for tasks at hand.
Writing is usually assessed with the patient’s pre-
ferred hand, although writing can be carried out with
either hand or, indeed, with almost any part of the
body (e.g., a pen can be grasped with the toes or
between the teeth). In special circumstances, testing
should include each hand since agraphia is occasion-
ally confined to the nondominant hand.
The ability to write single letters, numbers, words,
and longer narrative passages should be assessed.
Relevant tasks usually include copying printed text,
writing to dictation, and writing spontaneously.
Copying should include transcribing from one written
format to another (e.g., printed text to cursive text or
uppercase letters to lowercase letters). Because writing
is closely allied with spelling, written dictation at the
single word level should specifically assess words with
regular spellings (e.g., ‘‘hint’’ and ‘‘stuff’’), words with
irregular spellings (e.g., ‘‘pint’’ and ‘‘enough’’), and
made-up words (nonwords; e.g., ‘‘fint’’ and ‘‘zuff’’).
(Irregular words are those whose spelling does not
conform to common patterns of spelling-to-sound
correspondence.) Oral spelling should also be as-
sessed, and sometimes it is instructive to test spelling
with anagram letters, such as alphabet blocks.
AGRAPHIA ASSOCIATED WITH
LANGUAGE DISTURBANCES
The ability to communicate through writing is an
important aspect of language, and agraphia is most
commonly recognized in association with language
disorders. During the last half of the 19th century,
European scientists discovered that most language
functions are controlled by the left side of the brain,
at least in right-handed adults. Thus, damage to
specific regions of the left cerebral hemisphere
impairs the ability to express thought through speech
or to understand the speech of others, a condition
known as aphasia. Writing and reading represent the
expression and understanding of visual (as opposed
to oral) language, and most patients with aphasia are
simultaneously agraphic and alexic (alexia is a
disorder of reading resulting from damage to the
brain). The term aphasic agraphia is used the
designate the writing disturbance that accompanies
prominent impairments in oral language.
In aphasic agraphia, speech and writing are usually
affected in a similar manner. For example, patients
with Broca’s aphasia (an aphasic syndrome that
typically occurs as the result of injury to a specific
64 AGRAPHIA
portion of the left frontal lobe) speak slowly and
effortfully. They utter short phrases composed
primarily of nouns and verbs. Written productions
by these patients are also sparse, with short phrases
and a limited range of grammatical forms. Letters are
awkwardly formed, and individual words may be
spelled poorly. When injury to the left hemisphere
involves the posterior superior temporal lobe and
adjacent regions of the parietal lobe, symptoms of
Wernicke’s aphasia can appear. Patients with this
language disorder speak fluently and produce written
text with apparent ease. However, in both spoken
language and writing, their choice of words can be
incorrect. Misspellings occur frequently.
For some patients with left hemisphere damage,
writing is disrupted out of proportion to deficits in
oral communication. In the late 19th century, the
French neurologist Jules Dejerine demonstrated that
a lesion more or less restricted to the left angular
gyrus and underlying white matter, a portion of the
inferior parietal lobe, can severely impair both
reading and writing; oral language is only mildly
affected. Marked misspellings affect spontaneous
writing, written dictation, and text copying. This
disorder is often referred to as alexia with agraphia.
Dejerine believed that the left angular gyrus was
crucial for the visual memory of letters and words.
Other investigators suggest that multimodal sensory
integration within this brain region may be essential
for reading and writing.
Different aspects of spelling are occasionally
selectively disrupted by brain injury, suggesting that
accurate written spelling involves dissociable pro-
cesses. Modern studies focusing on patterns of spelling
errors, usually assessed on oral dictation tasks, suggest
the presence of several distinct agraphia syndromes.
Examples of disorders defined in this way are lexical,
phonological, deep, and semantic agraphia. Each of
these agraphias is associated with damage to language
areas within the left cerebral hemisphere, and other
aphasic manifestations are often prominent. Although
the left parietal lobe is often implicated, there is
considerable inconsistency from patient to patient
with regard to exact localization.
When agraphia is manifest by an inability to write
irregular words, the disorder is referred to as lexical
agraphia. Misspellings in this disorder often reflect
an accurate ‘‘sounding out’’ of the spelling (e.g.,
‘‘yot’’ or ‘‘hed’’ instead of ‘‘yacht’’ or ‘‘head’’).
Regular words are spelled accurately, and patients
are able to provide plausible spellings for nonwords.
In contrast, the principal characteristic of phonologi-
cal agraphia is the failure to spell unfamiliar words or
to spell nonwords. This deficit contrasts to preserva-
tion of spelling for familiar words, both regular and
irregular. Patients with deep agraphia are also unable
to spell nonwords, but the defining feature of this
disorder is the additional tendency to substitute an
incorrect word related in meaning to the intended
target (e.g., writing ‘‘chair’’ instead of ‘‘bench’’).
A deficit in understanding the meaning of words
(semantic deficits) is a common feature of dementia
due to Alzheimer’s disease. The term semantic
agraphia is used to describe the written manifestation
of this impairment. Semantic agraphia is most readily
identified when patients are asked to distinguish
between homophones (words pronounced the same
but spelled differently, such as ‘‘hymn’’ and ‘‘him’’).
The spelling is often incorrect, even when the context
is clear (e.g., ‘‘doe’’ may be written instead of
‘‘dough’’ in the sentence, ‘‘The baker used dough to
bake the bread’’). In semantic agraphia, writing to
dictation is typically much better than writing that
depends on a knowledge of word meaning. In
addition to the linguistic deficit of semantic agraphia,
the writing of Alzheimer patients suggests other
agraphic deficits that do not involve language
systems of the brain.
AGRAPHIA NOT ASSOCIATED WITH
LANGUAGE DISTURBANCES
Agraphia is usually recognized in association with a
disturbance in some particular aspect of language.
Pure agraphia, or agraphia as an isolated symptom,
is quite rare. Often, however, agraphia appears to be
the consequence of neurological or cognitive dys-
function that spares linguistic processing skills.
Writing impairments are almost inevitable when
motor systems of the brain are affected. Illnesses
affecting the corticospinal system, cerebellum, or
basal ganglia all disrupt the ability to form letters
normally when writing. It is almost trivial to point
out that mechanical aspects of writing are affected in
patients with partial paralysis, tremor, or the
involuntary jerky movements of chorea. A distinctive
writing impairment is seen in Parkinson’s disease, a
common disorder of the extrapyramidal motor
system due to a progressive loss of neurons that use
the neurotransmitter dopamine. Parkinson patients
have tremor, rigidity, a general tendency to move
very little (bradykinesia), and difficulty walking. In
addition, they often develop micrographia. This
handwriting pattern is distinguished not only by its

small size but also by the tendency for text to
diminish in height as it proceeds from the left side of
the page to the right, often trailing off to an illegible
scrawl. The concluding portion may resemble a
bumpy line more than actual words.
Excessive writing, or hypergraphia, accompanies
some neurological disorders. A small number of
epileptic patients with partial complex seizures
develop hypergraphia. Excessive writing does not
occur during the course of an epileptic seizure; rather,
the tendency for hypergraphia emerges as a stable
personality trait that persists even after seizures are
well controlled by medications. Affected persons may
begin to maintain a daily journal, or they may deluge
newspaper editors and public figures with letters.
Apart from the compulsion to write, motor, spelling,
and other linguistic aspects of writing remain
unaffected. Philosophical themes or moral concerns
are often reflected in the content. Some patients with
schizophrenia also evince hypergraphia.
Two examples of agraphia attributed to nonlin-
guistic cognitive impairments are apraxic agraphia
and spatial agraphia. Apraxia refers to a disorder of
skilled motor movement. Patients with apraxia may
be able to brush their hair normally but may be
unable to pretend to brush their hair; some apraxic
patients have difficulty carrying out the required
action even when actually holding a hair brush. For
right-handed persons, apraxia is almost always
associated with damage to the left cerebral hemi-
sphere (with or without aphasia). Occasionally,
apraxia will affect the ability to write. In apraxic
agraphia, spontaneous writing and writing to dicta-
tion may be quite illegible, whereas copying is better
preserved. Spelling words aloud, spelling with
anagram letters, reading, and other aspects of
language are spared.
A special case of apraxic agraphia occurs when
brain damage is largely limited to corpus callosum
fibers interconnecting the two cerebral hemispheres.
In this instance, agraphia may be confined to the left
hand (unilateral agraphia) and appears to represent a
disconnection between left hemisphere areas in-
volved in skilled motor movements and right hemi-
sphere motor cortex controlling more basic aspects
of arm and hand movement. Aphasic agraphia can
also be confined to the left hand, suggesting a
disconnection between language areas in the left
hemisphere and motor areas in the right hemisphere.
Damage to the right cerebral hemisphere can affect
visual–spatial aspects of writing, usually in associa-
tion with other features of the neglect syndrome. This
AGRAPHIA 65
syndrome is characterized in part by a tendency to
ignore stimuli originating from or affecting the
patient’s left side. For example, a woman with
unilateral neglect may fail to apply makeup to the
left side of her face or to eat food from the left side of
her food tray. Spatial agraphia as a part of the neglect
syndrome is indicated by abnormally wide left
margins, an upward slope of the line of text as it
progresses toward the right margin, and the addition
of extra strokes or loops (e.g., in cursive writing, ‘‘n’’
may be written as ‘‘m,’’ and ‘‘sleep’’ may be written as
‘‘sleeep’’). Writing spontaneously, writing to dicta-
tion, and copying are all affected in spatial agraphia.
Oral spelling and other language skills are spared.
OTHER VARIETIES OF AGRAPHIA
In addition to alexia with agraphia, damage to the
left angular gyrus is linked to a different and
somewhat controversial symptom complex. Deli-
neated during the first half of the 20th century by
the Viennese neurologist Josef Gerstmann, Gerst-
mann’s syndrome is defined by the co-occurrence of
four symptoms: difficulty distinguishing individual
fingers (sometimes referred to as finger agnosia; e.g.,
indicating which is the index finger and which is the
ring finger), difficulty distinguishing right from left,
difficulty with mathematical calculations (acalculia),
and agraphia. Word-finding difficulty (anomia) is
usually, but not inevitably, present, as are drawing
impairments. Although implicated regions of the left
parietal lobe subserve language functions, Gerst-
mann argued that the primary disturbance was one
of body image affecting the fingers. Other investiga-
tors believe that cardinal symptoms of the syndrome
are indeed language related.
Agraphia is very common in patients suffering
from an acute confusional state, a transient disorder
in which the ability to focus attention dominates the
clinical picture. Confusional states are caused by
intoxication, by metabolic derangements, and by
other processes that affect the brain in a diffuse
manner. There appear to be multiple determinants
for agraphia in these patients, with combinations of
motor, spatial, and linguistic impairments suggested
in writing samples. Other aspects of language are
often intact, and agraphia resolves as the confusional
state clears.
—Victor W. Henderson
See also–Acute Confusional State; Agnosia;
Alexia; Angular Gyrus Syndrome; Anomia;
66 AGRYPNIA
Aphasia; Apraxia; Language and Discourse;
Language Disorders, Overview; Writer’s Cramp/
Tremor
Further Reading
Chédru, F., and Geschwind, N. (1972). Writing disturbances in
acute confusional states. Neuropsychologia 10, 343–353.
Glosser, G., and Henderson, V. W. (2000). Writing impairments in
Alzheimer’s disease. In Neurobehavior of Language and
Cognition (L. T. Connor and L. K. Obler, Eds.), pp. 77–91.
Kluwer, Boston.
Roeltgen, D. P. (1993). Agraphia. In Clinical Neuropsychology (K.
M. Heilman and E. Valenstein, Eds.), 3rd ed., pp. 63–89.
Oxford Univ. Press, New York.
Agrypnia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGRYPNIA refers to total and prolonged insomnia
without a sensation of tiredness. The condition is
sometimes associated with involuntary movements
and hallucinations. Insomnia has been found with
lesions of raphe nuclei in the brainstem tegmentum,
the anterior hypothalamus, and the thalamus. In
some cases, agrypnia relates to a deficiency of
serotonin because symptoms are sometimes relieved
by the administration of 5-hydroxytryptophan, a
precursor of serotonin (5-hydroxytryptamine). Fatal
familial insomnia is a prion disease that affects the
thalamus, especially its anteroventral and medial
dorsal nuclei. Gamma-aminobutyric acid (GABA)
synapses appear to be disproportionately involved,
so GABA mechanisms are also sometimes relevant.
—G. Bryan Young
See also–Gamma Aminobutyric Acid (GABA);
Fatal Familial Insomnia; Insomnia; Insomnia,
Behavioral Treatment of; Sleep Disorders
Further Reading
Autret, A., Henry-Le Bras, F., Duvelleroy-Hommet, C., et al.
(1995). Les agrynies. Neurophysiol. Clin. 25, 360–366.
Fioromo, A. S. (1996). Sleep, genes and death: Fatal familial
insomnia. Brain Res. Brain Res. Rev. 22, 258–264.
Lugaresi, E., Tobler, I., Gambetti, P., et al. (1998). The
pathophysiology of fatal familial insomnia. Brain Pathol. 8,
521–526.
Montagna, P., Cortelli, P., Gambetti, P., et al. (1995). Fatal familial
insomnia: Sleep, neuroendocrine and vegetative alterations.
Adv. Neuroimmunol. 5, 13–21.
AIDS/HIV and Neurological
Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RECOGNIZED less than 20 years ago as the cause of
the acquired immunodeficiency syndrome (AIDS),
human immunodeficiency virus (HIV) infection has
rapidly become one of the leading causes of
morbidity and mortality worldwide. The World
Health Organization estimates that through the end
of 2001, over 40 million people worldwide are
infected with HIV. Rates of infection are particularly
high in central Africa and Southeast Asia. Most new
HIV infections are occurring in developing nations
with limited resources and little access to effective
therapies. In addition, HIV prevention programs are
very inadequate in some of the countries most
affected by the epidemic. Consequently, HIV infec-
tion represents a global health crisis of enormous
proportions.
In the United States, by the end of 2001, 816,149
cumulative cases of AIDS with 467,910 deaths had
been reported. The Centers for Disease Control
estimates that between 650,000 and 900,000 Amer-
icans are currently HIV infected. In the United States,
the epidemic has shifted over time, with an increas-
ing proportion of new infections occurring among
individuals with injection drug use or heterosexual
activity as underlying risk behaviors. Persons of color
and persons of low socioeconomic status have been
disproportionately affected.
Fortunately, the ability to manage HIV infection
has improved markedly during the past 5 years,
primarily due to the development of new medications
that directly inhibit HIV.
PATHOGENESIS OF HIV INFECTION
HIV is transmitted through contact with HIV-
infected blood, semen, vaginal secretions, or breast
milk. The major specific means of transmission are
through anal and vaginal intercourse, sharing of
needles for injection drug use, and mother-to-infant
transmission. Within 2–6 weeks of infection, most
persons will develop an acute febrile illness termed
primary HIV infection. This illness is self-limited and
most individuals will then have a relatively long
period of clinical latency before additional illness
develops. However, viral replication is active
66 AGRYPNIA
Aphasia; Apraxia; Language and Discourse;
Language Disorders, Overview; Writer’s Cramp/
Tremor
Further Reading
Chédru, F., and Geschwind, N. (1972). Writing disturbances in
acute confusional states. Neuropsychologia 10, 343–353.
Glosser, G., and Henderson, V. W. (2000). Writing impairments in
Alzheimer’s disease. In Neurobehavior of Language and
Cognition (L. T. Connor and L. K. Obler, Eds.), pp. 77–91.
Kluwer, Boston.
Roeltgen, D. P. (1993). Agraphia. In Clinical Neuropsychology (K.
M. Heilman and E. Valenstein, Eds.), 3rd ed., pp. 63–89.
Oxford Univ. Press, New York.
Agrypnia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGRYPNIA refers to total and prolonged insomnia
without a sensation of tiredness. The condition is
sometimes associated with involuntary movements
and hallucinations. Insomnia has been found with
lesions of raphe nuclei in the brainstem tegmentum,
the anterior hypothalamus, and the thalamus. In
some cases, agrypnia relates to a deficiency of
serotonin because symptoms are sometimes relieved
by the administration of 5-hydroxytryptophan, a
precursor of serotonin (5-hydroxytryptamine). Fatal
familial insomnia is a prion disease that affects the
thalamus, especially its anteroventral and medial
dorsal nuclei. Gamma-aminobutyric acid (GABA)
synapses appear to be disproportionately involved,
so GABA mechanisms are also sometimes relevant.
—G. Bryan Young
See also–Gamma Aminobutyric Acid (GABA);
Fatal Familial Insomnia; Insomnia; Insomnia,
Behavioral Treatment of; Sleep Disorders
Further Reading
Autret, A., Henry-Le Bras, F., Duvelleroy-Hommet, C., et al.
(1995). Les agrynies. Neurophysiol. Clin. 25, 360–366.
Fioromo, A. S. (1996). Sleep, genes and death: Fatal familial
insomnia. Brain Res. Brain Res. Rev. 22, 258–264.
Lugaresi, E., Tobler, I., Gambetti, P., et al. (1998). The
pathophysiology of fatal familial insomnia. Brain Pathol. 8,
521–526.
Montagna, P., Cortelli, P., Gambetti, P., et al. (1995). Fatal familial
insomnia: Sleep, neuroendocrine and vegetative alterations.
Adv. Neuroimmunol. 5, 13–21.
AIDS/HIV and Neurological
Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RECOGNIZED less than 20 years ago as the cause of
the acquired immunodeficiency syndrome (AIDS),
human immunodeficiency virus (HIV) infection has
rapidly become one of the leading causes of
morbidity and mortality worldwide. The World
Health Organization estimates that through the end
of 2001, over 40 million people worldwide are
infected with HIV. Rates of infection are particularly
high in central Africa and Southeast Asia. Most new
HIV infections are occurring in developing nations
with limited resources and little access to effective
therapies. In addition, HIV prevention programs are
very inadequate in some of the countries most
affected by the epidemic. Consequently, HIV infec-
tion represents a global health crisis of enormous
proportions.
In the United States, by the end of 2001, 816,149
cumulative cases of AIDS with 467,910 deaths had
been reported. The Centers for Disease Control
estimates that between 650,000 and 900,000 Amer-
icans are currently HIV infected. In the United States,
the epidemic has shifted over time, with an increas-
ing proportion of new infections occurring among
individuals with injection drug use or heterosexual
activity as underlying risk behaviors. Persons of color
and persons of low socioeconomic status have been
disproportionately affected.
Fortunately, the ability to manage HIV infection
has improved markedly during the past 5 years,
primarily due to the development of new medications
that directly inhibit HIV.
PATHOGENESIS OF HIV INFECTION
HIV is transmitted through contact with HIV-
infected blood, semen, vaginal secretions, or breast
milk. The major specific means of transmission are
through anal and vaginal intercourse, sharing of
needles for injection drug use, and mother-to-infant
transmission. Within 2–6 weeks of infection, most
persons will develop an acute febrile illness termed
primary HIV infection. This illness is self-limited and
most individuals will then have a relatively long
period of clinical latency before additional illness
develops. However, viral replication is active
66 AGRYPNIA
Aphasia; Apraxia; Language and Discourse;
Language Disorders, Overview; Writer’s Cramp/
Tremor
Further Reading
Chédru, F., and Geschwind, N. (1972). Writing disturbances in
acute confusional states. Neuropsychologia 10, 343–353.
Glosser, G., and Henderson, V. W. (2000). Writing impairments in
Alzheimer’s disease. In Neurobehavior of Language and
Cognition (L. T. Connor and L. K. Obler, Eds.), pp. 77–91.
Kluwer, Boston.
Roeltgen, D. P. (1993). Agraphia. In Clinical Neuropsychology (K.
M. Heilman and E. Valenstein, Eds.), 3rd ed., pp. 63–89.
Oxford Univ. Press, New York.
Agrypnia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AGRYPNIA refers to total and prolonged insomnia
without a sensation of tiredness. The condition is
sometimes associated with involuntary movements
and hallucinations. Insomnia has been found with
lesions of raphe nuclei in the brainstem tegmentum,
the anterior hypothalamus, and the thalamus. In
some cases, agrypnia relates to a deficiency of
serotonin because symptoms are sometimes relieved
by the administration of 5-hydroxytryptophan, a
precursor of serotonin (5-hydroxytryptamine). Fatal
familial insomnia is a prion disease that affects the
thalamus, especially its anteroventral and medial
dorsal nuclei. Gamma-aminobutyric acid (GABA)
synapses appear to be disproportionately involved,
so GABA mechanisms are also sometimes relevant.
—G. Bryan Young
See also–Gamma Aminobutyric Acid (GABA);
Fatal Familial Insomnia; Insomnia; Insomnia,
Behavioral Treatment of; Sleep Disorders
Further Reading
Autret, A., Henry-Le Bras, F., Duvelleroy-Hommet, C., et al.
(1995). Les agrynies. Neurophysiol. Clin. 25, 360–366.
Fioromo, A. S. (1996). Sleep, genes and death: Fatal familial
insomnia. Brain Res. Brain Res. Rev. 22, 258–264.
Lugaresi, E., Tobler, I., Gambetti, P., et al. (1998). The
pathophysiology of fatal familial insomnia. Brain Pathol. 8,
521–526.
Montagna, P., Cortelli, P., Gambetti, P., et al. (1995). Fatal familial
insomnia: Sleep, neuroendocrine and vegetative alterations.
Adv. Neuroimmunol. 5, 13–21.
AIDS/HIV and Neurological
Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RECOGNIZED less than 20 years ago as the cause of
the acquired immunodeficiency syndrome (AIDS),
human immunodeficiency virus (HIV) infection has
rapidly become one of the leading causes of
morbidity and mortality worldwide. The World
Health Organization estimates that through the end
of 2001, over 40 million people worldwide are
infected with HIV. Rates of infection are particularly
high in central Africa and Southeast Asia. Most new
HIV infections are occurring in developing nations
with limited resources and little access to effective
therapies. In addition, HIV prevention programs are
very inadequate in some of the countries most
affected by the epidemic. Consequently, HIV infec-
tion represents a global health crisis of enormous
proportions.
In the United States, by the end of 2001, 816,149
cumulative cases of AIDS with 467,910 deaths had
been reported. The Centers for Disease Control
estimates that between 650,000 and 900,000 Amer-
icans are currently HIV infected. In the United States,
the epidemic has shifted over time, with an increas-
ing proportion of new infections occurring among
individuals with injection drug use or heterosexual
activity as underlying risk behaviors. Persons of color
and persons of low socioeconomic status have been
disproportionately affected.
Fortunately, the ability to manage HIV infection
has improved markedly during the past 5 years,
primarily due to the development of new medications
that directly inhibit HIV.
PATHOGENESIS OF HIV INFECTION
HIV is transmitted through contact with HIV-
infected blood, semen, vaginal secretions, or breast
milk. The major specific means of transmission are
through anal and vaginal intercourse, sharing of
needles for injection drug use, and mother-to-infant
transmission. Within 2–6 weeks of infection, most
persons will develop an acute febrile illness termed
primary HIV infection. This illness is self-limited and
most individuals will then have a relatively long
period of clinical latency before additional illness
develops. However, viral replication is active

throughout the course of the disease. The CD4 þ T
lymphocyte is the primary target of HIV infection
and the loss of this cell population produces an
immunodeficiency that allows opportunistic infec-
tions and malignancies to occur. The rate of viral
replication predicts the rate at which clinical
immunodeficiency develops and can be estimated
by measuring the plasma HIV-1 RNA level (also
called the viral load). Although most individuals with
HIV infection will develop progressive immunodefi-
ciency, a small proportion of ‘‘long-term nonpro-
gressors’’ may not. Antiretroviral medications inhibit
HIV replication and its destruction of CD4 þ T
lymphocytes. In early HIV infection, these medica-
tions can prevent the development of immunodefi-
ciency. In advanced disease, these medications can
lead to immune reconstitution.
RECENT DEVELOPMENTS
IN HIV TREATMENT
The recent decline in the mortality of HIV infection
in the United States is primarily due to the licensure
of potent antiretroviral medications against HIV.
HIV replication requires a series of steps that include
attachment of the virus to host cell receptors, fusion
of the virus with the cell membrane, uncoating of the
virus, reverse transcription of viral RNA into DNA,
integration of the viral DNA into the host genome,
DNA replication, transcription of viral RNA, trans-
lation of viral proteins, cleavage of protein precur-
sors into enzymes and structural proteins using a
protease, assembly of the virus, and budding from
Figure 1
Life cycle of HIV.
AIDS/HIV AND NEUROLOGICAL DISEASE 67
the cell membrane (Fig. 1). Each of these steps offers
an opportunity for inhibition with a drug. In fact,
there are investigational HIV inhibitors for all of
these steps. The 16 currently licensed antiretroviral
agents inhibit either reverse transcriptase or protease.
Selected characteristics of these medications are
listed in Table 1. Of note, 12 of these medications
have been licensed during the past 8 years.
Antiretroviral medications are typically used in
combinations of three or four drugs. Current
antiretroviral treatment guidelines, available on the
World Wide Web at www.hivatis.org, reflect those
combinations that have been most successful in terms
of clinical efficacy and safety profile. The efficacy of
an individual treatment regimen is measured by
improvement in the clinical manifestations of HIV
infection, immunological improvement (i.e., rising
CD4 lymphocyte counts), and virologic improve-
ment (i.e., reduction in the plasma HIV-1 RNA
level). These medications do have potential limita-
tions, including side effects, drug interactions, and
the development of drug resistance.
Antiretroviral therapy has also dramatically re-
duced the rate of HIV transmission from mother to
infant. Studies done prior to the availability of
antiretroviral therapy indicated that the risk of
transmission from an HIV-infected mother to infant
was approximately 25%. Combination antiretroviral
therapy of mother and infant reduces this risk to less
than 5%.
Another important aspect of HIV care is the
treatment and prevention of opportunistic infections.
Many of these infections can be effectively managed
68 AIDS/HIV AND NEUROLOGICAL DISEASE

Table 1 CURRENTLY AVAILABLE ANTIRETROVIRAL AGENTS

Agent Trade name Drug class Side effects Usual dosea

Zidovudine (ZDV, AXT) Retrovir Nucleoside RTI Anemia, leukopenia, myopathy 300 mg PO BID
Didanosine (ddI) Videx Nucleoside RTI Pancreatitis, hepatitis, peripheral neuropathy 200 mg PO BID
Zalcitabine (ddC) HIVID Nucleoside RTI Peripheral neuropathy 0.75 mg PO BID
Stavudine (d4T) Zerit Nucleoside RTI Peripheral neuropathy 40 mg PO BID
Lamivudine (3TC) Epivir Nucleoside RTI Nausea 150 mg PO BID
Abacavir (ABC) Ziagen Nucleoside RTI Hypersensitivity reaction 300 mg PO BID
Tenofovir Viread Nucleoside RTI Nausea 300 mg PO QD
Nevirapine Viramune Nonnucleoside RTI Hepatitis, skin rash 200 mg PO BID
Delvirdine Rescriptor Nonnucleoside RTI Skin rash 400 mg PO BID
Efavirenz Sustiva Nonnucleoside RTI Skin rash, dizziness, other CNS side effects 600 mg PO BID
Saquinavir Invirase Protease inhibitor Nausea, diarrhea 600 mg PO BID
Fortovase 1200 mg PO BID
Ritonavir Norvir Protease inhibitor Nausea, diarrhea, hyperlipidemia 600 mg PO BID
Indinavir Crixivan Protease inhibitor Nausea, nephrolithiasis 800 mg PO BID
Nelfinavir Viracept Protease inhibitor Diarrhea 750 mg PO BID
Amprenavir Agenerase Protease inhibitor Nausea, diarrhea 1200 mg PO BID
Lopinavir with ritonavir Kaletra Protease inhibitor Elevated liver enzymes, hyperlipidemia Three capsules PO BID
a
Doses may vary based on weight, the presence of renal or hepatic failure, or when using combinations that have pharmacokinetic
interactions. Formulations combining zidovudine/lamivudine (Combivir) and zidovudine/lamivudine/abacavir (Trizivir) have been
developed.

with specific antibiotic therapy, and the immunolo-
gical improvement associated with antiretroviral
therapy also helps to control these diseases. A
number of these infections, including Pneumocystis
carinii pneumonia, toxoplasmosis, tuberculosis, and
disseminated Mycobacterium avium complex dis-
ease, are common enough that primary prevention
through antibiotic prophylaxis is recommended.
Recent studies demonstrate that these prophylactic
therapies can often be discontinued once immunolo-
gical improvement on antiretroviral therapy has
occurred. Current guidelines for the prevention and
treatment of opportunistic infections are also avail-
able on the World Wide Web (www.hivatis.org).
HUMAN IMMUNODEFICIENCY VIRUS AND
NEUROLOGICAL DISEASE
HIV infects the nervous system early after exposure
to the virus and clinical manifestations may affect all
areas of the nervous system. Initial manifestations of
AIDS occur in the nervous system in up to 20% of
patients, but the frequency of neurological complica-
tions related to AIDS increases significantly over time
and with declines in the CD4 þ T lymphocyte count.
Clinical symptoms occur in the central nervous
system (CNS) and the peripheral nervous system
(PNS) and may result from direct effects of HIV
infection, opportunistic infections or neoplasms
related to immunosuppression, or iatrogenic effects
of pharmacological intervention. The most common
disorders are peripheral neuropathy, HIV-1-asso-
ciated dementia, primary CNS lymphoma, and
opportunistic infections, including CNS toxoplasmo-
sis and progressive multifocal leukoencephalopathy
(Table 2).
CENTRAL NERVOUS SYSTEM
HIV-Associated Dementia
Shortly after the initial descriptions of AIDS, a
subacute, progressive dementing illness was de-
scribed. It was first referred to as the AIDS dementia
complex (ADC), but it is now commonly called HIV-
associated dementia (HAD). HAD is almost always
seen in patients with a CD4 þ T lymphocyte count
below 200 cells/mm3 and a previous AIDS-defining
condition, although rarely it may be the presenting
sign of AIDS. Prior to the introduction of zidovudine
and the subsequent development of combination
antiretroviral therapy, HAD was described in up to
approximately 27% of patients in the late stages of
AIDS. Pathological changes associated with HAD
 AIDS/HIV AND NEUROLOGICAL DISEASE 69

Table 2 ETIOLOGY OF SELECTED NEUROLOGICAL SYNDROMES IN HIV INFECTION

Syndrome Common etiologies

Meningitis Pneumococcus, treponema pallidum, mycobacterium tuberculosis, cryptococcus, histoplasma, HIV

Focal CNS deficits
Diffuse peripheral neuropathy
Myelopathy
Myopathy/myositis
Polyradiculopathy
Toxoplasmosis, PCNSL, bacterial brain abscess, progressive multifocal leukoencephalopathy
Didanosine, stavudine, zalcitabine, ritonavir, autoimmune reaction, HIV
VZV, CMV, HSV, B12 deficiency, PCNSL, HIV
Zidovudine, bacterial infection, HIV
CMV, carcinomatous or lymphomatous meningitis

were seen in an even greater percentage of AIDS
patients at autopsy. Although reliable estimates of
the current prevalence of HAD are difficult to obtain,
the introduction of combination antiretroviral ther-
apy appears to have had a profound impact on the
number of patients afflicted with this complication.
Symptoms may be very mild, the so-called minor
cognitive-motor disorder (MCMD), or very severe
(HAD or ADC). HAD is defined as a significant
decline in at least two cognitive functions for 1
month, moderate to severe functional decline, and
exclusion of other causes of cognitive-motor impair-
ment. In contrast, the cognitive-motor deficits in
MCMD have a less severe effect on functional
capacity. Usual symptoms reflect damage to the
white matter and subcortical gray structures, espe-
cially the basal ganglia, thalamus, and brainstem.
These include difficulties with attention, concentra-
tion, information processing speed and response
time, memory, verbal fluency, visuospatial and
visuoconstructive capacity, and abstract reasoning.
There may be significant personality change, irrit-
ability, social withdrawal, and emotional lability.
Patients often have signs similar to those of
Parkinson’s disease, including bradykinesia, tremor,
and gait disturbance, and may have increased
reflexes on neurological examination.
Examination of the cerebrospinal fluid often
reveals a modest lymphocytic pleocytosis, an ele-
vated protein, and a normal glucose level. Magnetic
resonance imaging (MRI) scans show diffuse atrophy
and a variable amount of T2-weighted lesions
affecting primarily the subcortical white matter and
basal ganglia. These lesions may be punctate, diffuse,
or confluent. Enhancement after the injection of
contrast material usually is not seen. Pathological
abnormalities include microglial nodules, multinu-
cleated giant cells, myelin pallor, and astrocytic
gliosis. Neuronal dropout can be severe, especially
in the frontal cortex, basal ganglia, and limbic
system.
HAD appears to be caused by HIV, although the
pathogenesis remains unclear. HIV enters the nervous
system early after acquisition of infection. This
probably occurs as infected macrophages traffic
through the CNS (the Trojan Horse theory) or via
infection of endothelial cells. Cell-free invasion also
may be possible. There is extensive variation among
HIV-1 substrains or quasispecies throughout the
world and, somewhat less, within individuals.
Quasi-species that diverge from those in other organ
systems within the same individual, and that are
unique to the nervous system, evolve in specific
neuroanatomical regions within the CNS. Some of
these quasi-species may be related to propagation of
HAD, although there is conflicting evidence in this
area of research. HIV-1 is found in the brains of
patients with and without symptoms of HAD, and
clinical symptoms and pathological damage are not
closely correlated with viral load assessed in the
brain or cerebrospinal fluid (CSF). Significant,
productive HIV infection in the CNS appears to be
limited to cells of the macrophage lineage. Symptoms
of HAD do appear to correlate with these infected
cells. A variety of HIV protein products, and cellular
products such as cytokines and chemokines, have
been implicated as potential direct or indirect
mediators of pathological damage.
Consistent with the idea that HAD is a direct result
of HIV infection in the brain, antiretroviral treat-
ment, especially with high doses of zidovudine
(ZDV), diminishes symptoms. In addition, the wide-
spread use of combination antiretroviral therapy
appears to be associated with a significant reduction
in the incidence and prevalence of HAD. However,
antiretroviral treatment failure may lead to a re-
bound of HIV infection and increased risk for HAD.
There are probably relatively isolated cellular and
anatomical reservoirs of HIV infection in treated
patients, including resting CD4 þ T lymphocytes
carrying integrated viral DNA, the male urogenital
tract, and the CNS. Penetration of antiretroviral
70 AIDS/HIV AND NEUROLOGICAL DISEASE
drugs such as protease inhibitors into the CNS may
be limited by the membrane efflux transporter P-
glycoprotein in the capillary epithelium. HIV pro-
tease inhibitor concentrations may be increased in
these reservoir sites by the addition of inhibitors of
this P-glycoprotein or of low-dose Ritonavir to
regimens with Idinavir, Saquinavir, Amprenavir, or
Lopinavir. Some of the antiretroviral medicines have
increased CNS penetration compared to others, but
specific treatment regimens which take this into
account have not been studied.
Vacuolar Myelopathy
Although clinical symptoms are rarely seen during
life, signs of a thoracic myelopathy associated with
vacuoles (VM) are seen in 40–55% in autopsy series.
Clinical features include painless leg weakness, gait
instability, sensory loss in the legs, impotence in men,
and urinary and bowel dysfunctions. When diag-
nosed during life, VM is almost exclusively found in
patients with HAD and CD4 þ T lymphocyte counts
less than 200 cells/mm3. There are no characteristic
CSF features, and MRI scans of the cord demonstrate
thoracic atrophy and/or T2-weighted hyperintense
lesions. Peripheral neuropathy is seen concomitantly
in approximately 50% of patients and may produce
symptoms that overlap with or mimic VM. Somato-
sensory evoked potentials may be useful in distin-
guishing VM from peripheral neuropathy. VM often
progresses to severe paraparesis and sphincteric
dysfunction, and it is a bad prognostic sign in AIDS
patients. Other causes of myelopathy, including
varicella-zoster virus (VZV), cytomegalovirus
(CMV), herpes simplex virus (HSV), primary CNS
lymphoma (PCNSL), and vitamin B12 deficiency,
should be excluded. The pathogenesis of VM is
unknown and there is no significant evidence that
treatment with antiretroviral therapy has any impact
on VM.
Opportunistic Infections
Patients infected with HIV-1 are prone to develop
opportunistic infections (OIs), especially when the
CD4 þ T lymphocyte count falls below 200 cells/
mm3. The nervous system may be infected by
bacteria, fungi, parasites, or viruses, with many of
these infections seen almost exclusively in immuno-
compromised patients.
Bacterial infections of the CNS are common in
HIV-infected patients. Syphilis may present sympto-
matically with either focal lesions, such as stroke,
optic neuropathy, or seventh cranial nerve palsy, or,
in a more generalized fashion, with meningitis or
dementia. The natural history of syphilis may be
accelerated in the setting of HIV infection, with
various forms of neurosyphilis occurring soon after
primary, secondary, or latent syphilis. Tuberculosis
may also occur, typically producing a basilar
meningitis affecting multiple cranial nerves and
inducing hydrocephalus. Bacterial abscesses, either
intracerebral or epidural, especially may be seen in
intravenous drug users with infected cardiac valves.
Diagnosis of specific bacterial infections is made by a
combination of imaging studies, CSF analyses,
microbiological studies, and serologies. Antibiotic
treatment is directed toward the specific bacterium
involved and abscesses may also require surgical
drainage.
A variety of fungal infections of the nervous system
have been described in HIV-infected patients. These
infections will produce either intracerebral abscesses
or meningitis. The most common fungal infection of
the CNS is cryptococcal meningitis. This infection
typically presents with a subacute headache, stiff
neck, and fever. Hydrocephalus or tumor-like cryp-
tococcomas may also be seen. Examination of the
CSF will reveal a variable number of white blood
cells, an elevated protein level, and a normal or
slightly reduced glucose level. Both CSF and serum
cryptococcal antigen tests will be positive in the vast
majority of patients. Acute treatment is with
amphotericin B, followed by secondary prophylaxis
with fluconazole. Histoplasmosis may produce ring-
enhancing mass lesions and meningitis.
Viral infections of the CNS are common in HIV
patients. Progressive multifocal leukoencephalopathy
(PML) is a demyelinating disorder of the CNS that
occurs in up to 5% of HIV-1-infected patients. It is
the result of infection with JC virus (JCV), a member
of the papillomavirus family, of oligodendrocytes,
the cells that make CNS myelin. JCV is probably
spread by respiratory means, and IgG antibodies to
JCV are seen in approximately 10% of young
children and up to 90% of adults. This suggests that
clinical disease represents a reactivation of latent
infection.
The clinical presentation of PML is typically
multifocal, with combinations of weakness, sensory
loss, visual loss, and ataxia. Seizures may be seen less
commonly. Cognitive impairments may also be seen,
including poor attention, memory problems, aphasia,
and behavioral and personality changes.
Pathologically, the lesions vary in size from 1-mm,
punctate lesions to confluent lesions of several

centimeters, and they consist of oligodendrocytes
with enlarged, hyperchromatic nuclei and bizarre
astrocytes with lobulated, hyperchromatic nuclei.
Lesions are typically not associated with inflamma-
tion, but this may be seen, especially in patients with
CD4 þ T lymphocyte counts above 300 cells/mm3.
Similarly, brain MRI usually does not reveal en-
hancement after the injection of contrast material
unless there is a significant inflammatory component
to the lesions. The brain MRI is not absolutely
diagnostic, however. In research studies, polymerase
chain reaction (PCR) of CSF may reveal evidence of
JCV DNA in the CSF in up to 90% of biopsy-proven
cases, but in practice the sensitivity of CSF PCR is
not that high. The CSF otherwise is typically not
abnormal, and brain biopsy is still frequently
required for definitive diagnosis. Prognosis remains
poor, and preliminary studies treating PML with
Cidofovir have been disappointing. Reconstitution of
the immune system with HAART sometimes may
lead to clinical stabilization.
CMV infection is often seen in the brain, although
it is commonly asymptomatic. It is found so
frequently in the brains of autopsied patients that
at one time it was believed to be a leading candidate
as the cause of HAD. When symptomatic, systemic
CMV infection is usually present. CMV in the brain
may cause a panencephalitis, presenting as a
subacute or acute encephalopathy with confusion
and disorientation. More focal findings, such as
seizures, weakness, or sensory loss, may also be seen.
MRI scans may reveal nonspecific white and gray
matter changes, meningeal enhancement, or a
ventricular/periventricular enhancement.
Interestingly, HSV encephalitis is not increased in
incidence in HIV-infected patients. When present, its
clinical and pathological features are similar to those
seen in immunocompetent patients. VZV may
produce a diffuse meningoencephalitis, a myelitis,
or a focal arteritis resulting in stroke.
In all these herpes family infections, there will be a
variable lymphocytic pleocytosis in the CSF, with
mildly elevated protein and normal glucose. All are
diagnosed with reasonably high specificity and
sensitivity with PCR analysis in the CSF. Treatment
of HSV and VZV CNS infections is with intravenous
acyclovir, whereas CMV is treated with ganciclovir
and/or foscarnet.
Occurring in up to 15% of AIDS patients in the
preantiretroviral era, toxoplasmosis is the most
common OI of the CNS. Toxoplasma gondii infec-
tion in humans occurs after ingestion of oocysts shed
AIDS/HIV AND NEUROLOGICAL DISEASE 71
by cat feces or bradyzoites found in undercooked
meat, and the primary infection is usually asympto-
matic. Cerebral toxoplasmosis in AIDS patients
represents reactivation of previously acquired infec-
tion and typically occurs when the CD4 þ T
lymphocyte count is below 100 cells/mm3. Manifes-
tations include fever, headache, seizures, and focal
deficits. Brain MRI scan typically reveals ring-
enhancing or nodular-enhancing lesions with sur-
rounding edema and mass effect. There are multiple
lesions in two-thirds of cases, and they may be
widespread. These lesions may be difficult to
distinguish from other OIs, especially PCNSL.
Imaging with thallium-201 single photon emission
computed tomography (SPECT) may be quite helpful
in this regard because brain uptake is typically
negative with toxoplasmosis and positive with
PCNSL. Thallium-201 uptake to contralateral scalp
ratios may also be helpful because patients with
PCNSL may have significantly higher ratios. The
absence of serum anti-toxoplasma antibodies makes
the diagnosis unlikely, with one study suggesting that
nearly all patients with toxoplasmosis in the CNS
have titers greater than 1:256 and all patients
without CNS toxoplasmosis have titers below this
level. In combination, thallium-201 and serological
evaluation lead to the greatest diagnostic accuracy.
PCR can detect T. gondii DNA in CSF in up to 81%
of untreated patients. Thus, PCR may also be helpful
if positive.
Treatment with sulfadiazine and pyramethamine is
highly effective. Patients with positive toxoplasma
serology and a CD4 þ T lymphocyte count less than
100 cells/mm3 should be treated with prophylactic
trimethoprim-sulfamethoxazole to prevent CNS tox-
oplasmosis.
Neoplastic Primary Central Nervous
System Lymphoma (PCNSL)
PCNSL is seen in up to 4% of AIDS patients and is
second to toxoplasmosis as a cause of focal mass
lesions in the CNS of AIDS patients. The vast
majority of PCNSLs occur when the CD4 þ T
lymphocyte count is less than 50 cells/mm3. The
lesions of PCNSL are multifocal in more than two-
thirds of cases and are seen throughout the brain.
Clinical signs are usually focal or multifocal. MRI
scans show multifocal, homogeneously enhancing
lesions. As noted previously, the major differential
diagnosis is with T. gondii, and these clinical entities
may be distinguished by a combination of MRI,
SPECT, serologies, and PCR in the CSF. In nearly
72 AIDS/HIV AND NEUROLOGICAL DISEASE
100% of patients with PCNSL, CSF PCR will be
positive for Epstein–Barr virus DNA, and this finding
is highly specific. PCNSL may also be associated with
another herpes virus family member, human herpes
virus-8, although this finding is less certain. Survival
of untreated patients with PCNSL is limited to a few
weeks, whereas treatment with radiation therapy and
corticosteroids will lengthen survival to 3 or 4
months. To date, chemotherapy has not been
associated with improvement in survival.
Patients with one or more intracerebral mass
lesions on imaging studies should undergo a combi-
nation of diagnostic studies, including serologies and
lumbar puncture. If a lumbar puncture is not possible
due to brain swelling, a diagnosis remains unclear
after tests are completed, or patients require therapy
while the tests are being completed, patients are
typically treated empirically for CNS toxoplasmosis.
If the patient worsens during the course of the first
week of empirical therapy and an alternative
diagnosis has not been determined, a brain biopsy
should be considered. If possible, it is best to avoid
the use of corticosteroids during the time of
diagnostic uncertainty because these agents will
decrease swelling due to infection and shrink
lymphomas, potentially enhancing the clinical re-
sponse and confusing the diagnostic issues.
Headache
Headache in HIV-1 patients is a common symptom.
A recent case–control study found that headache
occurred in 50% of HIV-1 patients. In part, this
reflects the facts that headaches, such as common
tension headache and migraine, are prevalent
throughout society and that HIV-1 patients take
many medicines that might induce headache. For
example, one study showed that headaches in HIV-1
patients were associated with anxiety, depression,
drug use, and non-HIV-1 neurological disease and
that headache at baseline did not predict onset of
new HIV-1-associated systemic or neurological dis-
ease. However, new-onset headache in this popula-
tion should raise concern for an intracranial infection
or neoplasm.
Headache may occur at any time throughout the
infection, including during primary HIV infection.
Many HIV-1 patients have a low-level, chronic
meningitis or meningoencephalitis that presumably
is a direct result of HIV-1 and results in a modest
lymphocytic pleocytosis and elevation of protein in
the CSF. There does not appear to be a significant
correlation, however, between headache and ab-
normality of typical CSF parameters. This may
complicate initial evaluation of a patient with head-
ache and HIV-1 infection, especially when the CD4 þ
T lymphocyte count is below 200/mm3. HIV-1 viral
load in the CSF, however, is significantly higher in
patients with neurological symptoms, such as head-
ache and signs of meningitis.
Thus, a significant question for the practitioner
confronted with an HIV-1-infected patient and
headache is when to do laboratory testing, including
an imaging study and/or a lumbar puncture. Several
recent studies have addressed the question of when to
do an imaging study, typically a computerized
tomography (CT) scan. In one study of 110 patients
with new or changed neurological signs or symp-
toms, 24% had focal lesions on CT, of which 18%
were new and 7% demonstrated mass effect.
Utilization of three clinical findings as screening
tools—change in quality of headache, seizure, or
depressed or altered orientation—would have identi-
fied 95% of new intracranial lesions and resulted in
53% less head CTs ordered in the emergency
department. Addition of the clinical symptom of a
headache prolonged for 3 or more days as a
screening tool would have identified all new intra-
cranial lesions, with a 37% reduction in CTs
ordered. In a different study, in patients with
headache but without altered mental status, menin-
geal signs, focal neurological abnormalities, or signs
of subarachnoid hemorrhage, 76% of CT scans were
negative or had atrophy only. The other 24% showed
mass lesions or white matter lesions. All these
positive cases occurred in patients with CD4 þ T
lymphocyte counts less than 200/mm3. Thus, a
significant number of head CT scans in HIV-1
patients and headache can be avoided by utilizing
the previously mentioned clinical and laboratory
studies as guidelines. Lumbar puncture should be
reserved for patients with new or worsening head-
ache and/or signs of meningeal irritation when a
diagnosis has not been determined and an imaging
study shows no sign of a lesion with mass effect.
Stroke
The incidence and prevalence of stroke, both
hemorrhagic and nonhemorrhagic, appears to be
slightly increased in HIV-1 patients. Nonhemorrha-
gic stroke in HIV-1 patients is associated with
intracranial infection, nonbacterial thrombotic en-
docarditis, cocaine or other drug use, and possibly
protein S deficiency. Rarely, a patient will have an
idiopathic CNS vasculitis. Hemorrhagic stroke is

associated with thrombocytopenia and tumors such
as PCNSL and Kaposi’s sarcoma.
Immune-Mediated Syndromes
A number of autoimmune disorders, such as throm-
bocytopenia and Reiter’s syndrome, are more com-
mon in HIV-1-infected patients. These commonly
occur early in the course of the illness, long before
immunosuppression sets in. A small number of HIV
patients have relapsing–remitting, episodic CNS
disease similar to multiple sclerosis (MS) that also
occurs when the patient is not immunocompromised.
Rarely, this can be a fulminant, fatal presentation
early in the course of the illness, when CD4 þ T
lymphocyte counts are still quite elevated. A mono-
phasic variation of this, similar to acute disseminated
encephalomyelitis (ADEM), has been seen rarely.
Both the MS-like and ADEM-like illnesses are
presumed secondary to immune overreactivity, such
as might be seen with molecular mimicry. Treatment
with corticosteroids may be helpful.
Seizures
Seizures are common in HIV-infected patients. The
incidence of new seizures has been noted to be
approximately 3% per year with a prevalence of
more than 11%. Although seizures occur most often
during the latter stages of the illness, they may be the
presenting sign of HIV infection. All types of seizures
are seen, with multiple causes identified. Simple
partial and complex partial seizures are less common
and are often associated with intracranial infections
and neoplasms, including toxoplasmosis, cryptococ-
cal meningitis, PML, and PCNSL. The majority of
seizures, however, are generalized tonic–clonic, and
these tend to be associated with metabolic derange-
ments and drug toxicities. Notably, in one-fourth to
one-half of all seizures, a cause is not identified. This
suggests that HIV infection is a prominent cause of
seizures. Imaging studies should be done in all HIV
patients with new-onset seizures, including those
with a generalized seizure and a nonfocal neurolo-
gical examination, due to the relatively high like-
lihood of identifying an intracranial infection or
neoplasm requiring treatment.
Treatment of new-onset seizures should be direc-
ted at identifiable causes. An important issue in the
treatment of seizures is the interaction of many of the
anticonvulsants with the antiretroviral medications
in use for treatment of the HIV infection. Many of
the commonly used anticonvulsants induce the
cytochrome P450 3A4 enzymes in the liver and thus
AIDS/HIV AND NEUROLOGICAL DISEASE 73
enhance metabolism of many of the anti-HIV drugs.
In addition, a number of anticonvulsants are highly
protein-bound and typically displace other protein-
bound drugs from albumin. In the case of antire-
troviral medicines, this may result in supratherapeu-
tic antiretroviral drug levels and intolerable side
effects. Attempting to predict the actual effects of
these interactions is quite difficult. Finally, valproic
acid may enhance HIV replication and thus should be
used with caution in HIV patients until more
information is available. In practice, from the
standpoint of drug interactions, gabapentin and
topiramate may be the best choices of anticonvul-
sants in HIV patients.
PERIPHERAL NERVOUS SYSTEM
A number of disorders affecting the peripheral nerve
and muscles have been described in HIV-1 patients.
As a group, the peripheral neuropathies are the most
common type of neurological complication seen in
HIV infection. One convenient manner of classifica-
tion of neuropathy relates to the timing of the
neuropathy in relation to onset of HIV infection. In
the early stages of infection, prior to onset of an
immunodeficient state, immune-mediated neuropa-
thies, such as acute (AIDP) or chronic (CIDP)
inflammatory demyelinating polyneuropathy, are
most common. In the middle and late stages, when
immunodeficiency becomes more apparent, a distal
sensory polyneuropathy (DSP) and autonomic neu-
ropathy, likely secondary to HIV infection, predomi-
nate. In the very late stages associated with very low
CD4 þ T lymphocyte counts, the peripheral nerves
are most likely to be affected by opportunistic
infections, nutritional deficiencies, and malignancies.
Finally, patients are also at risk throughout the
course of HIV infection to toxic damage to their
peripheral nerves due to use of antiretroviral and
other therapies. Similarly, myopathy secondary to
either HIV or antiretroviral therapy has been well
described.
Neuropathy
Immune-Mediated: As with HIV-1-related neuro-
logical illness in the CNS, a small number of HIV-1-
infected patients develop neuropathies in the early
phase of the illness that appear to be autoimmune in
nature. Most common are AIDP and CIDP. It is not
clear if these two illnesses are part of a spectrum of a
single disease, but they share a number of clinical,
74 AIDS/HIV AND NEUROLOGICAL DISEASE
pathological, and electrophysiological features, and
both act similarly in immunocompromised and
immunocompetent patients. Smaller numbers of
patients develop cranial mononeuropathies, brachial
plexopathies, and vasculitic neuropathies that also
appear to be autoimmune in nature. The pathogen-
esis of these autoimmune neuropathies in HIV-1
patients is unclear. AIDP has been associated with
antibodies to peripheral nerve myelin and sulpha-
tides, and circulating HIV-1 antigen antibody com-
plexes have been seen in the vasculitic neuropathies.
AIDP may be the initial presenting sign of HIV-1
infection and can occur at the time of seroconversion
or following other viral infections. It is an acute,
monophasic disorder that evolves over 7–21 days
and is manifested by progressive, asymmetrical,
motor more than sensory loss of all four extremities.
It may ascend or be more patchy, and ultimately it
may be quite confluent and involve muscles of
respiration. Electrical studies initially show only
delayed F waves but eventually demonstrate delayed
distal latencies, slow conduction velocities, and
conduction blocks typical of demyelination. CSF
analysis is slightly different from that of patients
without HIV-1 in that ‘‘albumino-cytological dis-
sociation’’ is not present. HIV-1 patients have both
an elevation of CSF protein and a modest lympho-
cytic pleocytosis (10–50 cells/mm3), whereas patients
without HIV-1 usually do not have pleocytosis.
Pathology is notable for perivenular lymphocytic
infiltrates and segmental demyelination associated
with macrophages. Treatment consists of either
intravenous IVIg or plasma exchange, and the
response appears to be similar to that in non-HIV-1
patients. This usually results in significant improve-
ment in symptoms and signs of the disease.
CIDP is very similar to AIDP with regard to signs,
symptoms, and pathology. In distinction, it evolves
over weeks to months, is not monophasic, usually
does not follow a viral illness (other than HIV-1),
and has a less favorable prognosis. CIDP is also
treated with corticosteroids, in addition to IVIg and
plasma exchange.
Mononeuritis multiplex is relatively uncommon.
In this disorder, there are multiple cranial nerve and
peripheral nerve palsies in a patient with a high
CD4 þ cell count. The disorder is self-limited and
often resolves spontaneously in this circumstance.
Painful Sensory Neuropathy: Approximately one-
third of HIV patients eventually develop a distal,
primarily sensory, peripheral neuropathy. This typi-
cally is seen in middle to late stages of infection,
often with CD4 þ T lymphocyte counts below 200
cells/mm3. The most debilitating symptom is pain,
which begins in the soles and dorsum of the feet and
may move further up both legs in a relatively
symmetric fashion. There also is loss of sensory
function in a graded fashion. Reflexes are dimin-
ished. Nerve conduction studies may reveal dimin-
ished amplitudes of sensory nerve action potentials
with relatively preserved velocities, as seen in
disorders affecting primarily the axon and relatively
sparing the myelin sheath.
The etiology of DSP is unknown but presumed
secondary to HIV infection. Whether this is via direct
or indirect mechanisms is not known. Some studies
have found HIV infection in dorsal root ganglion
cells, whereas others have not. In a recent pilot study
of HIV patients without neuropathy, patients who
were treated with highly active antiretroviral therapy
and responded with at least a 1.0 log decline in viral
load had improvement in perception thresholds for
warmth, cold, and heat pain. Treated patients who
showed no decline in viral load had no improvement
in sensory function. This study is consistent with the
idea that HIV is associated with DSP, and it suggests
that antiretroviral therapy may be helpful in treating
it. Symptomatic therapies, including peptide T,
amitriptyline, mexilitine, capsaicin, and acupunc-
ture, have not shown significant benefit. Recently
published studies suggest nerve growth factor and
lamotrigine may be more successful.
Opportunistic Infections: Unlike the CNS, OIs of
the PNS are relatively uncommon in AIDS. Neuro-
syphilis and tuberculosis may cause polyradiculo-
pathy due to arachnoiditis. Varicella-zoster infection
of the peripheral nerves producing the characteristic
shingles is a well-known complication of AIDS. As in
other immunocompromised states, it is more likely to
result in multidermatomal spread and invasion of the
spinal cord producing myelitis.
CMV Polyradiculopathy: A rare but potentially
devastating complication of AIDS is progressive
polyradiculopathy of the lumbosacral roots due to
CMV infection. There is subacute to acute develop-
ment of a painful, asymmetric cauda equina syn-
drome manifested by back pain radiating into one or
both legs and urinary incontinence. This is followed
by the development of saddle anesthesia and pro-
gressive leg weakness. Untreated, this condition
progresses to flaccid paraplegia with urinary and
bowel incontinence, and there may also be invasion

of the spinal cord with myelopathy, respiratory
insufficiency, and death within weeks. Electrodiag-
nostic studies are consistent with multiple lumbosa-
cral radiculopathies. Sural nerve biopsy is probably
not helpful. CSF examination reveals polymorpho-
nuclear pleocytosis with elevated protein and de-
pressed glucose levels. Amplification of viral DNA
sequences by PCR is the quickest way to confirm the
diagnosis and is highly sensitive and specific. Patho-
logical studies demonstrate marked inflammation and
necrosis of ventral and dorsal nerve roots. Early
treatment with ganciclovir, even before confirmation
of the diagnosis, is recommended, and it may result in
significant improvement of symptoms. Ganciclovir
resistance may occur, and it should be suspected in
individuals who progress despite therapy. Foscarnet
may be substituted in this circumstance. CMV may
also be associated with a mononeuritis multiplex
syndrome late in the course of AIDS, and this may
progress rapidly to quadriparesis.
Iatrogenic Neuropathy: The dideoxynucleoside
analog drugs ddI, ddC, and d4 T cause painful (or
painless) sensory neuropathies. The neuropathy is
dose related and reversible, and it occurs in 23% of
patients treated with these medicines for 10 or more
months. This neuropathy may be dose limiting, and
symptoms are very similar to those of DSP. Prior
history of DSP or other neuropathy is associated with
greater susceptibility to nucleoside analog-related
neuropathy. The pathogenesis of this neuropathy is
believed to be interference with mitochondrial DNA
synthesis. HIV-1 patients are also exposed to a
variety of cancer chemotherapeutic agents that can
cause toxic neuropathies, including vincristine, iso-
niazid, and thalidomide. Treatment of all toxic
neuropathies is withdrawal or dose reduction.
Symptom improvement may take up to 8 weeks
after withdrawal.
Myopathy
HIV Myopathy: Myopathy may occur at any time
during HIV-1 infection. Typical symptoms of prox-
imal muscle weakness, difficulty rising from a chair,
weight loss, and myalgia are seen. A mild elevation in
creatinine kinase (CK) is found in almost all patients
with this myopathy, although modest CK elevation is
also noted in HIV-1 patients without clinical signs of
myopathy. Electromyography shows typical features
of myopathic damage, often with irritative signs.
Muscle biopsy usually reveals scattered myofiber
degeneration, and there are occasional associated
AIDS/HIV AND NEUROLOGICAL DISEASE 75
inflammatory infiltrates. Myofiber inclusions and
cytoplasmic bodies are also sometimes seen.
It is likely that there are multiple etiologies of
myopathy in HIV patients. Immune mechanisms
similar to non-HIV polymyositis seem likely, and
rarely there may be opportunistic organisms that
infect muscle directly. A number of researchers have
noted an association between myopathy and ZDV
therapy, whereas others have found the frequency of
myopathy to be no different in treated and untreated
patients. Pathological features of mitochondrial
dysfunction have been suggested as characteristic
features of ZDV-associated myopathy, but these
features may be seen in untreated patients as well
and appear to correlate with the extent of myofiber
degeneration. Thus, the role of ZDV in HIV
myopathy is not clear.
Patients taking ZDV who develop HIV myopathy
are often treated with drug withdrawal, with variable
effectiveness. Treatment with corticosteroids, non-
steroidal agents, and IVIg may be helpful. Rare
patients with an identifiable OI associated with
myopathy should be treated with appropriate anti-
biotic agents.
—John R. Corboy and Steven C. Johnson
See also–CIDP (Chronic Inflammatory
Demyelinating Polyradiculoneuropathy);
Dementia; HIV Infection, Neurological
Complications of; Human T-Lymphotropic
Viruses (HTLV); Meningitis, Viral; Progressive
Multifocal Leukoencephalopathy (PML); Viral
Vaccines and Antiviral Therapy
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system mass lesions in patients with AIDS. J. Infect. 40, 274–
281.
Wong, M. C., Suite, N. D., and Labar, D. R. (1990). Seizures in
human immuodeficiency virus infection. Arch. Neurol. 47,
640–642.
Wulff, E. A., and Simpson, D. M. (1999). Neuromuscular
complications of the human immunodeficiency virus type 1
infection. Semin. Neurol. 19, 157–164.
Akathisia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKATHISIA means motor restlessness. Patients com-
plain of a feeling of inner tension in their limbs and
body and cannot sit down without continual voli-
tional movements of the legs or feet. Frequently,
akathisia is misinterpreted for anxiety, hyperactivity,
or agitation. Akathisia usually occurs after exposure
to drugs that block dopamine receptors in the basal
ganglia, such as antipsychotic drugs (neuroleptics),
but also with reserpine, tetrabenazine, benzamides,
and calcium channel blockers. Akathisia can be seen
soon after the initiation of the antidopaminergic
drugs or after long-term exposure (tardive akathisia).
The reported prevalence of this disorder ranges from
9 to 75% of patients receiving neuroleptics, and it is
more common in patients receiving high-potency
neuroleptics. In 50% of the cases, symptoms develop
within the first month of treatment with the offend-
ing drug, and in almost 90% of cases akathisia is
present after 2 or 3 months of neuroleptic exposure.
The pathophysiology of akathisia is not comple-
tely understood, but it may relate to the development
of imbalanced interactions between the dopaminer-
gic and cholinergic systems. Conditions that resem-
ble akathisia include restless leg syndrome,
dyskinesias due to drugs that augment the activity
of dopaminergic systems, chorea, and stereotypic
movements in psychiatric or mentally retarded
patients. To treat drug-induced akathisia, dose
reduction or cessation of the offending drug should
be considered. Lower potency neuroleptics can often
be substituted for the higher potency agents that
induce akathisia. In some cases, anticholinergics or
amantadine are useful. Other drugs, including
propranolol, clonidine, benzodiazepines, and pro-
poxyphene, have been found to be effective in a
number of patients.
—Esther Cubo and Christopher G. Goetz
See also–Chorea; Dopamine; Dyskinesias;
Hyperactivity; Restless Legs Syndrome (RLS)
Further Reading
Gershanik, O. S. (1998). Drug-induced dyskinesias. In Parkinson’s
Disease and Movement Disorders (J. Jankovic and E. Tolosa,
Eds.), pp. 579–600. Lippincott Williams & Wilkins, Baltimore.
Akinesia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKINESIA means lack of movement, and it encom-
passes a variety of motor deficits, including delayed
motor initiative; slow performance of voluntary
movements (bradykinesia); difficulty reaching a
76 AKATHISIA
Lanska, D. J. (1999). Epidemiology of human immunodeficiency
virus infection and associated neurologic illness. Semin. Neurol.
19, 105–111.
Marra, C. M. (1999). Bacterial and fungal brain infections in
AIDS. Semin. Neurol. 19, 177–184.
Maschke, M., Kastrup, O., Esser, S., et al. (2000). Incidence
and prevalence of neurologic disorders associated with
HIV since the introduction of highly active antirectrovial
therapy (HAART). J. Neurol. Neurosurg. Psychiatry 69, 376–
380.
Mellors, J. W., Rinaldo, C. R., Gupta, P., et al. (1996). Prognosis in
HIV-1 infection predicted by the quantity of virus in plasma.
Science 272, 1167–1170.
Palella, F. J., Delaney, K. M., Moorman, A. C., et al. (1998).
Declining morbidity and mortality among patients with
advanced human immunodeficiency virus infection. N. Engl.
J. Med. 338, 853–860.
Quereda, C., Corral, I., Laguna, F., et al. (2000). Diagnostic utility
of a multiplex herpesvirus PCR assay performed with cere-
brospinal fluid from human immunodeficiency virus-infected
patients with neurological disorders. J. Clin. Microbiol. 38,
3061–3067.
Romanelli, F., Jennings, H. R., Nath, A., et al. (2000). The use of
anticonvulsants in HIV-positive individuals. Neurology 54,
1404–1407.
Rothman, R. E., Keyl, P. M., McArthur, J. C., et al. (1999).
A decision guideline for emergency department utilization of
noncontrast head computed tomography in HIV-infected
patients. Acad. Emerg. Med. 6, 1010–1019.
Saag, M. S., Graybill, R. J., Larsen, R. A., et al. (2000). Practice
guidelines for the management of cryptococcal disease.
Infectious Diseases Society of America. Clin. Infect. Dis. 30,
710–718.
Simpson, D. M., and Berger, J. R. (1996). Neurologic manifesta-
tions of HIV infection. Med. Clin. North Am. 80, 1363–1394.
Skiest, D. J., Erdman, W., Chang, W. E., et al. (2000).
SPECT thallium-201 combined with toxoplasma serology
for the presumptive diagnosis of focal central nervous
system mass lesions in patients with AIDS. J. Infect. 40, 274–
281.
Wong, M. C., Suite, N. D., and Labar, D. R. (1990). Seizures in
human immuodeficiency virus infection. Arch. Neurol. 47,
640–642.
Wulff, E. A., and Simpson, D. M. (1999). Neuromuscular
complications of the human immunodeficiency virus type 1
infection. Semin. Neurol. 19, 157–164.
Akathisia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKATHISIA means motor restlessness. Patients com-
plain of a feeling of inner tension in their limbs and
body and cannot sit down without continual voli-
tional movements of the legs or feet. Frequently,
akathisia is misinterpreted for anxiety, hyperactivity,
or agitation. Akathisia usually occurs after exposure
to drugs that block dopamine receptors in the basal
ganglia, such as antipsychotic drugs (neuroleptics),
but also with reserpine, tetrabenazine, benzamides,
and calcium channel blockers. Akathisia can be seen
soon after the initiation of the antidopaminergic
drugs or after long-term exposure (tardive akathisia).
The reported prevalence of this disorder ranges from
9 to 75% of patients receiving neuroleptics, and it is
more common in patients receiving high-potency
neuroleptics. In 50% of the cases, symptoms develop
within the first month of treatment with the offend-
ing drug, and in almost 90% of cases akathisia is
present after 2 or 3 months of neuroleptic exposure.
The pathophysiology of akathisia is not comple-
tely understood, but it may relate to the development
of imbalanced interactions between the dopaminer-
gic and cholinergic systems. Conditions that resem-
ble akathisia include restless leg syndrome,
dyskinesias due to drugs that augment the activity
of dopaminergic systems, chorea, and stereotypic
movements in psychiatric or mentally retarded
patients. To treat drug-induced akathisia, dose
reduction or cessation of the offending drug should
be considered. Lower potency neuroleptics can often
be substituted for the higher potency agents that
induce akathisia. In some cases, anticholinergics or
amantadine are useful. Other drugs, including
propranolol, clonidine, benzodiazepines, and pro-
poxyphene, have been found to be effective in a
number of patients.
—Esther Cubo and Christopher G. Goetz
See also–Chorea; Dopamine; Dyskinesias;
Hyperactivity; Restless Legs Syndrome (RLS)
Further Reading
Gershanik, O. S. (1998). Drug-induced dyskinesias. In Parkinson’s
Disease and Movement Disorders (J. Jankovic and E. Tolosa,
Eds.), pp. 579–600. Lippincott Williams & Wilkins, Baltimore.
Akinesia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKINESIA means lack of movement, and it encom-
passes a variety of motor deficits, including delayed
motor initiative; slow performance of voluntary
movements (bradykinesia); difficulty reaching a
76 AKATHISIA
Lanska, D. J. (1999). Epidemiology of human immunodeficiency
virus infection and associated neurologic illness. Semin. Neurol.
19, 105–111.
Marra, C. M. (1999). Bacterial and fungal brain infections in
AIDS. Semin. Neurol. 19, 177–184.
Maschke, M., Kastrup, O., Esser, S., et al. (2000). Incidence
and prevalence of neurologic disorders associated with
HIV since the introduction of highly active antirectrovial
therapy (HAART). J. Neurol. Neurosurg. Psychiatry 69, 376–
380.
Mellors, J. W., Rinaldo, C. R., Gupta, P., et al. (1996). Prognosis in
HIV-1 infection predicted by the quantity of virus in plasma.
Science 272, 1167–1170.
Palella, F. J., Delaney, K. M., Moorman, A. C., et al. (1998).
Declining morbidity and mortality among patients with
advanced human immunodeficiency virus infection. N. Engl.
J. Med. 338, 853–860.
Quereda, C., Corral, I., Laguna, F., et al. (2000). Diagnostic utility
of a multiplex herpesvirus PCR assay performed with cere-
brospinal fluid from human immunodeficiency virus-infected
patients with neurological disorders. J. Clin. Microbiol. 38,
3061–3067.
Romanelli, F., Jennings, H. R., Nath, A., et al. (2000). The use of
anticonvulsants in HIV-positive individuals. Neurology 54,
1404–1407.
Rothman, R. E., Keyl, P. M., McArthur, J. C., et al. (1999).
A decision guideline for emergency department utilization of
noncontrast head computed tomography in HIV-infected
patients. Acad. Emerg. Med. 6, 1010–1019.
Saag, M. S., Graybill, R. J., Larsen, R. A., et al. (2000). Practice
guidelines for the management of cryptococcal disease.
Infectious Diseases Society of America. Clin. Infect. Dis. 30,
710–718.
Simpson, D. M., and Berger, J. R. (1996). Neurologic manifesta-
tions of HIV infection. Med. Clin. North Am. 80, 1363–1394.
Skiest, D. J., Erdman, W., Chang, W. E., et al. (2000).
SPECT thallium-201 combined with toxoplasma serology
for the presumptive diagnosis of focal central nervous
system mass lesions in patients with AIDS. J. Infect. 40, 274–
281.
Wong, M. C., Suite, N. D., and Labar, D. R. (1990). Seizures in
human immuodeficiency virus infection. Arch. Neurol. 47,
640–642.
Wulff, E. A., and Simpson, D. M. (1999). Neuromuscular
complications of the human immunodeficiency virus type 1
infection. Semin. Neurol. 19, 157–164.
Akathisia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKATHISIA means motor restlessness. Patients com-
plain of a feeling of inner tension in their limbs and
body and cannot sit down without continual voli-
tional movements of the legs or feet. Frequently,
akathisia is misinterpreted for anxiety, hyperactivity,
or agitation. Akathisia usually occurs after exposure
to drugs that block dopamine receptors in the basal
ganglia, such as antipsychotic drugs (neuroleptics),
but also with reserpine, tetrabenazine, benzamides,
and calcium channel blockers. Akathisia can be seen
soon after the initiation of the antidopaminergic
drugs or after long-term exposure (tardive akathisia).
The reported prevalence of this disorder ranges from
9 to 75% of patients receiving neuroleptics, and it is
more common in patients receiving high-potency
neuroleptics. In 50% of the cases, symptoms develop
within the first month of treatment with the offend-
ing drug, and in almost 90% of cases akathisia is
present after 2 or 3 months of neuroleptic exposure.
The pathophysiology of akathisia is not comple-
tely understood, but it may relate to the development
of imbalanced interactions between the dopaminer-
gic and cholinergic systems. Conditions that resem-
ble akathisia include restless leg syndrome,
dyskinesias due to drugs that augment the activity
of dopaminergic systems, chorea, and stereotypic
movements in psychiatric or mentally retarded
patients. To treat drug-induced akathisia, dose
reduction or cessation of the offending drug should
be considered. Lower potency neuroleptics can often
be substituted for the higher potency agents that
induce akathisia. In some cases, anticholinergics or
amantadine are useful. Other drugs, including
propranolol, clonidine, benzodiazepines, and pro-
poxyphene, have been found to be effective in a
number of patients.
—Esther Cubo and Christopher G. Goetz
See also–Chorea; Dopamine; Dyskinesias;
Hyperactivity; Restless Legs Syndrome (RLS)
Further Reading
Gershanik, O. S. (1998). Drug-induced dyskinesias. In Parkinson’s
Disease and Movement Disorders (J. Jankovic and E. Tolosa,
Eds.), pp. 579–600. Lippincott Williams & Wilkins, Baltimore.
Akinesia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKINESIA means lack of movement, and it encom-
passes a variety of motor deficits, including delayed
motor initiative; slow performance of voluntary
movements (bradykinesia); difficulty reaching a

target with a single continuous movement (hypoki-
nesia)—the movement must stop and resume to
touch the intended objective; rapid fatigue with
repetitive movements; inability to execute simulta-
neous actions (e.g., the patient cannot button clothes
while answering a question); and reduced automatic
function such as arm swing while walking or the loss
of facial expression. Any of these akinetic phenom-
ena may evolve independently, and a given patient
may have only one of them. Akinesia correlates well
with deficits in the activity of the nervous system
involving dopamine. Akinesia is one the four
cardinal features of Parkinson’s disease and other
parkinsonian syndromes.
A similar but distinct clinical sign is freezing,
characterized by difficulty in starting or continuing
rhythmic repetitive motions, such as speech, hand-
writing, and gait. Freezing is a well-known problem
in Parkinson’s disease and other gait disorders. The
neural mechanisms responsible for freezing remain
poorly understood, and chemical systems other than
the dopamine pathway may be more important.
Dopaminergic drugs, including levodopa and dopa-
mine agonists (that stimulate dopamine receptor
proteins), are not markedly useful in treating
freezing, and the noradrenergic system has been
suggested to be more important.
—Esther Cubo and Christopher G. Goetz
See also–Dopamine; Dyskinesias; Gait and Gait
Disorders; Movement Disorders, Overview;
Parkinsonism; Parkinson’s Disease
Further Reading
Delwaide, P., and Gonce, M. (1998). Pathophysiology of
Parkinson’s signs. In Parkinson’s Disease and Movement
Disorders (J. Jankovic and E. Tolosa, Eds.), pp. 159–176.
Lippincott Williams & Wilkins, Baltimore.
Akinetic Mutism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKINETIC MUTISM was described in the seminal paper
by Cairns and colleagues concerning a 14-year-old
girl with an epidermoid cyst of the third ventricle:
In the fully developed state she lay alert except that her eyes
followed the movement of objects or could be diverted by
sound. A painful stimulus would produce reflex withdrawal of a
AKINETIC MUTISM 77
limb ... but without tears, noise or other sign of pain or
displeasure .... [There were] bilateral signs of pyramidal tract
involvement, and she was totally incontinent. As one ap-
proached her bedside her steady gaze seemed to promise speech
but no sound [was produced].
She showed
loss of feeling tone, loss of emotional expression, of sponta-
neous and most of other voluntary movements. She was
incapable of originating movements of any kind, with the
notable exception that ocular fixation and movement occurred
in response to the movement of external objects and to sounds.
Additional descriptive comments concerned dis-
tractibility, the presence of wake and sleep cycles,
excessive sleep, and arousability from sleep. After the
cyst was drained, the patient’s behavior returned
transiently to normal, during which time she could
not recall anything of events during the state of
akinetic mutism. Thus, memory mechanisms were
impaired during akinetic mutism.
The clinical syndrome is not always manifest in
such a complete form; features may fluctuate,
including variable comprehension and obeying sim-
ple commands. Such efforts, however, are ineffective
or incomplete. Signs of pyramidal tract involvement
can progress to or alternate with decorticate or
decerebrate posturing.
Akinetic mutism occurs in association with acute
hydrocephalus, tumors of the pineal or thalamus,
hemorrhage into dorsal medial thalamus, posterior
thalamic–rostral midbrain lesions, strokes affecting
the anterior limbs of the internal capsules, various
lesions of the white matter of the frontal lobes, or
destructive lesions of the medial surfaces of the
frontal lobes, especially involving the cingulate gyri.
In some cases of encephalitis, the main damage is in
the posterior hypothalamus. Other diencephalic and
limbic structures are also often involved with
inflammatory lesions.
PATHOPHYSIOLOGY
Akinetic mutism likely relates to impaired ‘‘activa-
tion’’ of cortical, especially prefrontal, function from
reduced thalamic input, impaired connectivity of the
executive motor system, or both. In addition, there is
a profound disturbance in cognitive function, includ-
ing memory due to disruption of integrated cortical
(especially prefrontal) diencephalic function.
Akinetic mutism is occasionally partially reversed
by dopaminergic agents (e.g., bromocriptine). This
implies that there is a functional deficiency of

target with a single continuous movement (hypoki-
nesia)—the movement must stop and resume to
touch the intended objective; rapid fatigue with
repetitive movements; inability to execute simulta-
neous actions (e.g., the patient cannot button clothes
while answering a question); and reduced automatic
function such as arm swing while walking or the loss
of facial expression. Any of these akinetic phenom-
ena may evolve independently, and a given patient
may have only one of them. Akinesia correlates well
with deficits in the activity of the nervous system
involving dopamine. Akinesia is one the four
cardinal features of Parkinson’s disease and other
parkinsonian syndromes.
A similar but distinct clinical sign is freezing,
characterized by difficulty in starting or continuing
rhythmic repetitive motions, such as speech, hand-
writing, and gait. Freezing is a well-known problem
in Parkinson’s disease and other gait disorders. The
neural mechanisms responsible for freezing remain
poorly understood, and chemical systems other than
the dopamine pathway may be more important.
Dopaminergic drugs, including levodopa and dopa-
mine agonists (that stimulate dopamine receptor
proteins), are not markedly useful in treating
freezing, and the noradrenergic system has been
suggested to be more important.
—Esther Cubo and Christopher G. Goetz
See also–Dopamine; Dyskinesias; Gait and Gait
Disorders; Movement Disorders, Overview;
Parkinsonism; Parkinson’s Disease
Further Reading
Delwaide, P., and Gonce, M. (1998). Pathophysiology of
Parkinson’s signs. In Parkinson’s Disease and Movement
Disorders (J. Jankovic and E. Tolosa, Eds.), pp. 159–176.
Lippincott Williams & Wilkins, Baltimore.
Akinetic Mutism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AKINETIC MUTISM was described in the seminal paper
by Cairns and colleagues concerning a 14-year-old
girl with an epidermoid cyst of the third ventricle:
In the fully developed state she lay alert except that her eyes
followed the movement of objects or could be diverted by
sound. A painful stimulus would produce reflex withdrawal of a
AKINETIC MUTISM 77
limb ... but without tears, noise or other sign of pain or
displeasure .... [There were] bilateral signs of pyramidal tract
involvement, and she was totally incontinent. As one ap-
proached her bedside her steady gaze seemed to promise speech
but no sound [was produced].
She showed
loss of feeling tone, loss of emotional expression, of sponta-
neous and most of other voluntary movements. She was
incapable of originating movements of any kind, with the
notable exception that ocular fixation and movement occurred
in response to the movement of external objects and to sounds.
Additional descriptive comments concerned dis-
tractibility, the presence of wake and sleep cycles,
excessive sleep, and arousability from sleep. After the
cyst was drained, the patient’s behavior returned
transiently to normal, during which time she could
not recall anything of events during the state of
akinetic mutism. Thus, memory mechanisms were
impaired during akinetic mutism.
The clinical syndrome is not always manifest in
such a complete form; features may fluctuate,
including variable comprehension and obeying sim-
ple commands. Such efforts, however, are ineffective
or incomplete. Signs of pyramidal tract involvement
can progress to or alternate with decorticate or
decerebrate posturing.
Akinetic mutism occurs in association with acute
hydrocephalus, tumors of the pineal or thalamus,
hemorrhage into dorsal medial thalamus, posterior
thalamic–rostral midbrain lesions, strokes affecting
the anterior limbs of the internal capsules, various
lesions of the white matter of the frontal lobes, or
destructive lesions of the medial surfaces of the
frontal lobes, especially involving the cingulate gyri.
In some cases of encephalitis, the main damage is in
the posterior hypothalamus. Other diencephalic and
limbic structures are also often involved with
inflammatory lesions.
PATHOPHYSIOLOGY
Akinetic mutism likely relates to impaired ‘‘activa-
tion’’ of cortical, especially prefrontal, function from
reduced thalamic input, impaired connectivity of the
executive motor system, or both. In addition, there is
a profound disturbance in cognitive function, includ-
ing memory due to disruption of integrated cortical
(especially prefrontal) diencephalic function.
Akinetic mutism is occasionally partially reversed
by dopaminergic agents (e.g., bromocriptine). This
implies that there is a functional deficiency of
78 ALCOHOL-RELATED NEUROTOXICITY
dopaminergic activity, probably in the rostral fore-
brain (median forebrain bundle).
INVESTIGATIONS
Neuroimaging is usually necessary to exclude struc-
tural lesions in the brain, especially the frontal lobes
or medial diencephalic region. Functional neuroima-
ging (e.g., functional magnetic resonance imaging,
positron emission computed tomography, or single
photon emission computed tomography with various
agents) may show decreased perfusion of the frontal
lobes. The electroencephalograph shows diffuse delta
activity (slow waves r4 Hz).
Treatment depends on the underlying condition.
Decompression of diencephalic structures can relieve
the condition, as shown by Cairns’ case described
previously. Symptomatic treatment with dopamine
precursors or D2 receptor agonists may be worth
trying, especially in patients who cannot be helped
surgically or who remain abulic after surgical
decompression or ventricular drainage or shunting.
—G. Bryan Young
See also–Akinesia; Coma Scales; Eye
Movements, Overview; Persistent Vegetative
State (PVS); Sleep–Wake Cycle
Alcohol-Related Neurotoxicity
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
Alcohol is one of the most widely used psycho-
active drugs, and alcoholism is defined as its
chronic, repetitive, and excessive use such that the
drinker’s health, personal relationships, and liveli-
hood are negatively affected. Genetic, environ-
mental, and cultural factors likely contribute to
alcohol addiction, and it is estimated that 10% of
adult Americans are affected by alcohol abuse or
dependence.
The active ingredient in most common alcoholic
beverages is ethanol or ethyl alcohol, although other
chemicals, including methyl alcohol (methanol),
amyl alcohol, and acetaldehyde, may be contained
in some liquors, especially home brews. Alcohol is
absorbed from the stomach, duodenum, and jejunum
and can be detected in the blood within 5 min of
ingestion. Alcohol is metabolized mainly in the liver,
where it is oxidized to acetaldehyde and broken
down through action of the enzyme alcohol dehy-
drogenase. Alcohol has several effects on nervous
system function and particularly appears to act at the
interface between membrane lipids and integral
membrane proteins. Neurotransmitter-gated ion
channels are also likely affected, including those
associated with such nervous system chemicals as
nicotine, acetylcholine, g-aminobutyric acid (GABA),
and n-methyl-d-aspartate (NMDA). Alcoholism is
associated with malnutrition and vitamin depriva-
tion syndromes. Tolerance to alcohol is defined as the
acquired resistance to intoxicating effects of the
drug, and some researchers have hypothesized that
tolerance represents an adaptive change in the central
nervous system similar to the subcellular changes
associated with learning or memory and specifically
involving nerve growth factors termed neurotro-
phins. Several clinical syndromes are associated with
alcohol, some acute and short-lived, whereas others
are seen after chronic alcohol exposure and are long-
standing. In each case, withdrawal of alcohol and
nutritional supplementation are important treatment
interventions.
Acute intoxication (drunkenness) occurs with
elevated blood levels of alcohol, although individuals
vary in their behaviors at the same blood level.
Whereas blood levels of 100 mg/dl typically cause
drunkenness in occasional drinkers, chronic alcohol
abusers can tolerate levels up to 500 mg/dl without
any apparent effects. In the nervous system, alcohol
acts primarily as a depressant, although small doses
usually lead to disinhibition or a slight euphoria.
Drunkenness includes slurred speech, an erratic gait,
and disinhibited, often verbose behavior. Pathologi-
cal intoxication, or episodes of uncharacteristic
behavior such as violence or bizarre escapades, is
due to the disinhibiting effect of heavy consumption
of alcohol. It generally abates as the blood alcohol
level decreases and can be associated with little or no
avowed recollection (alcoholic blackout). The syn-
drome of drunkenness can be complicated by the
simultaneous ingestion of drugs or other intoxicants,
and the blood alcohol level is the most important
laboratory test to support a diagnosis of alcohol
intoxication. In all cases, the test result must be
interpreted in light of the person’s clinical status. The
most important danger of acute intoxication is
respiratory depression or alcohol coma when alcohol
levels are high. In a social context, coma is an
emergency because respiratory depression is an early
feature, and victims should be rushed to a medical
78 ALCOHOL-RELATED NEUROTOXICITY
dopaminergic activity, probably in the rostral fore-
brain (median forebrain bundle).
INVESTIGATIONS
Neuroimaging is usually necessary to exclude struc-
tural lesions in the brain, especially the frontal lobes
or medial diencephalic region. Functional neuroima-
ging (e.g., functional magnetic resonance imaging,
positron emission computed tomography, or single
photon emission computed tomography with various
agents) may show decreased perfusion of the frontal
lobes. The electroencephalograph shows diffuse delta
activity (slow waves r4 Hz).
Treatment depends on the underlying condition.
Decompression of diencephalic structures can relieve
the condition, as shown by Cairns’ case described
previously. Symptomatic treatment with dopamine
precursors or D2 receptor agonists may be worth
trying, especially in patients who cannot be helped
surgically or who remain abulic after surgical
decompression or ventricular drainage or shunting.
—G. Bryan Young
See also–Akinesia; Coma Scales; Eye
Movements, Overview; Persistent Vegetative
State (PVS); Sleep–Wake Cycle
Alcohol-Related Neurotoxicity
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
Alcohol is one of the most widely used psycho-
active drugs, and alcoholism is defined as its
chronic, repetitive, and excessive use such that the
drinker’s health, personal relationships, and liveli-
hood are negatively affected. Genetic, environ-
mental, and cultural factors likely contribute to
alcohol addiction, and it is estimated that 10% of
adult Americans are affected by alcohol abuse or
dependence.
The active ingredient in most common alcoholic
beverages is ethanol or ethyl alcohol, although other
chemicals, including methyl alcohol (methanol),
amyl alcohol, and acetaldehyde, may be contained
in some liquors, especially home brews. Alcohol is
absorbed from the stomach, duodenum, and jejunum
and can be detected in the blood within 5 min of
ingestion. Alcohol is metabolized mainly in the liver,
where it is oxidized to acetaldehyde and broken
down through action of the enzyme alcohol dehy-
drogenase. Alcohol has several effects on nervous
system function and particularly appears to act at the
interface between membrane lipids and integral
membrane proteins. Neurotransmitter-gated ion
channels are also likely affected, including those
associated with such nervous system chemicals as
nicotine, acetylcholine, g-aminobutyric acid (GABA),
and n-methyl-d-aspartate (NMDA). Alcoholism is
associated with malnutrition and vitamin depriva-
tion syndromes. Tolerance to alcohol is defined as the
acquired resistance to intoxicating effects of the
drug, and some researchers have hypothesized that
tolerance represents an adaptive change in the central
nervous system similar to the subcellular changes
associated with learning or memory and specifically
involving nerve growth factors termed neurotro-
phins. Several clinical syndromes are associated with
alcohol, some acute and short-lived, whereas others
are seen after chronic alcohol exposure and are long-
standing. In each case, withdrawal of alcohol and
nutritional supplementation are important treatment
interventions.
Acute intoxication (drunkenness) occurs with
elevated blood levels of alcohol, although individuals
vary in their behaviors at the same blood level.
Whereas blood levels of 100 mg/dl typically cause
drunkenness in occasional drinkers, chronic alcohol
abusers can tolerate levels up to 500 mg/dl without
any apparent effects. In the nervous system, alcohol
acts primarily as a depressant, although small doses
usually lead to disinhibition or a slight euphoria.
Drunkenness includes slurred speech, an erratic gait,
and disinhibited, often verbose behavior. Pathologi-
cal intoxication, or episodes of uncharacteristic
behavior such as violence or bizarre escapades, is
due to the disinhibiting effect of heavy consumption
of alcohol. It generally abates as the blood alcohol
level decreases and can be associated with little or no
avowed recollection (alcoholic blackout). The syn-
drome of drunkenness can be complicated by the
simultaneous ingestion of drugs or other intoxicants,
and the blood alcohol level is the most important
laboratory test to support a diagnosis of alcohol
intoxication. In all cases, the test result must be
interpreted in light of the person’s clinical status. The
most important danger of acute intoxication is
respiratory depression or alcohol coma when alcohol
levels are high. In a social context, coma is an
emergency because respiratory depression is an early
feature, and victims should be rushed to a medical

center or emergency help should be secured without
delay. Mechanical ventilatory support may be needed
along with correction of dehydration, blood sugar
problems, acid–base imbalance, and temperature
abnormalities. At a blood level of 5000 mg/liter,
50% of victims die.
Withdrawal syndromes from alcohol occur when a
person decreases or stops a high level of alcohol
intake, after a binge of heavy acute drinking, or
after the regular ingestion of alcohol over many
months. Most symptoms appear to relate to
overactivity or ‘‘rebound’’ after profound neural
suppression, and their chemical basis may be
alterations in the function of GABA or NMDA
receptor systems. The earliest findings of withdrawal
typically occur within 6–8 hr of alcohol cessation.
Tremulousness is the earliest and most common
complaint, and many alcoholics view their so-called
shakes as an indication that it is time to resume
drinking to avoid more severe problems. The tremor
appears gradually, increases to a peak within 1 or 2
days, and its character is irregular in rhythm and
amplitude. Although the tremor mainly involves the
hands, the neck and voice may be involved. The
tremor remits during relaxation and sleep but
often persists for weeks after discontinuation of
alcohol consumption. The pathophysiological me-
chanisms of the tremor are not known, but it
probably represents an exaggerated physiological
tremor. The tremulousness is associated with hyper-
reflexia, hypervigilance, anxiety, tachycardia, hyper-
tension, and insomnia. In mild forms of withdrawal,
the signs and symptoms usually resolve after 48 hr. In
severe reactions, patients may experience additional
symptoms including auditory hallucinations, which
may be accusatory and threatening. Hallucinations
generally appear within 24 hr of withdrawal
and may be accompanied by global confusion, and
the autonomic hyperactivity continues and may
become more pronounced. Between 6 and 48 hr
following alcohol discontinuation, seizures occur in
approximately 3 or 4% of patients; these can be
due to withdrawal or may relate to trauma or
an underlying brain problem, such as stroke, old
injury, or infection. Seizures are important to
recognize because not only are they a complicated
medical problem among alcoholics but also, in the
setting of withdrawal, they can sometimes be a
signal of oncoming delirium tremens (DTs). Thirty
to 40% of patients with seizures progress to
DTs, and this complication carries a substantial
risk of death.
ALCOHOL-RELATED NEUROTOXICITY 79
Delirium tremens comprises a combination
of severe behavioral problems and autonomic
nervous system hyperactivity, usually occurring
after 3–5 days of alcohol abstinence. Patients with
DTs are agitated, hallucinating, and confused. The
hallucinations are frequently of a visual nature,
but other types occur. In addition, fever, rapid heart
rates, shortness of breath, hypertension, and confu-
sion are typical. Seizures are uncommon during
this phase of withdrawal. Once present, the deli-
rium typically lasts 3 days, but during this period
many patients die from metabolic disturbances
and cardiac problems. High fever can suggest
infection, and because they have gone several
days without alcohol, blood levels will not suggest
alcohol as a cause. Vitamins (especially thiamine)
(see Wernicke–Korsakoff syndrome below), fluids,
glucose, and sedatives are important therapies,
along with careful cardiac therapy and seizure
precautions. Delirium tremens carries a 10–20%
mortality rate due to autonomic nervous system
dysfunction.
Other syndromes associated with alcohol exposure
are less likely to be due to alcohol as a neurotoxin
but rather relate to nutritional deficiencies and other
environmental problems associated with the life of
chronic alcoholism. Alcoholic dementia with cere-
bral atrophy is a term that has been used for decades,
but dementia and the brain shrinkage (atrophy) that
many alcoholics develop likely relate to chronic
dietary deficiencies, head trauma from falls or fights
during intoxication, and vascular accidents. Defi-
ciency amblyopia, or blindness, is likely due to
depletion of one or more B vitamins, and alcoholics
are at high risk for vitamin deficiencies. Patients with
this disorder experience gradual and symmetrical
loss of visual acuity, and colors perceived appear to
be washed out. On examination, the central por-
tion of vision is especially impaired, and on
ophthalmological examination patients occasionally
exhibit pallor of the optic disks. Patients often have
evidence of other syndromes of nutritional deficiency,
including a predominantly sensory polyneuropathy.
Cerebellar degeneration occurs frequently among
alcoholics, and staggering gait and poor coordina-
tion occur even when patients are not drinking.
Like the syndromes mentioned previously, the
cerebellar damage is believed to relate to chronic
nutritional deficiencies and not to alcohol as a
neurotoxin.
Wernicke–Korsakoff syndrome is due specifically
to thiamine deficiency and occurs frequently
80 ALCOHOL-RELATED NEUROTOXICITY
among alcoholics. In Wernicke’s encephalopathy,
cerebellar system problems in the form of ataxia,
or unsteadiness, are one of the features, along
with behavioral changes and ophthalmoplegia.
When confabulation occurs as a behavioral element
of the disorder, the condition is termed Korsakoff’s
psychosis. Any patient who is an alcoholic or is
alcohol intoxicated is usually given thiamine as a
treatment or prevention of Wernicke–Korsakoff
syndrome.
Marchiafava–Bignami disease is a rare disorder
that causes a selective degeneration of pathways
that connect the two hemispheres of the brain, the
corpus callosum. The reason for this particular
vulnerability of the corpus callosum is unknown,
but the rarity of this disorder when measured against
the prevalence of alcoholism suggests that factors
other than alcohol or even poor nutrition must be
involved. Patients become progressively demented,
disinhibited, or aggressive, and seizures and impaired
consciousness may be terminal events. Brain mag-
netic resonance imaging scans show lesions in the
corpus callosum. In most cases, the disorder pro-
gresses slowly, sometimes taking years to lead to
stupor, coma, and death.
Alcoholic myopathy takes two forms: (i) an
acute, painful myopathy associated with weakness,
cramps, swollen and tender muscles, high creatine
kinase levels in the blood, and muscle break-
down (rhabdomyolysis) with or without high levels
of the chemical myoglobin found in the urine
(myoglobinuria), and (ii) a chronic myopathy
that is painless and often unnoticed by the
patient, causing proximal weakness and selective
degeneration of muscle fibers called type II fibers on
biopsy. In addition to skeletal muscle involvement,
patients may have an associated cardiomyopathy.
Proposed mechanisms of muscle damage among
alcoholics include abnormalities in the energy-
producing subcellular organelle, the mitochondria,
phosphorus and potassium depletion, and rhabdo-
myolysis induced by alcohol-related seizures, trauma
from falls, fights, or limb compression during
intoxication. Alcohol may also act synergistically
with nutritional deficiencies to disrupt energy meta-
bolism.
Alcoholic neuropathy is difficult to separate from
nutritional neuropathy and specifically resembles the
clinical and pathological features of thiamine defi-
ciency or beriberi. The frequency of neuropathy in
hospitalized alcoholics ranges from 9 to 30%, and up
to 93% of ambulatory alcoholics have electrophy-
siological evidence of neuropathy. Although it is not
known how alcohol injures peripheral nerves,
theories include altered membrane lipid permeability
and oxidation injury from free radical formation.
Whereas good nutrition is an important element of
treatment and prevention of alcohol neuropathy, the
cellular mechanism of this effect is not known.
Clinically, the neuropathy may be asymptomatic and
unrecognized by the subject. If present, symptoms
begin with paresthesias and burning feet, and later
painful calves, numbness, cramps, weakness, and
sensory ataxia may develop. On examination,
patients may have sensory loss (vibratory and deep
sensation) in the distal legs, motor weakness,
areflexia, calf tenderness, and orthostatic hypoten-
sion. Typically, the skin of the legs becomes shiny,
swollen, and subject to trauma and ulceration. In all
these chronic conditions, treatment involves removal
from chronic alcohol exposure, education, and good
nutrition with particular attention to B vitamins.
Medical consciousness of the particular frequency of
associated depression among alcoholics and the
likelihood that the alcoholic may have multiple
addictions are important considerations for rehabi-
litation efforts.
Fetal alcohol syndrome is a particularly important
clinical problem described in children of mothers
who drink alcohol frequently during pregnancy. Fetal
alcohol syndrome results in low birth weight, small
head circumference, and frequent cranial and joint
deformities. The child feeds poorly and is irritable
and tremulous. Many mothers of affected babies
suffer from alcohol withdrawal seizures, DTs, or
other alcohol-related medical complications during
the pregnancy. Infants with fetal alcohol syndrome
have a higher than normal incidence of congenital
brain malformations, and those who do not die have
an increased risk of mental retardation. Because
alcoholics often abuse several drugs, it is important
to consider that an irritable, tremulous, small baby
may also be withdrawing from or experiencing direct
toxicity from other agents. There are no laboratory
tests that categorically determine the diagnosis of
fetal alcohol syndrome. Because there is no safe
minimum amount of alcohol consumption that can
be guaranteed not to be toxic to a fetus, and because
one in six babies born with fetal alcohol syndrome
die and half the survivors have permanent physical or
mental handicaps, prospective mothers are urged to
abstain entirely from alcohol throughout their
pregnancy. The mechanism by which the abnormal-
ities of fetal alcohol syndrome are produced is

unknown, but it is thought to be due to a direct
teratogenic effect of alcohol or one of its metabolic
products.
—Christopher G. Goetz
See also–Amphetamine Toxicity; Cocaine;
Depression; Hallucinations, Visual and Auditory;
Hallucinogens; Heroin; Intoxication; Marijuana;
Methyl Alchohol; Neuropathies, Nutritional;
Smoking and Nicotine; Substance Abuse
Further Reading
Cardellach, F., Grau, J. M., Casademont, J., et al. (1992).
Oxidative metabolism in muscle mitochondria from patients
with chronic alcoholism. Ann. Neurol. 31, 515–518.
Charness, M. E., Simon, R. P., and Greenberg, D. A. (1989).
Ethanol and the nervous system. N. Engl. J. Med. 321, 442–
454.
D’Amour, M. L., and Butterworth, R. F. (1994). Pathogenesis of
alcoholic peripheral neuropathy: Direct effect of ethanol or
nutritional deficit? Metab. Brain Dis. 9, 133–141.
Kinsella, L. J., and Riley, D. E. (2003). Nutritional deficiencies and
syndromes associated with alcoholism. In Textbook of Clinical
Neurology (C. G. Goetz, Ed.), pp. 798–818. Saunders,
Philadelphia.
Koller, W., O’Hara, R., Dorus, W., et al. (1985). Tremor in chronic
alcoholism. Neurology 35, 1660–1662.
Monforte, R., Estruch, R., Valls-Sole, J., et al. (1995). Autonomic
and peripheral neuropathies in patients with chronic alcohol-
ism. Arch. Neurol. 52, 45–51.
Peoples, R. W., Li, C., and Weight, F. F. (1996). Lipid vs protein
theories of alcohol action in the nervous system. Annu. Rev.
Pharmacol. Toxicol. 36, 185–201.
Alertness (Crude
Consciousness)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALERTNESS refers to an awake, eyes-open state.
However, an ‘‘awake’’ individual may not be aware
of self or the environment. The arousal component of
wakefulness is dependent on the ascending reticular
activating system (ARAS) in the upper brainstem and
diencephalon. Most knowledge about sites for
alertness in humans comes from studies of stroke.
BRAINSTEM AND DIENCEPHALON
Most coma-producing ischemic strokes involving
the brainstem are due to occlusion of the basilar
ALERTNESS 81
artery. The paramedian pontine tegmentum is
consistently involved in pathological studies.
Coma-producing lesions of the midbrain almost
invariably are associated with thalamic, pontine
tegmental, or more widespread damage to the
cerebral cortex. Extensive bilateral destructive
lesions of the midbrain tegmentum and thalamus
bilaterally consistently eliminate the capacity for
alerting. Transections of the brainstem at
the midbrain level result in permanent coma in
animals. Among patients with thalamic lesions, only
those with bilateral dorsal paramedian lesions have
shown coma or impaired arousal responses. How-
ever, not all patients with bilateral paramedian
thalamic lesions are in coma; when coma does
occur, it is almost never permanent if the person
survives for several weeks or more. Coma-producing
lesions often also involve the rostral midbrain,
manifested by Parinaud’s syndrome or paralysis of
vertical gaze, especially upgaze. Evidence indicates
that only the combination of rostral brainstem
tegmental and paramedian diencephalic destruction
is consistently associated with permanent coma in
humans.
CEREBRAL HEMISPHERES
There is surprisingly inconclusive evidence that
diffuse cerebral cortical dysfunction in humans
causes enduring coma. In human cases, dysfunction
is rarely, if ever, purely cortical; lesions usually
involve other sites. Furthermore, cortical dysfunction
profoundly influences numerous subcortical regions,
an effect called diaschisis. Occasionally, acute,
unilateral, especially left or dominant, cerebral
dysfunction produces transient coma or unrespon-
siveness. In contrast, this is uncommon in patients
with nondominant hemisphere lesions of comparable
size and territory.
NEUROCHEMISTRY OF ALERTNESS
Principal neurotransmitter systems relevant to
arousal are cholinergic, monoaminergic, and GA-
BAergic. Cholinergic pathways play a contributory
role in arousal and alertness as components of the
ARAS. Cholinergic activation of the thalamus
facilitates thalamocortical transmission by decreas-
ing the tonic inhibition of the thalamic reticular
nucleus. The desynchronized arousal response
on the electroencephalogram (EEG), a hallmark

unknown, but it is thought to be due to a direct
teratogenic effect of alcohol or one of its metabolic
products.
—Christopher G. Goetz
See also–Amphetamine Toxicity; Cocaine;
Depression; Hallucinations, Visual and Auditory;
Hallucinogens; Heroin; Intoxication; Marijuana;
Methyl Alchohol; Neuropathies, Nutritional;
Smoking and Nicotine; Substance Abuse
Further Reading
Cardellach, F., Grau, J. M., Casademont, J., et al. (1992).
Oxidative metabolism in muscle mitochondria from patients
with chronic alcoholism. Ann. Neurol. 31, 515–518.
Charness, M. E., Simon, R. P., and Greenberg, D. A. (1989).
Ethanol and the nervous system. N. Engl. J. Med. 321, 442–
454.
D’Amour, M. L., and Butterworth, R. F. (1994). Pathogenesis of
alcoholic peripheral neuropathy: Direct effect of ethanol or
nutritional deficit? Metab. Brain Dis. 9, 133–141.
Kinsella, L. J., and Riley, D. E. (2003). Nutritional deficiencies and
syndromes associated with alcoholism. In Textbook of Clinical
Neurology (C. G. Goetz, Ed.), pp. 798–818. Saunders,
Philadelphia.
Koller, W., O’Hara, R., Dorus, W., et al. (1985). Tremor in chronic
alcoholism. Neurology 35, 1660–1662.
Monforte, R., Estruch, R., Valls-Sole, J., et al. (1995). Autonomic
and peripheral neuropathies in patients with chronic alcohol-
ism. Arch. Neurol. 52, 45–51.
Peoples, R. W., Li, C., and Weight, F. F. (1996). Lipid vs protein
theories of alcohol action in the nervous system. Annu. Rev.
Pharmacol. Toxicol. 36, 185–201.
Alertness (Crude
Consciousness)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALERTNESS refers to an awake, eyes-open state.
However, an ‘‘awake’’ individual may not be aware
of self or the environment. The arousal component of
wakefulness is dependent on the ascending reticular
activating system (ARAS) in the upper brainstem and
diencephalon. Most knowledge about sites for
alertness in humans comes from studies of stroke.
BRAINSTEM AND DIENCEPHALON
Most coma-producing ischemic strokes involving
the brainstem are due to occlusion of the basilar
ALERTNESS 81
artery. The paramedian pontine tegmentum is
consistently involved in pathological studies.
Coma-producing lesions of the midbrain almost
invariably are associated with thalamic, pontine
tegmental, or more widespread damage to the
cerebral cortex. Extensive bilateral destructive
lesions of the midbrain tegmentum and thalamus
bilaterally consistently eliminate the capacity for
alerting. Transections of the brainstem at
the midbrain level result in permanent coma in
animals. Among patients with thalamic lesions, only
those with bilateral dorsal paramedian lesions have
shown coma or impaired arousal responses. How-
ever, not all patients with bilateral paramedian
thalamic lesions are in coma; when coma does
occur, it is almost never permanent if the person
survives for several weeks or more. Coma-producing
lesions often also involve the rostral midbrain,
manifested by Parinaud’s syndrome or paralysis of
vertical gaze, especially upgaze. Evidence indicates
that only the combination of rostral brainstem
tegmental and paramedian diencephalic destruction
is consistently associated with permanent coma in
humans.
CEREBRAL HEMISPHERES
There is surprisingly inconclusive evidence that
diffuse cerebral cortical dysfunction in humans
causes enduring coma. In human cases, dysfunction
is rarely, if ever, purely cortical; lesions usually
involve other sites. Furthermore, cortical dysfunction
profoundly influences numerous subcortical regions,
an effect called diaschisis. Occasionally, acute,
unilateral, especially left or dominant, cerebral
dysfunction produces transient coma or unrespon-
siveness. In contrast, this is uncommon in patients
with nondominant hemisphere lesions of comparable
size and territory.
NEUROCHEMISTRY OF ALERTNESS
Principal neurotransmitter systems relevant to
arousal are cholinergic, monoaminergic, and GA-
BAergic. Cholinergic pathways play a contributory
role in arousal and alertness as components of the
ARAS. Cholinergic activation of the thalamus
facilitates thalamocortical transmission by decreas-
ing the tonic inhibition of the thalamic reticular
nucleus. The desynchronized arousal response
on the electroencephalogram (EEG), a hallmark
82 ALEXANDER’S DISEASE
of arousal and heightened alertness, shows a positive
correlation with the amount of acetylcholine
released and is abolished by cholinergic antagonists.
Conversely, increased cholinergic activity in the
pontine tegmental nucleus of Gudden may
contribute to a reduced level of alertness by
rostral projections and atonia by descending
connections.
The noradrenergic system is activated by stimula-
tion of the locus ceruleus. This leads to activation
of b-adrenergic receptors in the hippocampus,
enhancing excitation though increasing cyclic
AMP formation and thus inhibiting calcium-
mediated potassium conductance. The effect is
the opposite on the neocortex, where the activation
of a-adrenergic receptors causes neurons to become
hyperpolarized and decrease their rate of sponta-
neous firing. The net effect is to assist in attending
to sudden contrasting or adverse stimuli and to
increase the relative response to stimulus-specific
stimuli. Destruction of the locus ceruleus in experi-
mental animals is followed by a modest increase
in sleep, but there is no chronic effect on arousal or
the EEG.
There is little evidence that dopamine plays a role
in arousal, but dopaminergic agonists may produce
remarkable improvement in responsiveness in certain
patients with akinetic mutism.
The serotonergic system has a stabilizing role in
information processing, inhibiting interference when
such processing is ongoing. Only signals that are of
sufficient intensity and relevance can interfere. In
conditions of serotonin deficiency (e.g., alcohol
withdrawal), the animal or human is distractible,
impulsive, and overreacts. The rostral projection of
the serotonergic pathway is also involved in sleep:
Stimulation inhibits the phasic portion of REM sleep.
After destruction of the raphe nucleus, there is
insomnia, likely due to the failure of inhibition of
waking stimuli. This is typically transient; serotonin
appears to have a modulatory role in the wake–sleep
cycle.
g-Aminobutyric acid (GABA)-mediated inhibition
allows a ‘‘sculpturing’’ and selecting of information
for processing. Nonphysiological increases in GA-
BAergic activity are produced by barbiturates or
exogenous or endogenous ‘‘ozepines’’ that facilitate
the binding of GABA to its receptor (linked in turn to
the chloride channel) or that directly act on the
GABA receptor (anesthetic barbiturates such as
thiopental and pentobarbital). This activity is pro-
duced in the rostral part of the ARAS. Such actions
produce a marked decrease in alertness and concen-
tration that is blocked by the antagonist flumazenil.
Glutamic and aspartic acid, neurotransmitters that
are synthesized in the cortex, play a key role in the
excitatory synaptic activity in the cortex, in cor
tiocofugal projections, and in at least some thala-
mocortical afferent connections. Although these
neurotransmitters probably do not play a role in
arousal, they provide a principal material for
cortical–cortical communication. A complex mixture
of peptides that may function as neurotransmitters or
neuromodulators include vasoactive intestinal poly-
peptide, cholecystokinin, somatostatin, neuropeptide
Y, and peptides that also serve elsewhere as
hormones or releasing factors. In addition, there
are receptors, and usually endogenous ligands, for
opiates, benzodiazepine-like substances, adenosine,
and other substances. Their role concerning cortical
functions is unclear, but it is probable that dis-
turbances or imbalances can significantly alter
cortical function.
—G. Bryan Young
See also–Ascending Reticular Activating System
(ARAS); Attention; Awareness; Coma;
Concentration; Gamma Aminobutyric Acid
(GABA); Wakefulness
Alexander’s Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALEXANDER’S DISEASE is a rare and fatal disorder of
the white matter of the brain, and a type of
leukodystrophy. It is a genetic condition that results
in diminished myelin in the central nervous system
and interferes with normal brain function. It is most
commonly found in young children, usually with
onset during the first 2 years of life. However, there
are also juvenile cases, with onset occurring in
childhood or the early teens, and it occurs rarely in
adults. Alexander first described the disorder in
1949 in an infant with mental retardation and
hydrocephalus. He was the first to describe the
widespread presence in the brain of astrocytic
inclusions called Rosenthal fibers, which are the
hallmark of this disorder. Recent studies have
identified mutations in the gene for the astrocytic
82 ALEXANDER’S DISEASE
of arousal and heightened alertness, shows a positive
correlation with the amount of acetylcholine
released and is abolished by cholinergic antagonists.
Conversely, increased cholinergic activity in the
pontine tegmental nucleus of Gudden may
contribute to a reduced level of alertness by
rostral projections and atonia by descending
connections.
The noradrenergic system is activated by stimula-
tion of the locus ceruleus. This leads to activation
of b-adrenergic receptors in the hippocampus,
enhancing excitation though increasing cyclic
AMP formation and thus inhibiting calcium-
mediated potassium conductance. The effect is
the opposite on the neocortex, where the activation
of a-adrenergic receptors causes neurons to become
hyperpolarized and decrease their rate of sponta-
neous firing. The net effect is to assist in attending
to sudden contrasting or adverse stimuli and to
increase the relative response to stimulus-specific
stimuli. Destruction of the locus ceruleus in experi-
mental animals is followed by a modest increase
in sleep, but there is no chronic effect on arousal or
the EEG.
There is little evidence that dopamine plays a role
in arousal, but dopaminergic agonists may produce
remarkable improvement in responsiveness in certain
patients with akinetic mutism.
The serotonergic system has a stabilizing role in
information processing, inhibiting interference when
such processing is ongoing. Only signals that are of
sufficient intensity and relevance can interfere. In
conditions of serotonin deficiency (e.g., alcohol
withdrawal), the animal or human is distractible,
impulsive, and overreacts. The rostral projection of
the serotonergic pathway is also involved in sleep:
Stimulation inhibits the phasic portion of REM sleep.
After destruction of the raphe nucleus, there is
insomnia, likely due to the failure of inhibition of
waking stimuli. This is typically transient; serotonin
appears to have a modulatory role in the wake–sleep
cycle.
g-Aminobutyric acid (GABA)-mediated inhibition
allows a ‘‘sculpturing’’ and selecting of information
for processing. Nonphysiological increases in GA-
BAergic activity are produced by barbiturates or
exogenous or endogenous ‘‘ozepines’’ that facilitate
the binding of GABA to its receptor (linked in turn to
the chloride channel) or that directly act on the
GABA receptor (anesthetic barbiturates such as
thiopental and pentobarbital). This activity is pro-
duced in the rostral part of the ARAS. Such actions
produce a marked decrease in alertness and concen-
tration that is blocked by the antagonist flumazenil.
Glutamic and aspartic acid, neurotransmitters that
are synthesized in the cortex, play a key role in the
excitatory synaptic activity in the cortex, in cor
tiocofugal projections, and in at least some thala-
mocortical afferent connections. Although these
neurotransmitters probably do not play a role in
arousal, they provide a principal material for
cortical–cortical communication. A complex mixture
of peptides that may function as neurotransmitters or
neuromodulators include vasoactive intestinal poly-
peptide, cholecystokinin, somatostatin, neuropeptide
Y, and peptides that also serve elsewhere as
hormones or releasing factors. In addition, there
are receptors, and usually endogenous ligands, for
opiates, benzodiazepine-like substances, adenosine,
and other substances. Their role concerning cortical
functions is unclear, but it is probable that dis-
turbances or imbalances can significantly alter
cortical function.
—G. Bryan Young
See also–Ascending Reticular Activating System
(ARAS); Attention; Awareness; Coma;
Concentration; Gamma Aminobutyric Acid
(GABA); Wakefulness
Alexander’s Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALEXANDER’S DISEASE is a rare and fatal disorder of
the white matter of the brain, and a type of
leukodystrophy. It is a genetic condition that results
in diminished myelin in the central nervous system
and interferes with normal brain function. It is most
commonly found in young children, usually with
onset during the first 2 years of life. However, there
are also juvenile cases, with onset occurring in
childhood or the early teens, and it occurs rarely in
adults. Alexander first described the disorder in
1949 in an infant with mental retardation and
hydrocephalus. He was the first to describe the
widespread presence in the brain of astrocytic
inclusions called Rosenthal fibers, which are the
hallmark of this disorder. Recent studies have
identified mutations in the gene for the astrocytic

protein, glial fibrillary acidic protein (GFAP), in
most cases of infantile and juvenile Alexander’s
disease. The adult form of this disease has not been
studied in detail.
CLINICAL PRESENTATION
Children with the infantile form of Alexander’s
disease may show evidence of abnormality at birth
but more commonly develop symptoms slowly during
the first 2 years of life, with increasing head size
(macrocephaly), loss of milestones and psychomotor
retardation, seizures, and sometimes obstructive
hydrocephalus. Children with the juvenile form may
seem normal for several years and then develop
difficulty swallowing, talking, breathing, and some-
times vomiting. This may be accompanied by gait
abnormality and leg spasticity. Both the infantile and
juvenile forms of Alexander’s disease reveal changes
on brain magnetic resonance imaging (MRI), with
evidence of myelin loss most prominently shown in
the frontal lobes and with involvement of the basal
ganglia. Affected children may live for only a few
months or as long as 5–10 years and sometimes
longer. Rarely, patients with the juvenile form have
survived as long as he fifth decade. There is no
difference in the occurrence of this disease in males
and females. The adult form is highly variable and
Figure 1
Light microscopic appearance of Rosenthal fibers in the cerebral
cortex in Alexander’s disease. They appear as dark, round bodies
with greatest concentration in the subpial area (arrow) and
surrounding blood vessels (arrowhead), but they are also scattered
throughout the cortex.
ALEXANDER’S DISEASE 83
Figure 2
Electron microscopic appearance of Rosenthal fibers in a cerebral
biopsy on a 212-year-old child with Alexander’s disease. (A) The
dark, round bodies (long arrows) are Rosenthal fibers. They are
often surrounded by dense collections of glial intermediate
filaments (arrowheads). Some normal-appearing, myelinated
axons (short arrows) are present. (B) A Rosenthal fiber at higher
magnification and labeled for GFAP by immunogold staining. Both
the Rosenthal fiber and the adjacent glial intermediate filaments
are decorated with small black dots, the reaction product of the
immunogold procedure. There was no staining when normal
mouse serum was substituted for the mouse monoclonal anti-
GFAP primary antibody. [Reproduced with permission from
J. Neuropathol. Exp. Neurol.]
much less well understood but may resemble the
juvenile form or multiple sclerosis, and in some
instances it may be familial.
PATHOLOGY
The hallmark of Alexander’s disease is the wide-
spread presence of Rosenthal fibers in the central
nervous system (Fig. 1). These structures are some-
times found in other conditions, such as astrocytic
gliomas, glial scars, and sometimes multiple sclero-
sis, but their number and distribution in Alexander’s
disease are unique. Rosenthal fibers occur through-
out the subpial and subependymal regions as well as
perivascularly. They may be diffusely scattered in the
gray matter but are more profuse throughout the
white matter. In very young patients, they can be
found within the perikarya of astrocytes. Electron
microscopic studies show that the Rosenthal fibers in
Alexander’s disease appear as large, dense, round or
oval bodies that are often surrounded by thick
clusters of astrocytic intermediate filaments and they
are immunoreactive for GFAP (Fig. 2). Rosenthal
fibers also contain alpha B-crystallin (a heat shock
84 ALEXANDER’S DISEASE
protein), heat shock protein 27, and ubiquitin. How
the gene mutations described lead to the manifesta-
tions of this disease is not currently understood.
GENETIC OBSERVATIONS
Due to the finding that GFAP is a component of
Rosenthal fibers, and also because a transgenic mouse
overexpressing GFAP was found to die early and its
brain contained Rosenthal fibers, GFAP was investi-
gated as a candidate gene for this disorder. Subse-
quently, mutations in the gene for GFAP have been
found in most cases of infantile and juvenile Alex-
ander’s disease, including many pathologically proven
cases. Studies of the adult form have not been done.
No mutations in Alexander’s disease have been
reported in the gene for alpha B-crystallin or for other
Rosenthal fiber constituents. All the mutations identi-
fied to date have been single point mutations involving
one codon of the gene for GFAP, most often changing
the coded amino acid from an arginine to some other
amino acid, but a stop codon has also been found.
Most of these mutations occur in exons 1, 4, or 8. All
the mutations identified thus far have been present on
only one of the GFAP alleles and thus are heterozygous
dominant mutations. In the many sets of parents
tested, the mutation present in the child has not been
identified in either parent. Thus, Alexander’s disease
appears to be caused in most cases by a spontaneous,
new mutation in one of the allelic genes for GFAP.
Although an autosomal recessive mode of inheri-
tance was once thought to underlie Alexander’s
disease, in most cases the disorder appears to be
caused by a single de novo mutation of one of the
genes for GFAP. The rare occurrence of reported
affected siblings may be the result of gonadal
mosaicism or, less likely, the possible occurrence of
an unusual autosomal recessive mutation. There are
no reports of genetic studies on affected siblings and
their parents. It is possible, however, that there may
also be other genetic causes of Alexander’s disease. In
one case of pathologically proven Alexander’s dis-
ease, sequencing of the GFAP gene failed to reveal a
mutation. Moreover, in one report of a child with a
clinical picture consistent with Alexander’s disease
but without any pathological studies, an autosomal
recessive mutation in a component of mitochondrial
complex I was identified. In another report, a child
thought to have clinical findings consistent with Leigh
disease was found at autopsy to have Alexander’s
disease, but no genetic studies were performed.
DIAGNOSIS
The clinical picture and the MRI findings, especially
the predominant loss of myelin in the frontal regions,
are the best guides for the tentative diagnosis of
Alexander’s disease. However, it is important that
other forms of leukodystrophy that can be diagnosed
by blood and urine tests are ruled out. Canavan’s
disease can particularly resemble the clinical picture
of Alexander’s disease and should be ruled out by a
urine test for N-acetylaspartic acid, an enzyme assay
for aspartoacylase activity, or magnetic resonance
spectroscopy. After other disorders are ruled out, a
blood sample from the child can be analyzed for
mutations of the gene for GFAP. A positive result is
diagnostic for Alexander’s disease, but a negative
result does not rule out this condition. The diagnosis
can also be established by brain biopsy or at
necropsy; however, brain biopsy is rarely indicated
because of the reliability of MRI and genetic studies.
Moreover, if an affected child had an identified GFAP
mutation, prenatal screening of a subsequent preg-
nancy can be performed to detect the possible
occurrence of Alexander’s disease in the sibling.
TREATMENT
Currently, there is no specific treatment, only
supportive care.
—Anne B. Johnson
See also–Leukodystrophy
Further Reading
Brenner, M., Johnson, A. B., Boespflug-Tanguy, O., et al. (2001).
Mutations in GFAP, encoding glial fibrillary acidic protein, are
associated with Alexander disease. Nat. Genet. 27, 117–120.
Johnson, A. B. (1996). Alexander disease. Handb. Clin. Neurol.
22, 701–710.
Johnson, A. B. (2001). Alexander disease. In Medlink Neurology
(S. Gilman, Ed.). Medlink, San Diego. [http://www.medlink.
com (updated annually)].
Messing, A., Goldman, J. E., Johnson, A. B., et al. (2001).
Alexander disease: New insight from genetics. J. Neuropathol.
Exp. Neurol. 60, 563–573.
Pridmore, C. L., Baraitser, M., Harding, B., et al. (1993).
Alexander’s disease: Clues to diagnosis. J. Child Neurol. 8,
134–144.
Rodriguez, D., Gautier, F., Bertini, E., et al. (2001). Infantile
Alexander disease: Spectrum of GFAP mutations and genotype–
phenotype correlation. Am. J. Hum. Genet. 69, 1134–1140.
van der Knaap, M. S., Naidu, S., Breiter, S. N., et al. (2001).
Alexander disease: Diagnosis with MR imaging. Am. J.
Neuroradiol. 23, 541–552.

Alexia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALEXIA refers to a disorder of reading. The term is
usually restricted to an acquired reading impairment
that occurs as a result of damage to the brain. When
acquisition of normal reading and spelling skills is
impeded, the disorder is usually referred to as develop-
mental dyslexia. For acquired disorders of reading, the
terms alexia and dyslexia are used interchangeably,
with alexia more often encountered in the American
literature and dyslexia in the European literature.
Reading is a complex activity that can be disrupted
in different ways, and symptoms of alexia can be
variously manifested. There is no systematic classi-
fication scheme for alexia (Table 1), and terminology
is not uniform. After discussing alexia assessment,
this entry categorizes alexic syndromes into those
associated with language impairments and those for
which language is not directly implicated.
ASSESSMENT OF ALEXIA
Reading implies two distinct activities: reading aloud
(i.e., uttering linguistic information presented in a
visual format) and understanding meaning conveyed
by printed text. The assessment of alexia must
therefore consider both oral reading and reading
comprehension.
When alexia is suspected, it is necessary to first
verify that the patient was previously literate and
currently possesses visual and mental capabilities
required for reading. The ability to read aloud and
the ability to comprehend text can then be assessed.
In some circumstances, it is helpful to test separately
the reading of numbers, letters, words, phrases,
longer passages, and even special symbols (e.g., b,
Table 1 EXAMPLES OF ACQUIRED DISORDERS OF READINGa
Alexia associated with a language disturbance
Aphasic alexia
Alexia with agraphia
Orthographic alexia
Phonological alexia
Semantic alexia
Deep alexia
Alexia not associated with a language disturbance
Pure alexia
Neglect alexia
a
This alexia classification scheme is neither systematic nor
comprehensive.
ALEXIA 85
þ , and &) or musical notation. More typically, the
assessment focuses on individual words, considering
such features as frequency of use within the
language, word length, word meaning, part of speech
(grammatical role), and orthographic regularity
(orthography refers to spelling).
ALEXIA ASSOCIATED WITH
LANGUAGE DISTURBANCES
Reading is an important aspect of language. In
general, damage to brain structures that affects oral
(spoken) language affects written language in an
analogous manner. During the second half of the
19th century, seminal studies by Paul Broca in
France, Carl Wernicke in Germany, and others
demonstrated that damage to critical regions of the
left cerebral hemisphere impaired language in a
manner that depended on which particular brain
region was affected. This condition is referred to as
aphasia. The model that emerged was that the ability
to express language fluently is disrupted by large
lesions of the left frontal lobe, especially those that
include the posterior portion of the inferior frontal
gyrus (Broca’s area, a cortical region corresponding
to Brodmann’s areas 44 and 45). The ability to
understand language is particularly disrupted by
large lesions of the left temporal and parietal lobes,
especially those that include the posterior portion of
the superior temporal gyrus (Wernicke’s area, in-
cluded within Brodmann’s area 22). Both of these
regions are in the central portion of the lateral
surface of the left hemisphere, near the lateral fissure.
Recent research that images the brain while subjects
are engaged in specific cognitive tasks generally
confirms this traditional model of language localiza-
tion but also indicates that other brain structures
contribute to language processing as well.
Aphasic Alexia
Aphasic alexia designates the reading disturbance
that accompanies prominent impairments in oral
language. When patients with damage that includes
Broca’s area read aloud, their words are spoken
slowly and effortfully. Phrases tend to be short, often
limited to just one or two words, and evince only a
limited range of grammatical forms (mainly nouns
and verbs). Their speech lacks fluency, regardless of
whether it emerges during spontaneous conversation
or oral reading. In contrast, patients with damage
that includes Wernicke’s area express themselves
fluently when speaking or reading aloud. However,
86 ALEXIA
their choice of words is often vague or incorrect.
Broca’s aphasics understand spoken and written
language relatively well; Wernicke’s aphasics under-
stand both poorly. Thus, in aphasic alexia, reading
deficits parallel those of oral language.
In contrast to patients with aphasic alexia, some
patients with damage to left hemisphere language
areas have disproportionately severe difficulties with
reading. For some patients, distinct patterns of
reading errors warrant special designation. Several
of these language-associated alexic syndromes are
described next.
Alexia with Agraphia
For some patients with injury to the left cerebral
hemisphere, reading is disrupted far out of propor-
tion to oral language deficits. Near the end of the
19th century, the French neurologist Jules Dejerine
convincingly demonstrated that small lesions in the
vicinity of the left angular gyrus, located in the
inferior parietal lobe and approximately correspond-
ing to Brodmann’s area 39, severely impaired reading
(both reading aloud and reading comprehension) and
writing, whereas oral language was only mildly
affected. Patients have difficulty spelling words aloud
or understanding words spelled aloud for them.
Dejerine believed that the left angular gyrus was
crucial for the visual memory of letters and words.
Modern investigators have suggested that multi-
modal sensory integration within this brain region
is essential for reading and writing.
Orthographic, Phonological, Semantic, and
Deep Alexia
In recent years, alexia has more often been classified
according to the pattern of reading errors, particu-
larly errors when reading single words aloud. Error
analyses in turn provide insight into how the brain
might process linguistic information. Many patients
classified in this way could also be considered as
having aphasic alexia or alexia with agraphia.
Responsible lesions typically involve left hemisphere
language areas. Some languages use ideograms to
represent units of meaning rather than alphabetical
letters to represent units of sound. In Japanese, in
which both forms are used, alexia after left hemi-
sphere damage typically involves both simulta-
neously, but it is also common for alexia to affect
one variety more than the other.
For some patients, errors occur in the reading of
orthographically ‘‘irregular’’ words but not regular
words. Irregular words are those that fail to conform
to common patterns of spelling-to-sound correspon-
dence. For example, the irregular word ‘‘onion’’
would be difficult to pronounce simply by sounding
out the letters o-n-i-o-n, and the irregular word
‘‘pint’’ might be mispronounced to rhyme with ‘‘hint’’
or ‘‘mint.’’ Patients with this form of alexia can still
read aloud even unfamiliar words as long as the
spelling is regular, and they can pronounce made-up
words (nonwords; e.g., ‘‘fint’’ would be read aloud to
rhyme with ‘‘hint’’). In a second group of patients,
errors occur in the oral reading of uncommon words
but not in familiar, frequently encountered words.
These patients can read and understand common
words such as ‘‘rabbit’’ or ‘‘woman’’ but might have
difficulty with words such as ‘‘hare’’ or ‘‘matron.’’ In
particular, they are unable to provide plausible
pronunciations for nonwords. The first of these
disorders is referred to as orthographic alexia and
the second disorder as phonological alexia, where
phonology refers to word sounds.
A third pattern of reading impairment occurs in
disorders such as Alzheimer’s disease, in which knowl-
edge about word meaning (semantic knowledge) is
progressively lost. In semantic alexia, reading compre-
hension is impaired despite preservation of the ability
to read aloud both real words and nonwords. A
different type of reading error characterizes the patient
with deep alexia. The defining error of this condition is
that related to the target word by meaning. For
example, the word ‘‘spouse’’ might be read as ‘‘wife,’’
or ‘‘bench’’ could be read as ‘‘chair.’’ In addition,
patients with deep alexia, like those with phonological
alexia, are unable to pronounce nonwords.
ALEXIA NOT ASSOCIATED WITH
LANGUAGE DISTURBANCES
Impairments in one area of mental functioning often
influence performances on tasks intended to assess
different mental capabilities. Thus, even when the
left angular gyrus and other left hemisphere language
areas are spared, reading performance can be altered.
Examples of two such alexic disorders are described
next.
Pure Alexia
Dejerine documented the anatomical substrate of
pure alexia, also referred to as alexia without
agraphia. This remarkable syndrome is characterized
by the inability to read aloud or to understand
written text. Milder cases are distinguished by
reading that is tediously slow. In pure alexia, damage

most often involves the left occipital lobe. This
region is primarily concerned with vision in the
opposite (right) field of vision, and patients with pure
alexia typically have lost vision on their right side.
This visual impairment by itself does greatly impede
reading. However, the usual lesion of pure alexia also
extends slightly forward to disrupt fibers emerging
from the splenium of the corpus callosum, a large
fiber bundle that interconnects the two cerebral
hemispheres. Patients with pure alexia can see
perfectly well with their intact left visual field.
Because language areas abutting the left lateral
fissure are spared, these patients have no difficulty
expressing themselves through speech or writing, and
they have no difficulty understanding the speech of
others. They can write with facility, but remarkably
they are unable to read what they have written. Both
the ability to spell words aloud and the capacity to
recognize words spelled aloud to them are spared.
The most widely accepted explanation is that visual
information from the right visual field is lost, and
information from the intact left visual field, after
processing in visual cortex of the right occipital lobe,
is not conveyed across the corpus callosum to the
other side of the brain. The left angular gyrus and
other left hemisphere regions necessary for reading
are thus intact, but these cortical areas are discon-
nected from visual input required for reading. Pure
alexia without loss of vision in either visual field can
result from a subcortical lesion deep to the left
angular gyrus that interrupts visual input to this
structure.
Some patients with pure alexia gradually recover
the capacity to read, and for others some reading
ability is retained from the onset. In these instances,
reading may proceed laboriously, letter by letter. In
milder cases, when words are no longer deciphered
one letter at a time, reading may still be slow and
tedious. Moreover, there is a word-length effect, such
that longer words are more likely to be misread than
shorter words. There is no effect of word frequency
or orthographic regularity. Unlike frequency and
regularity effects, word-length effects are not char-
acteristic of reading disorders attributed to under-
lying language disturbances.
Neglect Alexia
Disturbances in visual–spatial processing and atten-
tion can affect reading. A particular aspect of
inattention, referred to as unilateral neglect, concerns
the failure to orient to information conveyed from
ALIEN LIMB 87
one side of the body. In its most flagrant manifesta-
tion, the so-called neglect syndrome almost always
reflects damage to the right cerebral hemisphere and
affects stimuli from the patient’s left side. For
example, a man with unilateral neglect may fail to
shave the left side of his face or to eat food from the
left side of his food tray.
When manifestations of unilateral neglect are
severe, patients may fail even to read words on the
left-hand side of the page. In reading individual
words, the initial (left) portion may be altered (e.g.,
‘‘borough’’ misread as ‘‘through’’) or omitted alto-
gether (e.g., ‘‘clover’’ misread as ‘‘lover’’ or ‘‘over’’).
Patients with neglect alexia are unable to understand
text or words that are incorrectly read aloud. Word
frequency and orthographic regularity do not affect
reading accuracy, but there may be a word-length
effect.
—Victor W. Henderson
See also–Agnosia; Agrammatism; Agraphia;
Anomia; Aphasia; Apraxia; Language and
Discourse; Language Disorders, Overview;
Reading and Acquired Dyslexia
Further Reading
Friedman, R. B., Ween, J. E., and Albert, M. L. (1993). Alexia. In
Clinical Neuropsychology (K. M. Heilman and E. Valenstein,
Eds.), 3rd ed., pp. 37–62. Oxford Univ. Press, New York.
Henderson, V. W. (1986). Anatomy of posterior pathways in
reading: A reassessment. Brain Lang. 29, 119–133.
Sugishita, M., Otomo, K., Kabe, S., et al. (1992). A critical
appraisal of neuropsychological correlates of Japanese
ideogram (kanji) and phonogram (kana) reading. Brain 115,
1563–1585.
Alien Limb
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALIEN HAND, also known as anarchic hand, Strange-
lovian hand, and magnetic apraxia, describes the
phenomenon of a hand and arm that perform
complex, involuntary movements. The patient is
unable to explain the source of such movement and
may consider the limb to move as if it had a mind of
its own. Essentially two kinds of behavior are
covered by this term. The first consists of repetitive
grasping movements in an apraxic hand, and the
second describes involuntary goal-directed limb

most often involves the left occipital lobe. This
region is primarily concerned with vision in the
opposite (right) field of vision, and patients with pure
alexia typically have lost vision on their right side.
This visual impairment by itself does greatly impede
reading. However, the usual lesion of pure alexia also
extends slightly forward to disrupt fibers emerging
from the splenium of the corpus callosum, a large
fiber bundle that interconnects the two cerebral
hemispheres. Patients with pure alexia can see
perfectly well with their intact left visual field.
Because language areas abutting the left lateral
fissure are spared, these patients have no difficulty
expressing themselves through speech or writing, and
they have no difficulty understanding the speech of
others. They can write with facility, but remarkably
they are unable to read what they have written. Both
the ability to spell words aloud and the capacity to
recognize words spelled aloud to them are spared.
The most widely accepted explanation is that visual
information from the right visual field is lost, and
information from the intact left visual field, after
processing in visual cortex of the right occipital lobe,
is not conveyed across the corpus callosum to the
other side of the brain. The left angular gyrus and
other left hemisphere regions necessary for reading
are thus intact, but these cortical areas are discon-
nected from visual input required for reading. Pure
alexia without loss of vision in either visual field can
result from a subcortical lesion deep to the left
angular gyrus that interrupts visual input to this
structure.
Some patients with pure alexia gradually recover
the capacity to read, and for others some reading
ability is retained from the onset. In these instances,
reading may proceed laboriously, letter by letter. In
milder cases, when words are no longer deciphered
one letter at a time, reading may still be slow and
tedious. Moreover, there is a word-length effect, such
that longer words are more likely to be misread than
shorter words. There is no effect of word frequency
or orthographic regularity. Unlike frequency and
regularity effects, word-length effects are not char-
acteristic of reading disorders attributed to under-
lying language disturbances.
Neglect Alexia
Disturbances in visual–spatial processing and atten-
tion can affect reading. A particular aspect of
inattention, referred to as unilateral neglect, concerns
the failure to orient to information conveyed from
ALIEN LIMB 87
one side of the body. In its most flagrant manifesta-
tion, the so-called neglect syndrome almost always
reflects damage to the right cerebral hemisphere and
affects stimuli from the patient’s left side. For
example, a man with unilateral neglect may fail to
shave the left side of his face or to eat food from the
left side of his food tray.
When manifestations of unilateral neglect are
severe, patients may fail even to read words on the
left-hand side of the page. In reading individual
words, the initial (left) portion may be altered (e.g.,
‘‘borough’’ misread as ‘‘through’’) or omitted alto-
gether (e.g., ‘‘clover’’ misread as ‘‘lover’’ or ‘‘over’’).
Patients with neglect alexia are unable to understand
text or words that are incorrectly read aloud. Word
frequency and orthographic regularity do not affect
reading accuracy, but there may be a word-length
effect.
—Victor W. Henderson
See also–Agnosia; Agrammatism; Agraphia;
Anomia; Aphasia; Apraxia; Language and
Discourse; Language Disorders, Overview;
Reading and Acquired Dyslexia
Further Reading
Friedman, R. B., Ween, J. E., and Albert, M. L. (1993). Alexia. In
Clinical Neuropsychology (K. M. Heilman and E. Valenstein,
Eds.), 3rd ed., pp. 37–62. Oxford Univ. Press, New York.
Henderson, V. W. (1986). Anatomy of posterior pathways in
reading: A reassessment. Brain Lang. 29, 119–133.
Sugishita, M., Otomo, K., Kabe, S., et al. (1992). A critical
appraisal of neuropsychological correlates of Japanese
ideogram (kanji) and phonogram (kana) reading. Brain 115,
1563–1585.
Alien Limb
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALIEN HAND, also known as anarchic hand, Strange-
lovian hand, and magnetic apraxia, describes the
phenomenon of a hand and arm that perform
complex, involuntary movements. The patient is
unable to explain the source of such movement and
may consider the limb to move as if it had a mind of
its own. Essentially two kinds of behavior are
covered by this term. The first consists of repetitive
grasping movements in an apraxic hand, and the
second describes involuntary goal-directed limb
88 ALPERS’ DISEASE
movements, for example, when a patient touches
their right hand instead of their nose, despite
understanding the command and attempting to move
correctly to the command.
Alien limb syndrome has been associated with
different locations of structural damages, including
frontal and parietal lobes and the connecting fiber
tract between the two cerebral hemispheres known
as the corpus callosum. The frontal variant of alien
hand may reflect disinhibited movements, and the
parietal variant may represents inattention and lack
of orientation toward contralateral space (neglect
syndrome). Corpus callosum injury produces dis-
connection between brain hemispheres and is asso-
ciated with other signs, including dominant hand
constructional apraxia, nondominant hand ideomo-
tor apraxia, apraxic agraphia, and inability of one
hand to imitate the posture of the other hand. Alien
hand syndrome generally follows sudden cerebral
injuries (most commonly strokes), corpus callosal
surgery to treat epilepsy, and a variety of degenera-
tive, dementing cerebral disorders, such as cortical
basal degeneration, Alzheimer’s disease, Marchiafava–
Bignami disease, and prion diseases. When alien
hand originates from focal injury of sudden onset,
recovery generally occurs within 1 year, although the
problem may persist permanently. In contrast, alien
hand syndrome associated with progressive degen-
erative cerebral disorders persists until the patient
dies or until the cerebral degeneration is so advanced
that it interferes with limb mobilization. Alien hand
does not usually cause serious injury but can induce
self-slapping, self-choking, or grasping self-powered
tools, and patients should not drive. With regard to
treatment, rehabilitation for alien hand syndrome
has not been developed, and pharmacological ther-
apy has not been shown to be useful in treating this
condition.
—Esther Cubo and Christopher G. Goetz
See also–Anosognosia; Apraxia
Further Reading
Chamorro, A., Marshall, R. S., Valls-Sole, J., et al. (1997). Motor
behavior in stroke patients with isolated medial frontal ischemic
infarction. Stroke 28, 1755–1760.
Chan, J. L., and Ross, E. D. (1997). Alien hand syndrome:
Influence of neglect on the clinical presentation of frontal and
callosal variants. Cortex 33, 287–299.
Ventura, M. G., Goldman, S., and Hildebrand, J. (1995). Alien
hand syndrome without a corpus callosum lesion. J. Neurol.
Neurosurg. Psychiatry 58, 735–737.
Alpers’ Disease (Progressive
Infantile Poliodystrophy)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALPERS’ DISEASE, or progressive infantile poliody-
strophy, is not a well-defined clinical disease entity
but rather refers to a syndrome of progressive
psychomotor retardation, seizures, and deterioration
of the motor system. The eponym refers to a case
report of Alpers (1931) in which he described a young
infant who had acute onset of intractable seizures
followed by spasticity and resulting in death, and at
autopsy he was found to have severe degeneration of
cortical neurons. Less than 100 cases of this syndrome
have been described, with most patients presenting
with psychomotor retardation; intractable seizures
that can be generalized tonic–clonic; partial motor,
infantile spasms; and occasionally epilepsia partialis
continua. Abnormalities of the motor system occur
and patients usually present with generalized hypoto-
nia, but as the disease progresses they become spastic,
ultimately resulting in decerebration and death.
The age at onset of symptoms is usually between 1
and 3 years, with death occurring by the age of 5 or
6. There are atypical forms of this syndrome with a
later onset of symptoms and signs, with death
occurring between the ages of 10 and 20. A form
of progressive infantile poliodystrophy associated
with hepatic cirrhosis has been described that is
characterized by liver disease followed by develop-
mental delay and intractable seizures (Alpers–Hut-
tenlocher syndrome). Death occurs within the first 2
or 3 years of life. Rare cases with onset of symptoms
and signs in the late teens have been reported in
which the patients presented with subacute encepha-
lopathy, visual and sensory symptoms and signs, and
intractable seizures and at autopsy showed charac-
teristic progressive neuronal destruction of the
cerebral cortex and liver disease. Most cases have
been reported to have some complication at birth, an
antecedent infection, or some other stressor that
often heralds the onset of seizures.
DIAGNOSTIC STUDIES
Electroencephalographic findings are characterized
by severe high-amplitude slowing with polyspike and
wave typically more prominent in the posterior
cerebral quadrants. Laboratory studies have shown
88 ALPERS’ DISEASE
movements, for example, when a patient touches
their right hand instead of their nose, despite
understanding the command and attempting to move
correctly to the command.
Alien limb syndrome has been associated with
different locations of structural damages, including
frontal and parietal lobes and the connecting fiber
tract between the two cerebral hemispheres known
as the corpus callosum. The frontal variant of alien
hand may reflect disinhibited movements, and the
parietal variant may represents inattention and lack
of orientation toward contralateral space (neglect
syndrome). Corpus callosum injury produces dis-
connection between brain hemispheres and is asso-
ciated with other signs, including dominant hand
constructional apraxia, nondominant hand ideomo-
tor apraxia, apraxic agraphia, and inability of one
hand to imitate the posture of the other hand. Alien
hand syndrome generally follows sudden cerebral
injuries (most commonly strokes), corpus callosal
surgery to treat epilepsy, and a variety of degenera-
tive, dementing cerebral disorders, such as cortical
basal degeneration, Alzheimer’s disease, Marchiafava–
Bignami disease, and prion diseases. When alien
hand originates from focal injury of sudden onset,
recovery generally occurs within 1 year, although the
problem may persist permanently. In contrast, alien
hand syndrome associated with progressive degen-
erative cerebral disorders persists until the patient
dies or until the cerebral degeneration is so advanced
that it interferes with limb mobilization. Alien hand
does not usually cause serious injury but can induce
self-slapping, self-choking, or grasping self-powered
tools, and patients should not drive. With regard to
treatment, rehabilitation for alien hand syndrome
has not been developed, and pharmacological ther-
apy has not been shown to be useful in treating this
condition.
—Esther Cubo and Christopher G. Goetz
See also–Anosognosia; Apraxia
Further Reading
Chamorro, A., Marshall, R. S., Valls-Sole, J., et al. (1997). Motor
behavior in stroke patients with isolated medial frontal ischemic
infarction. Stroke 28, 1755–1760.
Chan, J. L., and Ross, E. D. (1997). Alien hand syndrome:
Influence of neglect on the clinical presentation of frontal and
callosal variants. Cortex 33, 287–299.
Ventura, M. G., Goldman, S., and Hildebrand, J. (1995). Alien
hand syndrome without a corpus callosum lesion. J. Neurol.
Neurosurg. Psychiatry 58, 735–737.
Alpers’ Disease (Progressive
Infantile Poliodystrophy)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALPERS’ DISEASE, or progressive infantile poliody-
strophy, is not a well-defined clinical disease entity
but rather refers to a syndrome of progressive
psychomotor retardation, seizures, and deterioration
of the motor system. The eponym refers to a case
report of Alpers (1931) in which he described a young
infant who had acute onset of intractable seizures
followed by spasticity and resulting in death, and at
autopsy he was found to have severe degeneration of
cortical neurons. Less than 100 cases of this syndrome
have been described, with most patients presenting
with psychomotor retardation; intractable seizures
that can be generalized tonic–clonic; partial motor,
infantile spasms; and occasionally epilepsia partialis
continua. Abnormalities of the motor system occur
and patients usually present with generalized hypoto-
nia, but as the disease progresses they become spastic,
ultimately resulting in decerebration and death.
The age at onset of symptoms is usually between 1
and 3 years, with death occurring by the age of 5 or
6. There are atypical forms of this syndrome with a
later onset of symptoms and signs, with death
occurring between the ages of 10 and 20. A form
of progressive infantile poliodystrophy associated
with hepatic cirrhosis has been described that is
characterized by liver disease followed by develop-
mental delay and intractable seizures (Alpers–Hut-
tenlocher syndrome). Death occurs within the first 2
or 3 years of life. Rare cases with onset of symptoms
and signs in the late teens have been reported in
which the patients presented with subacute encepha-
lopathy, visual and sensory symptoms and signs, and
intractable seizures and at autopsy showed charac-
teristic progressive neuronal destruction of the
cerebral cortex and liver disease. Most cases have
been reported to have some complication at birth, an
antecedent infection, or some other stressor that
often heralds the onset of seizures.
DIAGNOSTIC STUDIES
Electroencephalographic findings are characterized
by severe high-amplitude slowing with polyspike and
wave typically more prominent in the posterior
cerebral quadrants. Laboratory studies have shown

elevated serum lactate, pyruvate, and lactate/pyru-
vate ratio. Cerebrospinal fluid lactate is also elevated.
These findings suggest a disorder of pyruvate
metabolism as a possible etiology for this disease.
Magnetic resonance imaging of the brain can be
normal, show progressive gray matter atrophy, or
show bilateral high signal lesions in the thalami.
Abnormalities are most frequently seen in the
occipital cortex, basal ganglia, and thalami. Occa-
sionally, transient changes have been described in the
occipital white matter that may represent postictal
changes.
PATHOLOGY
The pathological changes of this syndrome are
primarily limited to the cerebral gray matter. Gross
examination of the brain shows diffuse atrophy of
the cerebrum and cerebellum, although the atrophic
changes are more pronounced in the cerebellum.
Histopathological changes of varying severity are
found in all areas of the cerebral cortex, with severe
thinning of the cortex, scattered focal spongy
degeneration, and gliosis. There is severe cortical
neuronal loss, which is most prominent in the
calcarine cortex. Neuronal loss is also seen in the
striate cortex, brainstem nuclei, and dentate nuclei.
The gray matter also shows glial proliferation,
capillary dilatation, and proliferation. Pathological
changes in the liver in Alpers–Huttenlocher syn-
drome include microvesicular steatosis with severe
loss of hepatocytes, fatty change infiltration, bile
duct proliferation, fibrosis, and cirrhosis.
ETIOLOGY
Much attention has been directed at the etiology of
progressive infantile poliodystrophy (Alpers’ dis-
ease). Most reports show evidence of disordered
pyruvate metabolism, and pyruvate dehydrogenase
complex deficiency, pyruvate carboxylase deficiency,
and cytochrome aa3 deficiency have all been
reported in patients with clinical Alpers’ disease.
The possibility of an infectious etiology was sug-
gested by a study in which a hamster developed
disease when injected with samples from a girl with
clinical Alpers’ disease.
GENETICS
Without knowing the etiology of this disease, it is not
possible to define any genetic inheritance pattern. It
ALPERS’ DISEASE 89
has been considered to be inherited as an autosomal
recessive trait, but a disorder of mitochondria is
possible.
DIFFERENTIAL DIAGNOSIS
Any of the neurodegenerative diseases with intract-
able seizures as a prominent clinical feature must be
considered in the differential diagnosis, including late
infantile neuronal ceroid lipofuscinosis, biotinidase
deficiency, Menkes disease, peroxisomal disorders,
glucose transporter protein deficiency, and organica-
cidopathies. In some cases, encephalitis must also be
considered. Liver failure and encephalopathy asso-
ciated with the administration of valproic acid must
be distinguished from Alpers–Huttenlocher syn-
drome.
PROGNOSIS
The prognosis of this syndrome is grim and most
patients die within 1 or 2 years from the onset of
symptoms and signs. Although seizures are charac-
teristically very difficult to control, careful vigorous
treatment with anticonvulsant drugs must be pur-
sued. Unfortunately, there is no known treatment
available to alter the rapidly progressive nature of
this devastating disease.
—Nancy Bass
Further Reading
Boyd, S. G., Harden, A., Egger, J., et al. (1986). Progressive
neuronal degeneration of childhood with liver disease (‘‘Alpers
disease’’): Characteristic neurophysiological features. Neurope-
diatrics 17, 75–80.
Chow, C. W., and Thorbun, D. R. (2000). Morphologic correlates
of mitochondrial dysfunction in children. Hum. Reprod. 15,
68–78.
Gabreels, F. J. M., Prick, M. J. J., Trijbels, J. M., et al. (1984).
Defects in citric acid cycle and the electron transport chain
in progressive poliodystrophy. Acta Neurol. Scand. 70,
145–154.
Harding, B. N., Alsanjani, N., Smith, S. J., et al. (1995).
Progressive neuronal degeneration of childhood with liver
disease (Alpers’ disease) presenting in young adults. J. Neurol.
Neurosurg. Psychiatry 58, 320–325.
Prick, M. J. J., Gabreels, F. J., Trijbels, J. M., et al. (1983).
Progressive poliodystrophy (Alpers’ disease) with a defect in
cytochrome aa3 in muscle: A report of two unrelated patients.
Clin. Neurol. Neurosurg. 85, 57–70.
Rasmussen, M., Sanengen, J., Skullerud, K., et al. (2000). Evidence
that Alpers–Huttenlocher syndrome could be a mitochondrial
disease. J. Child Neurol. 15, 473–477.
90 ALZHEIMER, ALOIS

was a keen observer of neurological and psychiatric

phenomena, he was able to correlate abnormalities in
Alzheimer, Alois brain structure and function with the behavioral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved. changes seen during the patient’s life. Alzheimer was
an illustrator as well as a scientist, and in collabora-
tion with Nissl he produced an exceptional six-
volume neuropathology textbook in 1904.
The work for which Alzheimer is best known,
however, is a short case study that appeared in 1907.
In this report, Alzheimer described a 55-year-old
woman with a 4-year course of progressive person-
ality change, memory loss, and aphasia and who, at
autopsy, had characteristic microscopic features in
the brain (Fig. 1). These changes, now known as
neuritic plaques and neurofibrillary tangles, were
interpreted as contributing to the clinical picture of
dementia. Alzheimer’s insight was to recognize an
association between the dementia in this relatively
young woman and the unusual changes in her
ALOIS ALZHEIMER (1864–1915) was a German autopsied brain.
neuropathologist and neurologist whose name is Alzheimer did not affix his own name to the
justifiably associated with one of the most important disease he described. Instead, his director Kraepelin
diseases in medicine today. In describing the disease credited him with the discovery and suggested the
that later came to bear his name, Alzheimer eponymic designation. Because of the young age of
inaugurated a century of progress in the diagnosis the first patient, Alzheimer’s disease also came to be
and characterization of the dementias. He also made known as presenile dementia, in contrast to senile
other important contributions to neurology by help-
ing to establish the neuropathological basis of a
variety of mental disorders.
Alzheimer was born in Markbreit, Bavaria, and
attended medical schools at the Universities of
Wurzburg, Tubingen, and Berlin from 1882 to
1887. After his internship, he took a post at the
Stadtische Irrenanstalt in Frankfurt-am-Main, where,
in 1888, he met the neuropathologist Franz Nissl.
The professional contact with Nissl would last a
lifetime. In 1902, Alzheimer was invited by the
prominent psychiatrist Emil Kraepelin to join him at
Heidelberg. In the following year, Alzheimer moved
to Munich, where he worked at the Anatomisches
Laboratorium der Psychiatrischen und Nervenklinik
until 1912. The last 3 years of his life were spent as
chair of psychiatry at the University of Breslau.
The association with Kraepelin was critical be-
cause he was one of the few psychiatrists of his day
to consider the neuroanatomical basis of mental
disorders. With Kraepelin’s encouragement, Alzhei-
mer productively investigated the neuropathology of
many diseases characterized by psychiatric dysfunc-
tion, including the form of neurosyphilis known as
general paresis, vascular dementia, Parkinson’s dis- Figure 1
ease, and Huntington’s disease. As a clinician who Auguste D., the first reported case of Alzheimer’s disease.

dementia, a term used vaguely by previous autho-
rities to describe the condition of older persons with
various types of cognitive dysfunction. Later research
determined that the neuropathological changes in the
two disorders were identical, and the distinction
between presenile and senile forms has since been
abandoned. Today, the sole term Alzheimer’s disease
refers to individuals of any age who develop the
disease.
Remarkably, many decades passed before the
importance of Alzheimer’s discovery was fully
recognized. It was not until the late 20th century
that this very common and irreversible disease was
appreciated as posing a major challenge to the older
population and to those charged with caring for the
afflicted. Today, Alzheimer’s disease has become a
household term. At least 4 million Americans are
affected with the disease, and this number is
projected to increase dramatically with the expected
aging of the population in the next few decades.
Alzheimer’s disease and other dementias are now
vigorously studied in neurology clinics and basic
science laboratories, whereas 30 years ago they were
scarcely mentioned in medical school curricula. Were
he alive today, Alzheimer would be astonished at the
attention generated by his three-page report in 1907.
Alzheimer deserves credit for many other con-
tributions to neurology. He devoted his considerable
talents primarily to neuropathology, the most ad-
vanced neuroscientific method of his era, and based
his clinical thinking on abnormalities in the brain he
was able to demonstrate at autopsy. Considered the
founder of the Munich school of neuropathology, he
was one of the most important figures in the
development of this field at the turn of the 20th
century. The growth of neuropathology in turn
stimulated further advances in neurology by provid-
ing a more complete understanding of the origin of
disease manifestations. Along with his colleague
Nissl and others of the time, Alzheimer helped
establish the neuropathological basis of many dis-
orders for the first time. In particular, Alzheimer
favored a biological approach to psychiatry and was
a pioneer in describing neuropathological aspects of
mental disorders. This perspective distinguished him
from many of his contemporaries and showed
Alzheimer to be remarkably modern in his thinking.
Alzheimer will doubtless be most remembered for
his initial description of the disease named after him.
However, his many other achievements in neurology
should not be forgotten. Alzheimer demonstrated the
value of interpreting clinical phenomena in light of
ALZHEIMER’S DISEASE 91
abnormalities in the brain, and his ability to link
basic science data with observations of clinical
neurology and psychiatry served to stimulate much
work in the years following his death. He helped lay
the foundation for the current understanding of brain
disorders that affect behavior, most notably Alzhei-
mer’s disease, and his contributions have had a
significant impact on the neurosciences.
—Christopher Mark Filley
See also–Aging, Overview; Alzheimer’s Disease;
Alzheimer’s Disease, Epidemiology; Dementia
(see Index entry Biography for complete list of
biographical entries)
Further Reading
Alzheimer, A. (1987). About a peculiar disease of the cerebral
cortex (L. Jarvik and H. Greenson, Trans.). Alzheimer’s Dis.
Assoc. Dis. 1, 7–8.
Berrios, G. E., and Freeman, H. (1991). Alzheimer and the
Dementias. Royal Society of Medicine, London.
Haymaker, W. (1953). The Founders of Neurology. Thomas,
Springfield, IL.
Maurer, K., Volk, K., and Gerbaldo, H. (1997). Auguste D. and
Alzheimer’s disease. Lancet 349, 1546–1549.
McHenry, L. C. (1969). Garrison’s History of Neurology. Thomas,
Springfield, IL.
Alzheimer’s Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
EPIDEMIOLOGY AND GENETICS
ALZHEIMER’S DISEASE (AD) is the most common
cause of dementia, accounting for approximately
two-thirds of all cases. Prevalence estimates of AD in
the United States and Europe vary widely from 3.6 to
10.3% of people older than age 65. In the United
States, estimates range from 1.5 to 4 million
Americans affected with AD. A recent meta-analysis
of 21 studies estimated a prevalence among white
Americans of 1.7–1.9 million.
Ethnicity plays a role in prevalence, even when
controlling for potential confounders, such as socio-
economic status and education. In particular, higher
prevalence rates are reported among African Amer-
icans and Hispanics. Prevalence rates among Asian
Americans are equivalent to or slightly lower than
rates among whites. Gender also appears to play a

dementia, a term used vaguely by previous autho-
rities to describe the condition of older persons with
various types of cognitive dysfunction. Later research
determined that the neuropathological changes in the
two disorders were identical, and the distinction
between presenile and senile forms has since been
abandoned. Today, the sole term Alzheimer’s disease
refers to individuals of any age who develop the
disease.
Remarkably, many decades passed before the
importance of Alzheimer’s discovery was fully
recognized. It was not until the late 20th century
that this very common and irreversible disease was
appreciated as posing a major challenge to the older
population and to those charged with caring for the
afflicted. Today, Alzheimer’s disease has become a
household term. At least 4 million Americans are
affected with the disease, and this number is
projected to increase dramatically with the expected
aging of the population in the next few decades.
Alzheimer’s disease and other dementias are now
vigorously studied in neurology clinics and basic
science laboratories, whereas 30 years ago they were
scarcely mentioned in medical school curricula. Were
he alive today, Alzheimer would be astonished at the
attention generated by his three-page report in 1907.
Alzheimer deserves credit for many other con-
tributions to neurology. He devoted his considerable
talents primarily to neuropathology, the most ad-
vanced neuroscientific method of his era, and based
his clinical thinking on abnormalities in the brain he
was able to demonstrate at autopsy. Considered the
founder of the Munich school of neuropathology, he
was one of the most important figures in the
development of this field at the turn of the 20th
century. The growth of neuropathology in turn
stimulated further advances in neurology by provid-
ing a more complete understanding of the origin of
disease manifestations. Along with his colleague
Nissl and others of the time, Alzheimer helped
establish the neuropathological basis of many dis-
orders for the first time. In particular, Alzheimer
favored a biological approach to psychiatry and was
a pioneer in describing neuropathological aspects of
mental disorders. This perspective distinguished him
from many of his contemporaries and showed
Alzheimer to be remarkably modern in his thinking.
Alzheimer will doubtless be most remembered for
his initial description of the disease named after him.
However, his many other achievements in neurology
should not be forgotten. Alzheimer demonstrated the
value of interpreting clinical phenomena in light of
ALZHEIMER’S DISEASE 91
abnormalities in the brain, and his ability to link
basic science data with observations of clinical
neurology and psychiatry served to stimulate much
work in the years following his death. He helped lay
the foundation for the current understanding of brain
disorders that affect behavior, most notably Alzhei-
mer’s disease, and his contributions have had a
significant impact on the neurosciences.
—Christopher Mark Filley
See also–Aging, Overview; Alzheimer’s Disease;
Alzheimer’s Disease, Epidemiology; Dementia
(see Index entry Biography for complete list of
biographical entries)
Further Reading
Alzheimer, A. (1987). About a peculiar disease of the cerebral
cortex (L. Jarvik and H. Greenson, Trans.). Alzheimer’s Dis.
Assoc. Dis. 1, 7–8.
Berrios, G. E., and Freeman, H. (1991). Alzheimer and the
Dementias. Royal Society of Medicine, London.
Haymaker, W. (1953). The Founders of Neurology. Thomas,
Springfield, IL.
Maurer, K., Volk, K., and Gerbaldo, H. (1997). Auguste D. and
Alzheimer’s disease. Lancet 349, 1546–1549.
McHenry, L. C. (1969). Garrison’s History of Neurology. Thomas,
Springfield, IL.
Alzheimer’s Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
EPIDEMIOLOGY AND GENETICS
ALZHEIMER’S DISEASE (AD) is the most common
cause of dementia, accounting for approximately
two-thirds of all cases. Prevalence estimates of AD in
the United States and Europe vary widely from 3.6 to
10.3% of people older than age 65. In the United
States, estimates range from 1.5 to 4 million
Americans affected with AD. A recent meta-analysis
of 21 studies estimated a prevalence among white
Americans of 1.7–1.9 million.
Ethnicity plays a role in prevalence, even when
controlling for potential confounders, such as socio-
economic status and education. In particular, higher
prevalence rates are reported among African Amer-
icans and Hispanics. Prevalence rates among Asian
Americans are equivalent to or slightly lower than
rates among whites. Gender also appears to play a
92 ALZHEIMER’S DISEASE
role in prevalence, with most studies showing an
increased frequency among women, unrelated to
their increased longevity. Above and beyond the
effects of ethnicity or gender, age has the strongest
effect on prevalence. Prevalence approximately
doubles every 5 years beyond age 65, and by age
85 at least one in four and perhaps closer to one in
two people will have AD. Studies of incidence, the
number of new cases of AD per year, are less
numerous but have also shown an approximate
doubling with age, increasing from approximately
1% in people aged 65–70 to 6–8% in people older
than age 85.
The molecular genetics of AD contribute to some
of the prevalence differences across ethnicity, gender,
and age. It has been estimated that genetics account
for 30–50% of the population risk for developing
AD, with uncharacterized environmental risks mak-
ing up the difference. Some studies examining
concordance rates for AD among monozygotic twins
suggest that the genetic component is even higher,
approaching 70%. The bulk of this genetic burden is
believed to be non-Mendelian, resulting from a
combined effect of one or more incompletely
penetrant genes.
However, in approximately 2% of cases AD is
transmitted as an autosomal dominant disease with
nearly complete penetrance. These autosomal domi-
nant cases, usually early onset, are due to mutations
in one of three genes. The b-amyloid precursor
protein (APP) gene on chromosome 21 was the first
to be identified and characterized, and new muta-
tions in the gene continue to be identified. These
mutations all result in excess production of Ab42,
the most neurotoxic of the three common forms of
amyloid. APP gene mutations account for a small
minority of the early onset autosomal dominant
cases. Most of the documented early onset cases are
due to mutations of Presenilin 1 (PS1), although a
few cases have been caused by mutations in a
homologous gene called Presenilin 2 (PS2). These
genes, found on chromosomes 14 and 1, respectively,
code for a pair of proteins with considerable
homology that both seem to favor production of
Ab42.
A fourth gene, apolipoprotein E (apoE), has been
implicated in the more common late-onset, sporadic
form of AD and increases susceptibility to AD. The
association between the apoE4 allele and AD was
detected originally in a familial form of late-onset
AD. Subsequently, this allele was found to be
overrepresented in patients with sporadic, late-onset
AD as well. At least one copy of the E4 allele is found
in 45–60% of patients with AD but only in 20–30%
of the general population. E4 homozygosity is found
in 12–15% of patients with AD but only 2 or 3% of
the general population. The largest study to examine
the effect of the E4 allele was a meta-analysis that
derived odds ratios (ORs) estimating the risk for AD
associated with the various apoE genotypes. Among
whites, the OR was 2.6 for the E2/E4 genotype, 3.2
for the E3/E4 genotype, and 14.9 for the E4/E4
genotype. Although the E4 effect was present in all
ethnic groups included in this meta-analysis, it was
attenuated among African Americans and Hispanics
and amplified in Japanese. The E4 effect was found
to be attenuated in patients older than age 70. Lastly,
an increased effect of E4 was detected in women
compared to men but not across all ethnic types,
suggesting that apoE status accounts for some but
certainly not all of the epidemiological differences
seen with ethnicity, gender, and age.
Currently, the apoE4 allele is regarded as a
susceptibility gene, neither necessary nor sufficient
for the development of AD. Because of its poor
sensitivity and specificity when used as an isolated
diagnostic test, initial guidelines were adopted
recommending that apoE screening not be used in
clinical settings. A recent consortium report con-
firmed the poor sensitivity (65%) and specificity
(68%) of apoE as an isolated diagnostic test, but it
suggested that it may be used judiciously as an
adjunct to the clinical diagnosis, noting that the test
can add to the specificity of diagnosis when used in
conjunction with clinical criteria.
Other potential susceptibility genes have been
proposed, including a2-macroglobulin, interleukins-
1 and -6, cathepsin D, and, most recently, cystatin C.
Each gene has a plausible pathophysiological con-
nection with AD, but the associations have not been
widely reproduced. In some cases, as with a2-
macroglobulin, the association has not held up in
specific ethnic groups. In the future, it will be
determined if these recently reported associations
are as widely reproducible as that of apoE4.
PATHOLOGY
AD has a number of signature pathological findings.
Grossly there can be generalized cortical atrophy, but
this is typically most prominent in the medial
temporal lobe and hippocampus. Microscopically,
affected brain regions demonstrate granulovacuolar
degeneration, Hirano bodies, neurofibrillary tangles
 ALZHEIMER’S DISEASE 93

(NFTs), and amyloid plaques. The true hallmarks of

AD, however, are the NFTs and amyloid plaques.
NFTs are collections of aggregated tau protein and
neurofilaments found in neuronal cell bodies (Figs. 1
and 2). They are seen in the earliest stages of AD
pathology, and the distribution and density of NFTs
appear to be the best correlate of clinical presenta-
tion. Related neurofibrillary/tau protein changes that
occur in AD include neuropil threads and neuritic
plaques. The threads are due to collections of tau in
neuronal dendrites. The neuritic plaques, although
consisting primarily of amyloid protein, also have a
component of dystrophic neurites that contain tau.
Neuropil threads tend to occur early with NFTs,
whereas neuritic plaques are typically found in later
stages of AD. Amyloid plaques (Fig. 1) are extra-
neuronal aggregates of Ab protein. There are two
varieties of plaque—neuritic and diffuse. Diffuse
plaques consist mainly of Ab protein. They are
considered less specific for AD and are commonly
found in elderly patients without dementia. Neuritic
plaques consist of Ab protein aggregates that are Figure 2
mixed with other components, such as tau-contain- Magnified view of a neurofibrillary tangle (Bielschowsky stain).
ing dystrophic neurites. These are much less com- (See color plate section.)
monly found in cognitively intact elderly patients and
hence considered more specific for AD. spread from its typical starting point in the transen-
The Consortium to Establish a Registry for torhinal region (stages I and II) through the limbic
Alzheimer’s Disease (CERAD) criteria use the fre- system (stages III and IV) to more distant locations in
quency of NFTs and amyloid plaques to establish a the neocortex (stages V and VI). A recent consensus
probability scale for AD pathology ranging from report on the postmortem diagnosis of AD used the
normal brain to definite AD. The severity of AD CERAD criteria and Braak and Braak staging in
pathology can also be determined by the location of combination to determine the likelihood that clinical
NFTs in the brain. The Braak and Braak staging dementia in life can be attributed to AD changes at
criteria reflect the degree to which AD pathology has autopsy.

Figure 1
Bielschowsky silver staining reveals a typical Alzheimer’s plaque
(left of center). Several neurofibrillary tangles are also present. (See
color plate section.)
PATHOGENESIS
The leading theory of AD pathogenesis favors
amyloid over tau as the principal causative factor.
Although there are arguments to be made against the
amyloid hypothesis (amyloid deposition does not
correlate closely with dementia severity, and neuro-
pathological changes, including NFTs, can predate
plaque deposition by several years), it remains the
dominant theory. This is due mainly to the fact that
all the known genetic factors that cause AD can be
linked to amyloid. Conversely, AD pathology rarely
occurs with the known tau mutations.
b-Amyloid protein, the main component of amy-
loid plaques, is a fragment of the APP protein. APP
can be cleaved initially by either an a-secretase or a
b-secretase. In either case, the resultant peptide is
94 ALZHEIMER’S DISEASE
then cleaved again by g-secretase. If APP is cleaved
first by b-secretase and then by g-secretase, an Ab
protein is formed. The Ab protein can have either 40
or 42 amino acids (Ab40 or Ab42), depending on the
site of cleavage. Although both forms have a
tendency to aggregate, Ab42, which has two addi-
tional hydrophobic amino acids, does so much more
rapidly. Thus, a relative increase in levels of Ab42
results in more rapid protein aggregation and
formation of the early diffuse plaques. Formation
of the Ab42 nidus is believed to speed aggregation of
Ab40 such that more mature plaques will demon-
strate an Ab42 core surrounded by Ab40. The
aggregation of Ab40 and Ab42 precipitates further
accumulation of a number of other proteins, includ-
ing apoE, which are found in amyloid plaques. The
deposition of plaques is believed to trigger a cascade
of events, involving some combination of oxidative
injury, cytoskeletal damage, and inflammatory re-
sponses, that ultimately ends in neuronal cell death.
The amyloid hypothesis is buttressed by its
capacity to incorporate the various genetic defects
associated with AD. Mutations in the APP gene can
either decrease the rate of a-secretase activity or
increase the rate of b-secretase activity. The pre-
senilin proteins appear to act at the g-secretase level,
with recent evidence suggesting that they may even
constitute the g-secretase molecule. Some mutations
inhibit the subsequent cleavage of C-100 (the b-
secretase product) to Ab40, thus favoring production
of Ab42. Others seem to promote directly the
cleavage of C-100 to Ab42. The apoE4 allele has
been implicated in promoting amyloid deposition
and possibly impairing clearance of amyloid plaques.
Lastly, among the newer candidates for genetic risk
factors in AD, a2-macroglobulin mutations appear to
impair the clearance of Ab plaques.
DIAGNOSIS
A consensus on establishing the clinical diagnosis for
AD was reached in 1984 with the development of the
National Institute of Neurological and Communica-
tive Disorders and Stroke and the Alzheimer’s
Disease and Related Disorders Association
(NINCDS–ADRDA) criteria. To meet the diagnostic
criteria for probable AD, a demented patient must
have deficits in at least two areas of cognitive
function, progressive worsening of memory and
other cognitive functions, and onset between ages
40 and 90. In addition, there should be no distur-
bance of consciousness and no other neurological
explanation for the cognitive decline. These criteria
are weighted toward memory dysfunction, the most
common presenting complaint in AD. The memory
loss affects short-term memory disproportionately so
that immediate memory and remote memory are
often preserved early in the course. Following
memory dysfunction, the typical patient will often
develop additional deficits in a predictable order such
that executive function, semantic processing, and
visuospatial skills subsequently begin to decline.
Occasionally, as is seen with the focal variants of
AD, memory loss is not a prominent early feature.
Initially, isolated, focal impairments may occur in
language, executive function, visuospatial skills, or
praxis. In these cases, AD may mimic other focal
degenerative disorders, such as frontotemporal de-
mentia presenting with primary progressive aphasia
or corticobasal degeneration presenting with aprax-
ia. In addition to the classic neuropsychological
symptoms, AD patients frequently develop psychia-
tric symptoms, particularly as the illness progresses.
In addition to relatively mild behavioral problems,
such as irritability and sleep disturbance, major
depression occurs in up to 20% of patients, and in
later stages up to 40% will have delusions. AD is
slowly progressive but ultimately fatal. The average
time to death following diagnosis is estimated to be
8 years.
The NINCDS–ADRDA criteria have been shown
to have adequate sensitivity (90–95%) but poor
specificity (60–70%). With the prospect of preven-
tive interventions for AD, enhanced understanding of
genetic risks, and growing awareness that many
patients with minimal cognitive impairment progress
to AD, techniques are being investigated that
increase diagnostic specificity in demented and in
at-risk individuals. Enormous effort has been made
to increase specificity by using adjunctive testing,
such as blood tests, cerebrospinal fluid analysis of
Ab42, and neuroimaging. As evidenced by the recent
consensus report of the working group on molecular
and biochemical markers of AD, most such efforts
have not proven entirely successful. The consensus
group did note that apoE genotyping improves
specificity when used in conjunction with clinical
criteria. Cerebrospinal fluid analysis of Ab42 did not
fulfill ‘‘criteria for a useful biomarker.’’ In addition to
biochemical markers, investigators have studied
different neuroimaging techniques for diagnostic aids
but with equally limited results. Positron emission
tomography (PET) and single photon emission
tomography have been used as adjunctive tests in

patients with probable AD with the fairly consistent
finding of decreased perfusion or metabolism in the
temporoparietal regions. Measurements of hippo-
campal and entorhinal cortex atrophy using structur-
al magnetic resonance imaging (MRI) have also been
used to increase diagnostic accuracy. Studies of
functional imaging using PET or MRI are still
relatively few in number, but they suggest a pattern
of increased activation in the earliest clinical and
perhaps even preclinical state progressing to de-
creased activation once patients become more
symptomatic. Currently, neuroimaging can only
distinguish group differences and cannot be used
with any certainty on an individual basis.
TREATMENT
Pharmacological treatments of AD can be classified
as drugs that slow progression of disease, drugs that
treat particular neuropsychiatric symptoms, and
drugs that prevent disease. The most effective
treatment in slowing progression of AD works
through the cholinergic system. The cholinergic
projections from the basal forebrain are known to
be disproportionately affected early in AD and have
been the target of pharmacological intervention for
many years. Tacrine, a nonselective, reversible antic-
holinesterase, was approved for the treatment of AD
in 1993, but is rarely used today, owing to its short
half-life (requiring four daily doses), prominent
peripheral cholinergic side effects (nausea, vomiting,
and diarrhea), and its common elevation of liver
function tests. Donepezil, a selective, reversible
anticholinesterase approved for AD in 1996, has
proven to be much better tolerated. Its longer half-
life allows for once-daily dosing and it has milder
peripheral cholinergic side effects allowing for
approximately 80% of patients to complete the drug
trial versus only 45% in the tacrine trial. In patients
with mild to moderate AD treated for 24 weeks,
donepezil improved cognitive scores on the ADAS by
up to 4% and improved scores on the Clinician’s
Interview-Based Impression of Change Scale by 6%.
A third anticholinesterase, rivastigmine, was recently
approved for use in the United States. Trials using
high doses have shown improvement on the ADAS
cognitive subscale of approximately 5%, but there
was a patient drop out rate of approximately 30–
40% due to peripheral cholinergic side effects. The
two other agents frequently used to slow progression
of disease, a-tocopherol (vitamin E) and selegiline,
are believed to work mainly as antioxidants. A large,
ALZHEIMER’S DISEASE 95
placebo-controlled trial showed that either drug
delayed the time to excessive dependence or death
by approximately 200 days. Improvement was not
detected on any cognitive scales. The major side
effects were syncope and falls, again seen with either
drug but more frequent with the combination of the
two. The combination of the two drugs was not more
effective than either drug alone, and this finding led
to the routine recommendation of vitamin E (1000
IU twice daily) due to its lower cost and lower
toxicity profiles.
Given our limited ability to slow the progression of
AD, the symptomatic treatment of associated neu-
ropsychiatric problems continues to be an important
responsibility for clinicians. The treatment of depres-
sion in AD is best attempted with newer antidepres-
sants with fewer side effects, such as the selective
serotonin reuptake inhibitors and the newer mixed
antidepressants with serotonin and noradrenergic
boosting profiles. The other commonly used class of
antidepressants, tricyclics, may have untoward cog-
nitive effects owing to their anticholinergic proper-
ties. Delusions and severe agitation can be treated
cautiously with antipsychotics, taking care to mini-
mize sedation or extrapyramidal side effects.
Although traditional agents such as haldol may work
more quickly, atypical antipsychotics are probably
better for long-term use. A recent randomized
clinical trial of olanzapine, for example, showed it
to be effective and well tolerated in nursing home-
dwelling AD patients with psychosis or agitation.
Management of sleep disturbances may involve mild
sedatives such as trazodone but should not include
anticholinergic compounds or prolonged use of
benzodiazepines. Lastly, there is evidence that the
anticholinesterases may also improve behavioral
problems in AD, particularly apathy, visual halluci-
nations, and irritability.
Prevention of AD remains a distant goal. Evidence
from both retrospective and prospective trials sug-
gests that estrogen replacement may be effective in
preventing or delaying the onset of AD in post-
menopausal women. The methodological limitations
of these observational studies preclude a definite
recommendation at this time. Given the risks
associated with estrogen replacement, randomized
clinical trials will need to be carried out before a
general consensus is reached. The role of inflamma-
tion in the pathogenesis of AD has prompted interest
in anti-inflammatory agents and nonsteroidal anti-
inflammatory drugs (NSAIDs) in particular. Retro-
spective and cross-sectional studies suggest that
96 ALZHEIMER’S DISEASE, EPIDEMIOLOGY
long-term NSAID use may delay or prevent AD. As
with estrogen replacement, however, the risks asso-
ciated with chronic NSAID use would require proof
of their efficacy in a randomized clinical trial before
they could be formally recommended. Recently,
interest has turned to the prospect of immunizing
patients against amyloid plaques. A mouse study
showed that immunization with Ab42 reduced AD-
like pathology. Although the first trial testing of a
vaccine in AD patients was halted due to adverse
inflammatory reactions, it is hoped that refined
formulations of the vaccine will prove both safe
and efficacious. Another potential preventive therapy
is the use of drugs that inhibit g-secretase, the
protease that leads to production of Ab42. Several
of these g-secretase inhibitors are being developed by
pharmaceutical companies, but none have yet
reached the clinical trial stage.
—Michael D. Greicius, Howard J. Rosen, and
Bruce L. Miller
See also–Aging, Overview; Alzheimer, Alois;
Alzheimer’s Disease, Epidemiology; Anomia;
Cognitive Impairment; Dementia; Memory,
Overview; Women’s Health, Neurology of
Further Reading
Braak, H., and Braak, E. (1991). Neuropathological staging of
Alzheimer-related changes. Acta Neuropathol. 82, 239–259.
Braak, H., and Braak, E. (1998). Diagnostic criteria for
neuropathologic assessment of Alzheimer’s disease. Neurobiol.
Aging 18, S85–S88.
Farrer, L. A., Cupples, L. A., Haines, J. L., et al. (1997). Effects of
age, sex, and ethnicity on the association between apolipopro-
tein E genotype and Alzheimer disease: A meta-analysis. J. Am.
Med. Assoc. 278, 1349–1356.
Hendrie, H. C. (1998). Epidemiology of dementia and Alzheimer’s
disease. Am. J. Geriatric Psychiatry 6, S3–S18.
Mayeux, R., and Sano, M., (1999). Drug therapy: Treatment of
Alzheimer’s disease. N. Engl. J. Med. 341, 1670–1679.
Mayeux, R., Saunders, A. M., Shea, S., et al. (1998). Utility of the
apolipoprotein E genotype in the diagnosis of Alzheimer’s
disease. N. Engl. J. Med. 338, 506–511.
Petersen, R. C., Smith, G., Waring, S. C., et al. (1999). Mild
cognitive impairment. Arch. Neurol. 56, 303–308.
St. George-Hyslop, P. H. (2000). Molecular genetics of Alzheimer’s
disease. Biol. Psychiatry 47, 183–199.
Schenk, D., Barbour, R., Dunn, W., et al. (1999). Immunization
with amyloid-beta attenuates Alzheimer-disease-like pathology
in the PDAPP mouse. Nature 400, 173–177.
Selkoe, D. J. (1997). Alzheimer’s disease: Genotypes, phenotype,
and treatments. Science 275, 630–631.
Selkoe, D. J. (1998). The cell biology of amyloid precursor protein
and presenilin in Alzheimer’s disease. Trends Cell Biol. 8,
447–453.
Street, J., Clark, W., Gannon K. S., et al. (2000). Olanzapine
treatment of psychotic and behavioral symptoms in patients
with Alzheimer disease in nursing care facilities: A double-
blind, randomized, placebo-controlled trial. The HGEU Study
Group. Arch. Gen. Psychiatry 57, 968–976.
Alzheimer’s Disease,
Epidemiology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN 1976, Dr. Robert Katzman called attention to the
extraordinarily high ‘‘prevalence and malignancy’’ of
Alzheimer’s disease, a deadly process in the elderly
that dramatically reduces the quality of life and
survival. During the past five decades, industrial
societies have observed an increase in the number of
elderly and have become increasingly concerned
about the prevalence of Alzheimer’s disease and
related disorders. Alzheimer’s disease increases in
risk with advancing age; therefore, projected esti-
mates of the frequency of Alzheimer’s disease during
the next few years are staggering. Important clues to
the etiology of Alzheimer’s disease have come from
the epidemiological investigation of patients and
their families.
DIAGNOSIS AND DIAGNOSTIC CRITERIA
The standard for the clinical diagnosis of Alzheimer’s
disease is a set of guidelines published in 1984 by a
joint working group the National Institute for
Neurological and Communicative Disorders and
the Alzheimer’s Disease and Related Disorders
Association (NINCDS–ADRDA). These criteria (a
modified version of them is shown in Table 1), were
designed to be consistent with the Diagnostic and
Statistical Manual of Mental Disorders, third edition.
The NINCDS–ADRDA criteria provide diagnoses of
probable, possible, and definite (autopsy confirmed)
Alzheimer’s disease. The American Academy of
Neurology has worked with several organizations
to develop practice parameters for the diagnostic
evaluation of patients with Alzheimer’s disease. The
diagnostic categories of probable and possible
Alzheimer’s disease have been shown to provide a
high sensitivity with moderate specificity using
autopsy confirmation as the gold standard. Labora-
tory studies that include routine blood tests that
screen for common metabolic disorders are helpful in
excluding these diagnoses but not in making the
96 ALZHEIMER’S DISEASE, EPIDEMIOLOGY
long-term NSAID use may delay or prevent AD. As
with estrogen replacement, however, the risks asso-
ciated with chronic NSAID use would require proof
of their efficacy in a randomized clinical trial before
they could be formally recommended. Recently,
interest has turned to the prospect of immunizing
patients against amyloid plaques. A mouse study
showed that immunization with Ab42 reduced AD-
like pathology. Although the first trial testing of a
vaccine in AD patients was halted due to adverse
inflammatory reactions, it is hoped that refined
formulations of the vaccine will prove both safe
and efficacious. Another potential preventive therapy
is the use of drugs that inhibit g-secretase, the
protease that leads to production of Ab42. Several
of these g-secretase inhibitors are being developed by
pharmaceutical companies, but none have yet
reached the clinical trial stage.
—Michael D. Greicius, Howard J. Rosen, and
Bruce L. Miller
See also–Aging, Overview; Alzheimer, Alois;
Alzheimer’s Disease, Epidemiology; Anomia;
Cognitive Impairment; Dementia; Memory,
Overview; Women’s Health, Neurology of
Further Reading
Braak, H., and Braak, E. (1991). Neuropathological staging of
Alzheimer-related changes. Acta Neuropathol. 82, 239–259.
Braak, H., and Braak, E. (1998). Diagnostic criteria for
neuropathologic assessment of Alzheimer’s disease. Neurobiol.
Aging 18, S85–S88.
Farrer, L. A., Cupples, L. A., Haines, J. L., et al. (1997). Effects of
age, sex, and ethnicity on the association between apolipopro-
tein E genotype and Alzheimer disease: A meta-analysis. J. Am.
Med. Assoc. 278, 1349–1356.
Hendrie, H. C. (1998). Epidemiology of dementia and Alzheimer’s
disease. Am. J. Geriatric Psychiatry 6, S3–S18.
Mayeux, R., and Sano, M., (1999). Drug therapy: Treatment of
Alzheimer’s disease. N. Engl. J. Med. 341, 1670–1679.
Mayeux, R., Saunders, A. M., Shea, S., et al. (1998). Utility of the
apolipoprotein E genotype in the diagnosis of Alzheimer’s
disease. N. Engl. J. Med. 338, 506–511.
Petersen, R. C., Smith, G., Waring, S. C., et al. (1999). Mild
cognitive impairment. Arch. Neurol. 56, 303–308.
St. George-Hyslop, P. H. (2000). Molecular genetics of Alzheimer’s
disease. Biol. Psychiatry 47, 183–199.
Schenk, D., Barbour, R., Dunn, W., et al. (1999). Immunization
with amyloid-beta attenuates Alzheimer-disease-like pathology
in the PDAPP mouse. Nature 400, 173–177.
Selkoe, D. J. (1997). Alzheimer’s disease: Genotypes, phenotype,
and treatments. Science 275, 630–631.
Selkoe, D. J. (1998). The cell biology of amyloid precursor protein
and presenilin in Alzheimer’s disease. Trends Cell Biol. 8,
447–453.
Street, J., Clark, W., Gannon K. S., et al. (2000). Olanzapine
treatment of psychotic and behavioral symptoms in patients
with Alzheimer disease in nursing care facilities: A double-
blind, randomized, placebo-controlled trial. The HGEU Study
Group. Arch. Gen. Psychiatry 57, 968–976.
Alzheimer’s Disease,
Epidemiology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN 1976, Dr. Robert Katzman called attention to the
extraordinarily high ‘‘prevalence and malignancy’’ of
Alzheimer’s disease, a deadly process in the elderly
that dramatically reduces the quality of life and
survival. During the past five decades, industrial
societies have observed an increase in the number of
elderly and have become increasingly concerned
about the prevalence of Alzheimer’s disease and
related disorders. Alzheimer’s disease increases in
risk with advancing age; therefore, projected esti-
mates of the frequency of Alzheimer’s disease during
the next few years are staggering. Important clues to
the etiology of Alzheimer’s disease have come from
the epidemiological investigation of patients and
their families.
DIAGNOSIS AND DIAGNOSTIC CRITERIA
The standard for the clinical diagnosis of Alzheimer’s
disease is a set of guidelines published in 1984 by a
joint working group the National Institute for
Neurological and Communicative Disorders and
the Alzheimer’s Disease and Related Disorders
Association (NINCDS–ADRDA). These criteria (a
modified version of them is shown in Table 1), were
designed to be consistent with the Diagnostic and
Statistical Manual of Mental Disorders, third edition.
The NINCDS–ADRDA criteria provide diagnoses of
probable, possible, and definite (autopsy confirmed)
Alzheimer’s disease. The American Academy of
Neurology has worked with several organizations
to develop practice parameters for the diagnostic
evaluation of patients with Alzheimer’s disease. The
diagnostic categories of probable and possible
Alzheimer’s disease have been shown to provide a
high sensitivity with moderate specificity using
autopsy confirmation as the gold standard. Labora-
tory studies that include routine blood tests that
screen for common metabolic disorders are helpful in
excluding these diagnoses but not in making the
 ALZHEIMER’S DISEASE, EPIDEMIOLOGY 97

Table 1 CRITERIA FOR THE DIAGNOSIS OF ALZHEIMER’S DISEASEa

1. The development of multiple cognitive deficits manifested by both:

1.1. memory impairment (impaired ability to learn new information or to recall previously learned information);
1.2. one (or more) of the following cognitive disturbances:
1.2.1. an aphasia (language disturbance)
1.2.2. an apraxia (impaired ability to carry out motor activities despite intact sensory function)
1.2.3. an agnosia (failure to recognize or identify objects despite intact sensory function)
1.2.4. a disturbance in executive functioning (i.e. planning, organizing, sequencing, abstracting).
2. The cognitive deficits in points 1.1 and 1.2 each cause significant impairment in social or occupational functioning and represent a
significant decline from a previous level of functioning.
3. The dementia does not occur exclusively during the course of delirium.
4. Either (4.1) or (4.2):
4.1. There is evidence from the history, physical examination, or laboratory tests of a specific organic factor (or factors) judged to be
etiologically related to the disturbance.
4.2. In the absence of such evidence, an etiological organic factor can be presumed if the disturbance cannot be accounted for by any
nonorganic mental disorder, e.g., major depression accounting for cognitive impairment.
a
Modified from McKhann et al. (1984).

diagnosis. The importance of brain imaging, includ-
ing magnetic resonance imaging, computed tomo-
graphy, and function brain imaging, in the diagnosis
has been increasing. Genetic tests are currently not
recommended for use in the diagnosis.
The clinical criteria used in the diagnosis of
Alzheimer’s disease are not perfect but do provide a
consistently high degree of accuracy that should
improve as biological markers for the disease emerge.
Differentiation of Alzheimer’s disease from normal
aging or depression does not currently constitute a
diagnostic challenge. The premorbid diagnosis of
other forms of dementia, the Lewy body variant of
Alzheimer’s disease, or Alzheimer’s disease with
concurrent stroke remains difficult. Nonetheless,
the NINCDS–ADRDA criteria provide sufficient
sensitivity and specificity for most epidemiological
studies concerning the rates of disease and for
analytical studies of risk factors.
the combination of both urban and rural populations
and the use of brain imaging.
The prevalence of Alzheimer’s disease increases
dramatically at ages 65 and older. Several represen-
tative studies concerning prevalence defined by
NINCDS–ADRDA criteria are shown in Fig. 1. The
prevalence of Alzheimer’s disease increases 15-fold
from 3% among individuals between the ages of 65
and 74 to 47% for individuals age 85 and older.
Compared with prevalence rates from studies from
Europe and Asia as well as from some areas of the
United States, the prevalence of Alzheimer’s disease

MEASURES OF DISEASE FREQUENCY

Prevalence
Before 1985, the literature concerning the prevalence
of Alzheimer’s disease included individuals that were
evaluated or treated in tertiary care medical centers,
chronic care institutions or nursing homes, and
psychiatric hospitals. Significantly higher prevalence
estimates have been found in studies that include
mild cases or those that use a sample of a population
rather than the total population. Other factors
contributing to higher prevalence estimates include
Figure 1
A series of representative studies of the prevalence of Alzheimer’s
disease in the United States, Europe, and north India. The
percentages on the y axis represent proportions, and the age
groups are shown on the x axis. As indicated in the text, there is a
high degree of variability due to the inclusion of patients with mild
disease, sampling variability, and when rural and urban
populations are combined.
98 ALZHEIMER’S DISEASE, EPIDEMIOLOGY
appeared to be much higher in east Boston (Fig. 1).
Prevalence of dementia and Alzheimer’s disease may
be higher among African-American and Hispanic
populations living in the United States but lower for
Africans in their homeland.
Survival with Alzheimer’s disease can vary from 2
to as long as 20 years, but recent population-based
studies suggest that the median survival is 3 or 4
years. Alzheimer’s disease significantly increases the
risk of mortality by twofold, particularly among
men. Individuals with extrapyramidal signs such as
rigidity have a shorter duration of survival and a
more rapid progression of manifestations of Alzhei-
mer’s disease.
Incidence Rates
Several studies have shown that the incidence rate for
Alzheimer’s disease increases with advancing age for
nearly all populations. Two factors contribute
significantly to the difficulty in establishing accurate
estimates of the incidence of Alzheimer’s disease:
determining the age at onset and defining a disease-
free population. Despite this difficulty, accurate
estimates of the incidence rate of Alzheimer’s disease
are now available. In contrast to the prevalence of
Alzheimer’s disease, the incidence rates worldwide
are remarkably more consistent. However, in some
Asian and African populations the incidence rates are
lower than estimates from more developed countries,
and in at least two studies individuals from African-
American and Hispanic ethnic groups appear to have
higher rates of disease relative to white non-
Hispanics. Figure 2 illustrates the dramatic increase
in incidence rates with age. This is particularly true
for the elderly, for whom the incidence rate increases
from approximately 0.5% per year among indivi-
duals ages 65–70 to approximately 6–8% for
individuals older than age 85. Some of the variation
in Fig. 2 may be due to the different methods of case
ascertainment, but the increase in incidence with
advancing age is undeniable. There does not appear
to be a leveling of incidence rates after age 85, as
previously suspected.
Gender and Alzheimer’s Disease
Alzheimer’s disease may be more frequent among
women than men, although studies provide conflict-
ing data. Some researchers have argued that the risk
of Alzheimer’s disease is greater in women than men
based on studies of the incidence rate. In families
with at least one affected individual, women who are
first-degree relatives have a higher lifetime risk of
Figure 2
A series of representative studies of the incidence rates for
Alzheimer’s disease in the United States, Europe, and Africa. The
percentages on the y axis represent proportions as percentage per
year, and the age groups are shown on the x axis.
developing Alzheimer’s disease than men. Hebert
et al. suggested that the excess number of women
with Alzheimer’s disease is due to the longer life
expectancy of women rather than sex-specific risk
factors for the disease. Thus, the apparent increased
risk of Alzheimer’s disease among women, based on
prevalence studies, might simply reflect this differ-
ential mortality.
ANALYTICAL EPIDEMIOLOGY
Genetic Factors That Modify the Risk of
Alzheimer’s Disease
Mutations in three genes—the amyloid precursor
protein gene on chromosome 21, presenilin-1 (PS-1)
on chromosome 14, and PS-2 on chromosome 1—
result in an autosomal dominant form of the disease
beginning as early as the third decade of life (Table
2). The existence of more than 100 mutations in PS-1
also suggests that this may be the most common form
of familial early onset Alzheimer’s disease. Studies of
the clinically relevant mutant genes from some of
these families indicate that many lead to enhanced
generation or aggregation of amyloid b peptide,
which is deposited in the brain in the form of neuritic
plaques that characterize the disease, suggesting a
pathogenic role.
The e4 variant allele of the apolipoprotein-E
(APOE) gene on chromosome 19 has been associated
with both sporadic and familial disease, with onset
usually after age 65 (Table 2). In some families with
late-onset Alzheimer’s disease, each APOE-e4 allele

Table 2 VARIANTS IDENTIFIED IN GENES AND OTHER CHROMOSOMAL LOCATIONS WITH SUGGESTIVE VARIATION IN GENES
ASSOCIATED WITH ALZHEIMER’S DISEASE
Chromosome Gene Age-at-onset
ch21q21.3 APP 30 to 60
ch14q24.13 PS1 30 to 50
ch1q31.42 PS2 50 to 70
ch19q13.2 APOE 50 to 80 þ
ch12p13* ? 4age 65 years
ch10q* ? 4age 65 years
ch9p* ? 4age 65 years
Note: APP refers to the gene encoding the amyloid precursor protein, PS1 and PS2 refers to the presenilin 1 and presenilin 2 genes. APOE refers to the
apolipoprotein E gene. AD in the column labeled pattern refers to the mendelian autosomal dominant pattern of inheritance. ‘‘Familial’’ refers non-Mendelian
inheritance resulting from incomplete penetrance, epistatic effects, or multiple genes. *Chromosomal location identified by linkage.
lowers the age at onset. This may also be true for
some families with mutations in the amyloid
precursor protein gene and in adults with Down’s
syndrome who develop dementia as they age.
The association between the APOE-e4 allele and
Alzheimer’s disease has been established worldwide,
but it is less robust among some ethnic groups.
APOE genotyping for the diagnosis of Alzheimer’s
disease has been suggested because of the strong
association with the APOE-e4 allele. However, in a
large collaborative study involving more than 2000
patients with dementia who had come to autopsy, the
APOE genotype provided a small degree of improve-
ment in the overall specificity for those patients
meeting NINCDS–ADRDA criteria for Alzheimer’s
disease. The APOE genotype used alone was
inadequate in terms of sensitivity or specificity. Thus,
when used in combination with clinical criteria, the
APOE genotype improves the specificity of the
diagnosis by slightly decreasing the rate of false-
positive diagnoses. It would not improve case
detection. Consistent with other genes involved in
Alzheimer’s disease, APOE may also act through a
complex and poorly understood relationship with
amyloid-b (Ab) deposition. ApoE is an obligatory
participant in Ab accumulation and postmortem data
indicate that ApoE isoforms exert at least some of
their effects via controlling Ab accumulation or the
clearance of Ab peptides.
Genetic linkage studies show at least three new
loci with association with Alzheimer’s disease (Table
2). A putative gene on chromosome 12 conferring
susceptibility to Alzheimer’s disease has been difficult
to confirm due to locus heterogeneity related to
APOE-e4 and to clinical heterogeneity as a result of
the identification of Lewy bodies, which are small
ALZHEIMER’S DISEASE, EPIDEMIOLOGY 99
Pattern Variants
AD 10 (exons 16, 17)
AD and familial 100 (exons 4–12) þ
AD 6 (exons 4, 5, 7)
familial 3 isoforms
familial ?
familial ?
familial ?
intracellular inclusions found in the brains of
patients. A locus on chromosome 10 has been
associated with Alzheimer’s disease and with a
putative biomarker of altered Ab in plasma of family
members. Other locations on this chromosome have
also been identified but not confirmed, and a locus on
chromosome 9p with linkage to Alzheimer’s disease
was restricted to a series of families in whom the
diagnosis was confirmed by postmortem examina-
tion.
MEDICAL ILLNESSES ASSOCIATED WITH
ALZHEIMER’S DISEASE
Down’s Syndrome
Adults with Down’s syndrome develop the neuro-
pathological changes of Alzheimer’s disease by age
40, but not all patients become demented. The risk of
Alzheimer’s disease associated with a family history
of Down’s syndrome is increased two- or threefold.
Schupf et al. found the risk of Alzheimer’s disease
among mothers who were 35 years of age or younger
when their children with Down’s syndrome were
born to be substantially higher than the risk in
mothers who had children with other types of mental
retardation. The authors proposed that this associa-
tion might implicate a form of accelerated aging in
the mothers.
Depression
A history of depression has been associated with a
higher risk of Alzheimer’s disease. Whether depres-
sion represents incipient disease or is an early
manifestation remains to be determined, but even
when depression occurred 10 years earlier, the risk
100 ALZHEIMER’S DISEASE, EPIDEMIOLOGY
remained significant in some studies. Devanand et al.
found that even a persistently depressed mood might
increase in parallel with cognitive failure, and that
depressed mood alone was associated with increased
risk of incident dementia in a study of elderly
individuals. However, the presence of a depressed
mood also increased with increasing cognitive
difficulty, suggesting that it was probably an early
manifestation of disease.
Traumatic Head Injury
Several studies suggest an association between head
injury and Alzheimer’s disease, but these observa-
tions have remained inconsistent. The effect may be
to lower the age at onset of Alzheimer’s disease,
suggesting a complex interaction possibly related to
amyloid metabolism.
Cardiovascular Disease and Related
Risk Factors
Cardiovascular disease and dementia are frequent
disorders among the elderly. Several investigators
have proposed that heart disease and its antecedents
may also predispose to dementia, specifically Alzhei-
mer’s disease. However, in many studies, it has been
difficult to determine whether these risk factors are
related to stroke and heart disease that occur as
concomitant illnesses in patients with Alzheimer’s
disease or true etiological risk factors. Recently, the
association between Alzheimer’s disease and hyper-
tension has not been confirmed. Disorder lipid
metabolism, diabetes, and other vascular risk factors
may be strong precursors for dementia associated
with cerebrovascular disease but do not appear to
have independent effects on the risk of Alzheimer’s
Table 3 FACTORS THAT MODIFY THE RISK OF ALZHEIMER’S DISEASE
Risk factor or antecedent Direction
Down syndrome in family Increased
History of depression Increased
Traumatic head injury Increased
Cardiovascular disease Increased
Smoking Increased
Alcohol Decreased
Leisure activity Decreased
Education Decreased
Anti-inflammatory agents Decreased
Antioxidant agents Decreased
Postmenopausal estrogen replacement Decreased
disease. Some authors have proposed that vascular
risk factors may be important 20–30 years before the
onset of Alzheimer’s disease, but this has not been
confirmed. The observation that lipid-lowering
agents (3-hydroxy-3-methyglutaryl coenzyme A re-
ductase inhibitors) or statins are associated with
lower risk of Alzheimer’s disease has renewed
interest in the relationship of vascular disease to this
illness.
BEHAVIORAL RISK FACTORS
Table 3 summarizes the major risk factors thought to
be precipitating or protective features in the devel-
opment of Alzheimer’s disease.
Smoking
Prospective studies of dementia and Alzheimer’s
disease have observed that smokers have a statisti-
cally significant two- to fourfold increase in risk of
Alzheimer’s disease, particularly individuals without
an APOE-e4 allele. In these studies, smoking is
considered to increase the risk of dementia through a
complex interaction with the cerebral vessels. In fact,
an association between smoking and dementia
associated with cerebrovascular disease has also been
established.
Alcohol Use
Alcohol abuse is a possible cause of dementia, mainly
due to associated nutritional deficiencies and acute
direct toxicity. A study in France found that elderly
individuals who drank wine in moderate amounts
daily were less likely to develop Alzheimer’s disease
than heavier drinkers or abstainers.
Presumed mechanism
Shared susceptibility to advanced aging
Neurotransmitter alterations
Ab and APP in brain
Interaction with lipid metabolism
Affects small cerebral vessels
Improves lipid metabolism
Improves lipid metabolism, mental stimulation
Provides cognitive reserve
Reduces local inflammatory response to amyloid deposition in brain
Reduces oxidative stress in neurons
Throphic factor and may interact with Ab-APP metabolism

Mental and Leisure Activity
Time spent engaged in physical and mental activities
during late life has been associated with a lower risk
of Alzheimer’s disease. Risk was lowest for those
individuals with complex activity patterns that
included frequent intellectual, passive, and physical
activities. In the Canadian Study of Health and
Aging, it was found that the strongest effects were
related to physical activities such as vigorous
exercise.
Education
Educational achievement has been associated with
risk of Alzheimer’s disease. A ‘‘cognitive reserve’’
may develop in direct response to the increase in
educational experience. In support of this is the
observation that illiteracy and the lack of formal
education have been associated with Alzheimer’s
disease among Chinese women. Whether these
effects are direct or mediated through genetic or
environmental effects is unknown. For example,
Snowdon et al. found that linguistic ability during
the second decade of life might predict cognitive
impairment and Alzheimer’s disease during later
years.
MEDICATION AND ANTIOXIDANTS
Anti-inflammatory Agents
Use of anti-inflammatory agents was found to be less
frequent among patients with Alzheimer’s disease
than among controls. This is consistent with the
known pathogenesis because inflammation is a
component of amyloid deposition that activates
complement. Because chronic inflammation has been
associated with amyloid deposition, and because
amyloid deposition may actually activate the com-
plement cascade, anti-inflammatory agents could
play an important role in the disease by slowing or
inhibiting the pathogenesis.
Antioxidants
Oxidative stress may contribute to the aging process
and the pathological changes associated with Alzhei-
mer’s disease. Antioxidants can reduce oxidative
stress in vitro and have been proposed as a protective
factor for poor memory and dementia. Both serum
antioxidant levels and a history of supplemental
antioxidant use have been association with memory
performance in the elderly. Decreased serum levels of
ALZHEIMER’S DISEASE, EPIDEMIOLOGY 101
vitamin E—but not vitamins A and C, b-carotene,
and selenium—were associated with poor memory
performance. In a double-blind, placebo-controlled,
multicenter trial, patients with Alzheimer’s disease
were randomized into groups administered 2000 IU
per day a-tocopherol, 10 mg per day selegiline, both,
or placebo. Those receiving both drugs fared better
in terms of survival than those on placebo but
slightly poorer than those on either agent alone,
indicating that the effects of selegiline and
a-tocopherol were not additive. Neither drug was
associated with an improvement in cognitive
function.
Estrogen
The use of estrogen by postmenopausal women has
been associated with a decreased risk of Alzheimer’s
disease. Women who took estrogen had an approxi-
mately 50% reduction in the occurrence of Alzhei-
mer’s disease. The age at onset for Alzheimer’s
disease was significantly later, and the relative risk
was significantly lower for women who took estro-
gen compared to women who did not, even after
adjustment for differences in education, ethnic
group, age, and APOE genotype in these popula-
tion-based studies. A meta-analysis of published
studies of the effects of estrogen on cognitive
function in women with dementia revealed primarily
positive results but concluded that prospective
placebo-controlled, double-blind evaluations were
required to assess the effectiveness of estrogen
replacement in delaying or preventing Alzheimer’s
disease.
CONCLUSION
The frequency of Alzheimer’s disease increases with
advancing age in nearly all populations investigated.
Genetic factors appear to have a major influence on
risk. However, several important medical and beha-
vioral factors can modify the baseline risk of the
disease.
Major gaps in knowledge remain. The basis
of ethnic variability in the frequency of disease
remains unexplained. Clearly, more genes will
be identified that influence the risk of disease, but
it is uncertain whether these different genes act
together or as independent factors. How genes
interact with environmental factors has not been
investigated. Nonetheless, studies currently in pro-
gress should provide important clues to the etiology,
102 ALZHEIMER’S DISEASE, EPIDEMIOLOGY
pathogenesis, and eventual prevention of this
disease.
—Richard Mayeux
See also–Aging, Overview; Alzheimer, Alois;
Alzheimer’s Disease; Cognitive Impairment;
Dementia; Depression; Down’s Syndrome;
Memory, Overview; Neuroepidemiology,
Overview; Women’s Health, Neurology of
Acknowledgments
This work is from The Taub Institute on Alzheimer’s Disease
and the Aging Brain, The Gertrude H. Sergievsky Center,
The Departments of Neurology and Psychiatry in the College
of Physicians and Surgeons, and the Department of Epidemiology
in the School of Public Health. Support was provided by
Federal Grants AG15473, AG08702, AG07232, the Charles S.
Robertson Memorial Gift for Alzheimer’s Disease Research from
the Banbury Fund, and the Blanchette Hooker Rockefeller
Foundation.
Further Reading
Breteler, M. M. (2000). Vascular risk factors for Alzheimer’s
disease: An epidemiologic perspective. Neurobiol. Aging 21,
153–160.
Breteler, M. M., Claus, J. J., van Duijn, C. M., et al. (1992).
Epidemiology of Alzheimer’s disease. Epidemiol. Rev. 14,
59–82.
Devanand, D. P., Sano, M., Tang, M. X., et al. (1996). Depressed
mood and the incidence of Alzheimer’s disease in the
elderly living in the community. Arch. Gen. Psychiatry 53,
175–182.
Devi, G., Ottman, R., Tang, M., et al. (1999). Influence of APOE
genotype on familial aggregation of AD in an urban population.
Neurology 53, 789–794.
Farrer, L. A., Cupples, L. A., Haines, J. L., et al. (1997). Effects of
age, sex, and ethnicity on the association between apolipopro-
tein E genotype and Alzheimer disease. A meta-analysis. APOE
and Alzheimer Disease Meta Analysis Consortium. J. Am. Med.
Assoc. 278, 1349–1356.
Hebert, L. E., Scherr, P. A., McCann, J. J., et al. (2001). Is the risk
of developing Alzheimer’s disease greater for women than for
men? Am. J. Epidemiol. 153, 132–136.
in ‘t Veld, B. A., Ruitenberg, A., Hofman, A., et al. (2001).
Nonsteroidal antiinflammatory drugs and the risk of Alzhei-
mer’s disease. N. Engl. J. Med. 345, 1515–1521.
Jick, H., Zornberg, G. L., Jick, S. S., et al. (2000). Statins and the
risk of dementia. Lancet 356, 1627–1631.
Katzman, R. (1976). Editorial: The prevalence and malignancy
of Alzheimer disease. A major killer. Arch. Neurol. 33,
217–218.
Laurin, D., Verreault, R., Lindsay, J., et al. (2001). Physical
activity and risk of cognitive impairment and dementia in
elderly persons. Arch. Neurol. 58, 498–504.
Mayeux, R., Saunders, A. M., Shea, S., et al. (1998). Utility of the
apolipoprotein E genotype in the diagnosis of Alzheimer’s
disease. Alzheimer’s Disease Centers Consortium on Apolipo-
protein E and Alzheimer’s Disease. N. Engl. J. Med. 338, 506–
511.
McKhann, G., Drachman, D., Folstein, M., et al. (1984). Clinical
diagnosis of Alzheimer’s disease: Report of the NINCDS–
ADRDA work group under the auspices of Department of
Health and Human Services Task Force on Alzheimer’s Disease.
Neurology 34, 939–944.
Merchant, C., Tang, M. X., Albert, S., et al. (1999). The influence
of smoking on the risk of Alzheimer’s disease. Neurology 52,
1408–1412.
Morris, M. C., Scherr, P. A., Hebert, L. E., et al. (2001).
Association of incident Alzheimer disease and blood
pressure measured from 13 years before to 2 years after
diagnosis in a large community study. Arch. Neurol. 58,
1640–1646.
Orgogozo, J. M., Dartigues, J. F., Lafont, S., et al. (1997). Wine
consumption and dementia in the elderly: A prospective
community study in the Bordeaux area. Rev. Neurol. (Paris)
153, 185–192.
Perkins, A. J., Hendrie, H. C., Callahan, C. M., et al.
(1999). Association of antioxidants with memory in a
multiethnic elderly sample using the Third National Health
and Nutrition Examination Survey. Am. J. Epidemiol. 150,
37–44.
Plassman, B. L., Havlik, R. J., Steffens, D. C., et al. (2000).
Documented head injury in early adulthood and risk of
Alzheimer’s disease and other dementias. Neurology 55,
1158–1166.
Report of the Quality Standards Subcommittee of the American
Academy of Neurology (1994). Practice parameter for diagnosis
and evaluation of dementia. Neurology 44, 2203–2206.
Rogers, J., and Shen, Y. (2000). A perspective on inflammation in
Alzheimer’s disease. Ann. N. Y. Acad. Sci. 924, 132–135.
St. George-Hyslop, P. H. (2000). Molecular genetics of Alzheimer’s
disease. Biol. Psychiatry 47, 183–199.
Sano, M., Ernesto, C., Thomas, R. G., et al. (1997). A trial of
selegiline, alpha-tocopherol, or both as treatment for Alzhei-
mer’s disease. The Alzheimer’s Disease Cooperative Study. N.
Engl. J. Med. 336, 1216–1222.
Schupf, N., Kapell, D., Lee, J. H., et al. (1994). Increased risk of
Alzheimer’s disease in mothers of adults with Down’s syn-
drome. Lancet 344, 353–356.
Snowdon, D. A., Kemper, S. J., Mortimer, J. A., et al. (1996).
Linguistic ability in early life and cognitive function and
Alzheimer’s disease in late life. Findings from the Nun Study.
J. Am. Med. Assoc. 275, 528–532.
Stern, Y., Gurland, B., Tatemichi, T. K., et al. (1994). Influence of
education and occupation on the incidence of Alzheimer’s
disease. J. Am. Med. Assoc. 271, 1004–1010.
Stewart, W. F., Kawas, C., Corrada, M., et al. (1997). Risk of
Alzheimer’s disease and duration of NSAID use. Neurology 48,
626–632.
van Duijn, C. M., Clayton, D., Chandra, V., et al. (1991). Familial
aggregation of Alzheimer’s disease and related disorders: A
collaborative re-analysis of case-control studies. EURODEM
Risk Factors Research Group. Int. J. Epidemiol. 20, S13–S20.
Wolfson, C., Wolfson, D. B., Asgharian, M., et al. (2001). A
reevaluation of the duration of survival after the onset of
dementia. N. Engl. J. Med. 344, 1111–1116.
Yaffe, K., Sawaya, G., Lieberburg, I., et al. (1998). Estrogen therapy
in postmenopausal women: Effects on cognitive function and
dementia. J. Am. Med. Assoc. 279, 688–695.

Amaurosis Fugax
see Transient Monocular Blindness
American Trypanosomiasis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THERE are an estimated 10 million people living
mainly in rural areas of Latin America infected by
American trypanosomiasis (AT), a parasitic disease
caused by Trypanosoma cruzi. This protozoan
parasite and the disease were first described at the
beginning of the 20th century by Carlos Chagas; for
this reason, AT is also called Chagas’ disease. AT is
endemic in the Western Hemisphere between 251
north and 381 south latitudes and is independent of
climate, temperature, and altitude.
GENERAL ASPECTS OF AT
Etiopathogenesis
The disease is endemic in rural areas where human
transmission and transmission from domestic ani-
mals to humans is maintained by vectors. Transmis-
sion to man is accomplished by the sting of assassin
or cone-nosed bugs, several species of the hemato-
phagous order Hemiptera, genus Triatominae, family
Reduviidae, adapted to precariously built houses in
which they live in cracks and crevices. They leave
their shelter to feed especially during the night. They
feed by biting and defecate in the area near the
wound. Mucous membranes or skin lesions serve as
an entrance for trypomastigote forms of T. cruzi
present in the bug’s excrement. The parasite invades
cells of adjacent structures, assumes the amastigote
form, reproduces, and fills the cell. Parasitized cells
then rupture. Free T. cruzi then assumes the
trypomastigote form and penetrates local lymphatic
barrier. Bloodstream invasion and hematogenous
dissemination then ensue. Secondary foci of infection
are established in several tissues. Human parasitism
may result from less common events, such as
infection through blood transfusions.
Pathophysiology and Clinical
Manifestations
Studies on laboratory animals, such as mice and rats,
have largely contributed to the knowledge of the
AMERICAN TRYPANOSOMIASIS 103
pathophysiology of the disease. Human infection by
T. cruzi is long-lasting and manifestations vary
according to the stage of the disease. Acute
manifestations are observed 1 or 2 months following
infection. A prolonged period of inapparent infection
(usually more than 10 years) elapses before manifes-
tations of the chronic stage appear. Chronic cardio-
myopathy and disorders of hollow visceral organs
(e.g., magaesophagus and megacolon) are the most
common manifestations in the chronic stage. Para-
sitic pseudocysts develop as the disease progresses to
the chronic stage and help to maintain the infection
in a quiescent state. Changes in the immune state of
the host may cause rupture of the cysts and onset of a
recurrent acute attack of AT.
Diagnosis and Treatment
Diagnosis is established by immunological tests for
detection of anti-T. cruzi antibodies in blood serum
and/or by detection of the parasite in the blood or
other body fluids and also by techniques of molecular
parasitology such as polymerase chain reaction.
Nitrofurans and imidazoles are among the drugs
indicated for treatment during the acute stage of AT.
Results are poor and side effects are common.
Prophylaxis is based on fighting Triatomina in regions
endemic for AT. Wild species are many and forests are
their habitat. T. cruzi transmission is maintained
among wild animals, which are natural reservoirs.
INVOLVEMENT OF THE NERVOUS SYSTEM
IN THE COURSE OF AT
Manifestations of nervous system involvement occur
in the several stages of AT. In 1995, Massaro
confirmed that manifestations are due to involve-
ment of (i) the central and (ii) the peripheral and
autonomic nervous systems and (iii) the embolic
stroke of the chronic cardiopathy of AT.
Central Nervous System
Intracellular nests of the parasite are found through-
out the central nervous system (CNS). An acute
nonsuppurative granulomatous encephalomyelitis
occurs in the acute stage of the disease. Inflammatory
foci of various sizes and wide distribution are found
throughout both white and gray matter. Macro-
phages, astrocytes, microglia, neurons, and endothe-
lial cells may all bear amastigote forms. Neuronal
damage that has occurred during the acute stage
accounts for neuronal loss, which is the main finding
in the chronic stage. CNS involvement is marked by
104 AMERICAN TRYPANOSOMIASIS
two kinds of symptoms—acute meningoencephalitis
and chronic encephalopathy.
Meningoencephalitis is among the rarest manifes-
tations. Signs proceed progressively over 1 or 2 weeks
and usually prove fatal. Usually, it occurs in children.
Diagnosis is based on demonstration of the parasite
or T. cruzi-specific antibodies in the cerebrospinal
fluid (CSF). Cases observed in the neonatal period are
attributed to maternal–fetal transmission of the
parasite. The acquired immunodeficiency syndrome
(AIDS) is the main condition that causes changes in
the immune state of the host that provoke the onset of
a recurrent acute attack of AT. Meningoencephalitis
is the main manifestation of the resulting new acute
attack of AT. Brain granulomata recognized as space
occupying lesions in neuroimaging appear first. They
are soon followed by fatal meningoencephalitis.
Living T. cruzi are detected in the CSF.
Encephalopathy detected in the chronic stage may be
ascribed to the disease. Clinical manifestations are mild
and minor, sometimes detected only by electroence-
phalography or evoked potentials studies. Among the
many presentation forms reported, cognitive impair-
ment was pointed out by Mangone et al. in 1994.
Peripheral and Autonomic Nervous System
Involvement of the peripheral nervous system by T.
cruzi is marked by perivascular infiltrates observed in
the neural sheath and interfascicular spaces as well as
in adjacent connective tissue. Amastigote forms of T.
cruzi are found in perineurium, endoneurium, and
periepithelial cells. Nests of amastigotes are found in
macrophages. Focal damage to the myelin sheath
results in segmental demyelination.
Peripheral neuropathy in the chronic stage is mild
and signs predominate in the lower limbs. Electro-
myographic findings are consistent with axonal
denervation.
Digestive forms, such as megaesophagus and
megacolon, are signs of autonomic involvement.
Other ‘‘mega’’ conditions include bronchiectasis,
megagaster, megaduodenum, megagallbladder, and
megaureter. The cause is thought to be invasion and
destruction of ganglion cells in the wall of a viscus
with secondary dysmotility.
Embolic Stroke
Stroke is a severe complication of the chronic
cardiopathy. Left ventricular mural thrombi are
common in the chronic cardiomyopathy of AT. They
often lie at the apex and cover fibrotic endocardial
lesions. Fragments of thrombi may become detached,
migrate with the bloodstream, and cause embolic
phenomena in distant vessels such as brain arteries.
Embolic cerebrovascular infarcts result. Embolic stroke
in AT is not clinically distinct from other embolic
events. The cardiomyopathy of AT may be a major
cause of cerebrovascular disease in endemic regions.
Diagnosis and Differential Diagnosis
AT has to be considered in the diagnosis of patients
with neurological complaints that come from en-
demic regions, with special attention to stroke in the
chronic cardiopathy and to meningitis in AIDS.
Treatment
The occurrence of nervous system disorders caused by
T. cruzi does not imply specific therapeutic measures
other than those already mentioned. Etiological
treatment by nitrofurans (nifurtimox) or imidazoles
(benzonidazole) is indicated when signs of active
infection by T. cruzi are present, and they include the
acute meningoencephalitic forms. (Recommended
doses were quoted by Rassi and coworkers in 1982.
Nifurtimox is given three times/day for a total oral
daily dose of 8–10 mg/kg of body weight for 2 or 3
months. Benzonidazole is given twice/day for a total
daily dose of 5 mg/kg of body weight for 2 months.)
Reversible side effects include nausea and vomiting
for the first drug, cutaneous erythema for the second,
and peripheral neuropathy for both.
Prevention
Fighting Triatomina by massive use of insecticides
such as hexachlorocyclohexan in the human habitat
has proven useful in avoiding domestic transmission
of the parasite to humans. Blood transfusion in
endemic regions or using blood from donors from
those regions are safe if the blood sample to be
transfused is treated for 24 hr with gentian violet
(0.24 g/1000 ml blood), causing destruction of
parasites present in the sample. This procedure was
first introduced in 1953 by Nussenzweig and cow-
orkers and proved useful in killing the trypomasti-
gote forms of the parasite present in blood.
—Antonio Spina-Franc¸a
See also–Human African Trypanosomiasis
Further Reading
Mangone, C. A., Sica, R. E. P., Pereyra, S., et al. (1994). Cognitive
impairment in human chronic Chagas’ disease. Arq. Neuropsi-
quiatr. 52, 200–203.

Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical
Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663–
667. Churchill Livingstone, New York.
Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸ão
de corantes tri-fenil-metânicos sobre o Trypanosoma cruzi in
vitro: Emprego da violeta de genciana na profilaxia da
transmissão da moléstia de chagas por transfusão de sangue.
O Hospital (Rio de Janeiro) 44, 731–744.
Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al.
(1999). Cerebral tumor-like American trypanosomiasis in
acquired immunodeficiency syndrome. Ann. Neurol. 45,
403–406.
Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸a de
Chagas. In Doenc¸as Infecciosas e Parasitárias (R. Veroesi, Ed.),
7th ed., pp. 674–712. Guanabara Koogan, São Paulo, Brazil.
Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988).
South American trypanosomiasis (Chagas’ disease). In
Handbook of Clinical Neurology (P. J. Vinken, G. W. Bruyn,
and H. Klawans, Eds.), Vol. 52, pp. 45–349. Elsevier,
Amsterdam.
Amino Acid Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MORE THAN 70 inherited disorders of amino acid
metabolism are known, including many that cause
neurological impairment. The diagnosis and manage-
ment of these disorders often requires measurement
of amino acid concentrations in body fluids.
CLINICAL AMINO ACID ANALYSIS
The development of automated amino acid analyzers
has made measurements of amino acid concentra-
Figure 1
A normal plasma amino acid profile. The labeled peaks include the 20 amino acids commonly found in proteins. Instead of free cysteine, the
disulfide cystine is seen. Peaks corresponding to citrulline, a-aminobutyric acid, ornithine, ammonium, and an internal standard are also
noted.
AMINO ACID DISORDERS 105
tions in biological fluids relatively easy. These
analyzers separate amino acids either by ion-ex-
change chromatography or by high-pressure liquid
chromatography. The results are plotted as a graph
(Fig. 1). The concentration of each amino acid can
then be calculated from the size of the corresponding
peak on the graph.
Most amino acid disorders can be diagnosed by
measuring the concentrations of amino acids in
blood plasma; however, some disorders of amino
acid transport are more easily recognized through the
analysis of urine amino acids. Therefore, screening
for amino acid disorders is best done using both
blood and urine specimens. Occasionally, analysis of
cerebrospinal fluid (CSF) amino acids will provide a
diagnostic finding. For example, patients with non-
ketotic hyperglycinemia typically have an elevation
of CSF glycine that exceeds the corresponding
increase in plasma glycine.
DISORDERS OF AMINO ACID CATABOLISM
Most of the known disorders of amino acid
metabolism are disorders of amino acid catabolism.
When an enzyme deficiency interferes with one of
these pathways, a specific amino acid or amino acid
by-product may accumulate to toxic levels. Of
course, a deficiency of downstream products may
also be detrimental. Reflecting important differences
in treatment strategies, the disorders of amino acid
catabolism may be divided into three categories: urea
cycle disorders, defects in the catabolism of specific
essential amino acids, and defects in the catabolism
of specific nonessential amino acids.

Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical
Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663–
667. Churchill Livingstone, New York.
Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸ão
de corantes tri-fenil-metânicos sobre o Trypanosoma cruzi in
vitro: Emprego da violeta de genciana na profilaxia da
transmissão da moléstia de chagas por transfusão de sangue.
O Hospital (Rio de Janeiro) 44, 731–744.
Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al.
(1999). Cerebral tumor-like American trypanosomiasis in
acquired immunodeficiency syndrome. Ann. Neurol. 45,
403–406.
Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸a de
Chagas. In Doenc¸as Infecciosas e Parasitárias (R. Veroesi, Ed.),
7th ed., pp. 674–712. Guanabara Koogan, São Paulo, Brazil.
Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988).
South American trypanosomiasis (Chagas’ disease). In
Handbook of Clinical Neurology (P. J. Vinken, G. W. Bruyn,
and H. Klawans, Eds.), Vol. 52, pp. 45–349. Elsevier,
Amsterdam.
Amino Acid Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MORE THAN 70 inherited disorders of amino acid
metabolism are known, including many that cause
neurological impairment. The diagnosis and manage-
ment of these disorders often requires measurement
of amino acid concentrations in body fluids.
CLINICAL AMINO ACID ANALYSIS
The development of automated amino acid analyzers
has made measurements of amino acid concentra-
Figure 1
A normal plasma amino acid profile. The labeled peaks include the 20 amino acids commonly found in proteins. Instead of free cysteine, the
disulfide cystine is seen. Peaks corresponding to citrulline, a-aminobutyric acid, ornithine, ammonium, and an internal standard are also
noted.
AMINO ACID DISORDERS 105
tions in biological fluids relatively easy. These
analyzers separate amino acids either by ion-ex-
change chromatography or by high-pressure liquid
chromatography. The results are plotted as a graph
(Fig. 1). The concentration of each amino acid can
then be calculated from the size of the corresponding
peak on the graph.
Most amino acid disorders can be diagnosed by
measuring the concentrations of amino acids in
blood plasma; however, some disorders of amino
acid transport are more easily recognized through the
analysis of urine amino acids. Therefore, screening
for amino acid disorders is best done using both
blood and urine specimens. Occasionally, analysis of
cerebrospinal fluid (CSF) amino acids will provide a
diagnostic finding. For example, patients with non-
ketotic hyperglycinemia typically have an elevation
of CSF glycine that exceeds the corresponding
increase in plasma glycine.
DISORDERS OF AMINO ACID CATABOLISM
Most of the known disorders of amino acid
metabolism are disorders of amino acid catabolism.
When an enzyme deficiency interferes with one of
these pathways, a specific amino acid or amino acid
by-product may accumulate to toxic levels. Of
course, a deficiency of downstream products may
also be detrimental. Reflecting important differences
in treatment strategies, the disorders of amino acid
catabolism may be divided into three categories: urea
cycle disorders, defects in the catabolism of specific
essential amino acids, and defects in the catabolism
of specific nonessential amino acids.
106 AMINO ACID DISORDERS

However, human beings and other terrestrial verte-

Figure 2
The urea cycle. 1, N-acetylglutamate synthetase; 2, carbamoyl
phosphate synthetase; 3, ornithine transcarbamoylase; 4,
argininosuccinate synthetase; 5, argininosuccinate lyase; 6,
arginase; 7, mitochondrial ornithine transporter; 8, ornithine
aminotransferase; NAG, N-acetylglutamate, an allosteric activator
of carbamoyl phosphate synthetase; P5C, D1-pyrroline-5-
carboxylate; UMP, uridine monophosphate.
Urea Cycle Disorders
The catabolism of amino acids liberates unneeded
nitrogen in the form of ammonia (NH3). If ammonia
accumulates to higher than normal levels, it becomes
toxic, especially to the brain. In most lower organ-
isms and marine creatures, excess NH3 is eliminated
by diffusion into the surrounding environment.
brates are unable to eliminate sufficient ammonia by
this route. Instead, we have evolved a series of
biochemical reactions, known as the urea cycle, that
serve to convert ammonia to urea, which is then
excreted in urine (Fig. 2). The complete urea cycle is
functional only in the liver.
Eight inherited disorders of the urea cycle are
known (Table 1). Their collective incidence is
approximately 1 in 8000 live births. Except for
ornithine aminotransferase (OAT) deficiency, all
these disorders cause hyperammonemia and may
result in mental retardation. OAT deficiency, also
known as gyrate atrophy of the choroid and retina,
causes visual loss due to retinal degeneration.
Overall, the clinical presentations of the hyper-
ammonemic syndromes are similar. Severe enzyme
defects tend to present in neonates with life-
threatening episodes of hyperammonemia and cere-
bral edema. Typically, an affected child is well at
birth but then develops lethargy, irritability, and/or
vomiting at 1 or 2 days of age. Tachypnea and a
transient respiratory alkalosis are frequent. Sepsis is
usually considered a likely diagnosis. If the hyper-
ammonemia is not detected and appropriate treat-
ment is not begun promptly, the child’s disease is
likely to progress to seizures, coma, and death. Less
severe enzyme defects may present later in infancy
with poor growth, hepatomegaly, developmental
delay, spasticity, and/or other neurological symp-
toms. Older children or adults may present with

Table 1 UREA CYCLE DISORDERSa

Suggestive plasma Urine

Enzyme defect Disorder amino acid findings orotate Other distinguishing features

N-acetylglutamate synthetase NAGS deficiency N/ + citrulline N

(NAGS)
Carbamoyl phosphate synthetase CPS deficiency + citrulline N
(CPS)
Ornithine transcarbamoylase OTC deficiency + citrulline ** X-linked; random X-inactivation
(OTC) affects phenotype in females
Argininosuccinate synthetase Citrullinemia * * citrulline *
Argininosuccinate lyase Argininosuccinic aciduria * citrulline * Hepatomegaly, cirrhosis, brittle
* argininosuccinate hair
Arginase Argininemia * arginine * Commonly presents with spastic
diplegia
Mitochondrial ornithine HHH syndrome * ornithine * Homocitrullinuria
transporter
Ornithine aminotransferase (OAT) OAT deficiency * ornithine N Normal ammonia levels; gyrate
atrophy of choroid and retina
a
Abbreviations used: N, normal; * , increased; + , decreased; HHH, hyperammonemia, hyperornithinemia, homocitrullinuria.

acute episodes of metabolic encephalopathy brought
on by a physical stress or they may present with
chronic symptoms, such as learning disorders, mental
retardation, or seizures. Some have presented with
stroke-like episodes. A dietary history may reveal an
aversion to high-protein foods. Magnetic resonance
imaging of the brain is often abnormal in both acute
and chronic presentations.
The pathophysiology of urea cycle defects is
incompletely understood. As with most metabolic
defects, substrates upstream of the enzymatic block
accumulate, and downstream products may become
depleted. Glutamine and alanine levels generally
increase together with the ammonia level. Evidence
suggests that at least some of the cerebral edema is
due to the osmotic force of accumulated intracellular
glutamine.
When a urea cycle defect is present, the plasma
amino acid pattern and urine orotic acid level often
suggest the specific diagnosis (Table 1). Low citrul-
line levels characterize N-acetylglutamate synthetase
deficiency, carbamoyl phosphate synthetase defi-
ciency, and ornithine transcarbamoylase (OTC)
deficiency. Among these, the urine orotic acid level
is elevated only in OTC deficiency. Citrullinemia,
argininosuccinic aciduria, argininemia, and the
HHH syndrome can be distinguished by specific
amino acid patterns. Enzyme assays or gene sequen-
cing may be useful to confirm a suspected diagnosis
or to provide a prenatal diagnosis in an at-risk
pregnancy. A small fraction of patients with hyper-
ammonemia and elevated plasma citrulline levels will
have citrullinemia type II, a secondary disturbance of
the urea cycle that is caused by mutations in the gene
for citrin, a mitochondrial aspartate/glutamate trans-
porter.
The acute treatment of hyperammonemic crises
may require hemodialysis. The long-term treatment
of urea cycle defects generally requires a protein-
restricted diet, often including replacement of natural
protein with preparations of essential amino acids.
Treatment with extra arginine and citrulline to
replace depleted urea cycle intermediates is bene-
ficial. Administration of benzoate, phenylacetate, or
phenylbutyrate increases the excretion of nitrogen by
alternative routes. Treatment of seizures with val-
proic acid should be avoided because this drug may
worsen hyperammonemia. Despite careful dietary
and pharmacological treatment, the long-term prog-
nosis for cognitive function in patients with severe
urea cycle defects is poor. Liver transplantation is an
option that is being used more frequently.
AMINO ACID DISORDERS 107
Defects in the Catabolism of Essential
Amino Acids
Table 2 lists selected disorders of the catabolism of
specific essential amino acids. Because these parti-
cular amino acids are not synthesized by human
beings, many of these disorders may be effectively
treated by reducing the dietary intake of the relevant
amino acid(s). However, early treatment may be
essential to prevent irreversible consequences, such
as brain damage. Some patients may also benefit
from treatment with specific enzyme cofactors. For
example, thiamine, a cofactor required for the
function of the branched-chain ketoacid dehydro-
genase, helps some patients with maple syrup urine
disease. Biotin can be used to treat multiple
carboxylase deficiency due to either biotinidase
deficiency or a partial loss of holocarboxylase
synthetase activity.
Defects in the Catabolism of Nonessential
Amino Acids
Table 3 lists selected disorders of the catabolism of
nonessential amino acids. Because these amino acids
are synthesized within the human body, restricting
the dietary intake of the offending amino acid is
usually not sufficient to prevent disease progression.
Thus, these disorders tend to be more difficult to
treat than those involving essential amino acids.
Disorders of tyrosine catabolism may be amelio-
rated to some extent by restricting the dietary intake
of both tyrosine and its precursor phenylalanine.
Recently, the medical treatment of tyrosinemia type I
has been revolutionized by the use of 2-(2-nitro-4-
trifluoromethylbenzoyl)-1,3-cyclohexane dione, also
known as NTBC or nitisinone. This compound
prevents the accumulation of the toxic tyrosine
metabolites fumarylacetoacetate, maleylacetoace-
tate, and succinylacetone by blocking the catabolism
of tyrosine at an earlier step. NTBC is also being
tried as a treatment for alkaptonuria. In the future,
other metabolic disorders may be treated using the
same general strategy of inhibiting an earlier step in
the affected pathway.
DISORDERS OF AMINO ACID SYNTHESIS
Serine Deficiency
Very few disorders of amino acid biosynthesis are
known. One such disorder, which is of significant
neurological interest, is serine deficiency due to
reduced activity of 3-phosphoglycerate dehydrogen-
108 AMINO ACID DISORDERS

Table 2 SELECTED DISORDERS OF THE CATABOLISM OF ESSENTIAL AMINO ACIDSa

Amino acid Disorder Enzyme defect Selected clinical features

Phenylalanine Phenylketonuria (PKU) Phenylalanine hydroxylase MR, hypopigmentation, eczema, seizures,

‘‘mousy’’ odor
Tetrahydrobiopterin (BH4) GTP cyclohydrolase, 6- MR, microcephaly, infantile Parkinsonism,
deficienciesb,d pyruvoyltetrahydropterin seizures, hyperphenylalaninemia,
synthase, tetrahydropterin deficiencies of serotonin and dopamine;
carinolamine dehydratase, treated with BH4, precursors of serotonin
dihydropteridine reductase and dopamine, low phenylalanine diet
Leucine, isoleucine, Maple syrup urine disease Branched-chain ketoacid MR, PI, ketoacidosis, cerebral edema, ‘‘maple
and valine dehydrogenase syrup’’ odor (urine, sweat, and cerumen)
Multiple carboxylase deficiencyc Holocarboxylase synthetase, MR, ketoacidosis, lethargy, hypotonia,
biotinidase seizures, other neurological abnormalities,
skin rash, alopecia
Isoleucine and valine Propionic aciduriac Propionyl-CoA carboxylase MR, PI, ketoacidosis, hyperammonemia,
hypoglycemia, neutropenia
Methylmalonic aciduriac Methylmalonyl-CoA mutase, MR, PI, ketoacidosis, hyperammonemia,
Cbl reductase, Cbl hypoglycemia, neutropenia
adenosyltransferase
Leucine Isovaleric aciduriac Isovaleryl-CoA dehydrogenase MR, PI, ketoacidosis, hyperammonemia,
neutropenia, ‘‘sweaty feet’’ odor
3-Methylcrotonyl glycinuriac 3-Methylcrotonyl-CoA MR, PI, ketoacidosis, hyperammonemia,
carboxylase ‘‘cat’s urine’’ odor
3-Methylglutaconic aciduria type 3-Methylglutaconyl-CoA Reported in eight patients; mild to severe
Ic hydratase neurological impairments
3-Hydroxy-3-methylglutaric 3-Hydroxy-3-methylglutaryl- MR, latic acidosis, hypoglycemia,
aciduriac CoA lyase hyperammonemia
Isoleucine 2-Methylacetoacetic aciduriac Mitochondrial acetoacetyl- MR, ketoacidosis, hyper- or hypoglycemia
CoA thiolase
Histidine Histidinemia Histidase Probably a benign abnormalitye
d
Urocanic aciduria Urocanase MR reported (probably coincidental)
Lysine Glutaric aciduria type Ic Glutaryl-CoA dehydrogenase Macrocephaly, progressive dystonia and
dyskinesia, acute episodes of ketoacidosis
7hyperammonemia
a
Abbreviations used: MR, mental retardation; PI, protein intolerance; CoA, coenzyme A; Cbl, cobalamin.
b
Tetrahydrobiopterin is a cofactor required by the phenylalanine, tyrosine, and tryptophan hydroxylases.
c
Diagnosis requires analysis of urine organic acids.
d
Diagnosis requires specialized assay.
e
Initial reports of neurological impairment appear to have been coincidental; many asymptomatic patients are known.

ase. These patients have congenital microcephaly D1-Pyrroline-5-Carboxylate

and develop spastic quadriplegia, psychomotor
retardation, and intractable seizures. The pathogen-
esis of these symptoms most likely involves not
only a deficiency of serine in the brain but also
deficiencies of various serine derivatives, such as
glycine, serine phospholipids, sphingomyelins, or
cerebrosides. In the proper clinical setting, this
diagnosis is suggested by low levels of serine and
glycine in the CSF and fasting plasma. Oral treat-
ment with supplemental serine usually stops the
seizures and ameliorates some of the other features of
the disorder.
Synthase Deficiency
D1-Pyrroline-5-carboxylate (P5C) synthase catalyzes
the reduction of glutamate to P5C, a critical step in
the biosynthesis of proline, ornithine, citrulline, and
arginine. Baumgartner et al. reported homozygous
mutations in P5C synthase in two siblings who suffer
from progressive neurodegeneration, joint laxity,
skin hyperelasticity, and bilateral subcapsular catar-
acts. Metabolic studies have shown these patients to
have paradoxical preprandial episodes of hyperam-
monemia and low plasma levels of proline, ornithine,
 AMINO ACID DISORDERS 109

Table 3 SELECTED DISORDERS OF THE CATABOLISM OF NONESSENTIAL AMINO ACIDSa

Amino acid Disorder Enzyme defect Selected clinical features

Tyrosine Tyrosinemia type I Fumarylacetoacetate hydrolase Liver failure, renal dysfunction, rickets, episodic
polyneuropathy, liver cancer
Tyrosinemia type II Tyrosine transaminase MR, palmar keratosis, corneal ulcers
Tyrosinemia type III 4-Hydroxyphenylpyruvate MR possible; some patients asymptomatic
dioxygenase (1st component)
Hawkinsinuria 4-Hydroxyphenylpyruvate Asymptomatic in adults; metabolic acidosis,
dioxygenase (2nd component) FTT, or liver dysfunction in some infants
Alcaptonuriab Homogentisic acid oxidase Osteoarthritis, ochronosis
Glycine Nonketotic Glycine cleavage system MR, hypotonia, seizures, lethargy, coma; often
hyperglycinemia fatal in early infancy
Proline Hyperprolinemia type I Proline oxidase Asymptomatic, incidental finding
Hyperprolinemia type IIc Pyrroline-5-carboxylate Relatively benign disorder; some patients have
dehydrogenase seizures
Iminopeptiduria Prolidase MR, dermatitis, skin ulcers, recurrent infections,
risk of lupus suggested
Cysteine Sulfite oxidase deficiencyc Molybdenum cofactor, sulfite Seizures, MR, dislocated optic lenses, death in
oxidase childhood frequent
N-acetyl- Canavan diseaseb Aspartoacylase Macrocephaly, leukodystrophy, hypotonia, early
aspartate death
a
Abbreviations used: MR, mental retardation.
b
Diagnosis requires analysis of urine organic acids.
c
Diagnosis requires specialized assay.

citrulline, and arginine. The hyperammonemia ap-
parently results from the decreased availability of
ornithine, a urea cycle intermediate that is synthe-
sized from P5C (Fig. 2). The connective tissue
abnormalities might reasonably be attributed to the
deficiency of proline, which is a major constituent of
collagens. Confirmation and further delineation of
this fascinating syndrome await the identification of
additional patients.
Homocystinuria
The biochemical pathway that humans use to
synthesize cysteine (Fig. 3) serves simultaneously as
the catabolic pathway for methionine and as a source
of the important methyl donor S-adenosylmethio-
nine. Homocysteine, an intermediate in this pathway,
accumulates in each of the several forms of homo-
cystinuria. The most common form, homocystinuria
type I (inherited as an autosomal recessive trait), is
due to deficiency of cystathionine-b-synthase. Clin-
ical features may include subluxations of the lenses
of the eyes, mental retardation, psychiatric disorders,
a tall and thin body habitus with long fingers and
other skeletal abnormalities reminiscent of Marfan
syndrome, a fair complexion, and a predisposition to
thromboembolic events, especially in the brain.
Laboratory abnormalities include the presence of
homocystine in the urine and elevations of plasma
methionine and homocysteine. Cystathionine-b-
synthase uses pyridoxal 50 -phosphate (a derivative
of pyridoxine) as a cofactor, and approximately 40%
of patients with homocystinuria type I respond to
treatment with high doses of pyridoxine (vitamin B6).
Treatment should also include folate, cysteine, a low
methionine diet, and, in some cases, betaine.
Homocystinuria type II may be caused by any of
several recessive defects in vitamin B12 metabolism
that interfere with production of methylcobalamin, a
cofactor required by methionine synthase. Cell
complementation studies have revealed the existence
of at least five such defects, designated cblC–cblG. In
addition to homocystinuria, these patients have
megaloblastic anemia, poor growth, developmental
delay, seizures, and other neurological abnormalities.
Their plasma homocysteine levels are elevated;
however, in contrast to homocystinuria type I, their
methionine levels are decreased. Patients with cblC,
cblD, and cblF also suffer from methylmalonic
aciduria due to defective formation of adenosylco-
balamin (a cofactor for methylmalonyl-CoA mu-
tase). Treatment should include both vitamin B12 and
betaine.
110 AMINO ACID DISORDERS
Figure 3
Homocystinuria: abnormalities of methionine, homocysteine, and cysteine metabolism. 1, Cystathionine-b-synthase; 2, methionine synthase;
3, methylene tetrahydrofolate reductase; Vit B12, vitamin B12; MeCbl, methylcobalamin; AdoCbl, adenosylcobalamin; THF,
tetrahydrofolate. The letters A-G indicate the metabolic blocks observed in complementation groups cblA–cblG, respectively. Note that cblG
defects result from mutations in methionine synthase.
Homocystinuria type III, inherited as an autoso-
mal recessive trait, is caused by deficiency of
methylene tetrahydrofolate reductase. Patients with
a complete absence of enzyme activity present with
neonatal apneic episodes and myoclonic seizures,
progressing to coma and death. Incomplete enzyme
deficiencies can produce a range of phenotypes,
including mental retardation, seizures, microcephaly,
spasticity, psychiatric symptoms, peripheral neuro-
pathy, and/or premature vascular disease. Megalo-
blastic anemia does not occur. Laboratory findings
typically show moderate elevations of plasma homo-
cysteine and low or low-normal levels of methionine.
Treatment is difficult, and various combinations of
agents have been recommended. Regimens that
include betaine appear to be the most successful.
DISORDERS OF AMINO ACID TRANSPORT
A variety of specific transport mechanisms catalyze
the movement of amino acids across biological
membranes. Some such transporters operate on
groups of structurally related amino acids, whereas
others serve only one specific amino acid. Table 4
lists most of the known disorders of amino acid
transport. These transport mechanisms may be
specific to certain cell types and may even be
localized to specific portions of the plasma mem-
brane. For example, lysinuric protein intolerance is
caused by deficiency of a dibasic amino acid
transporter that in renal and intestinal epithelial
cells is localized to the basolateral membrane. When
this transporter is defective, intestinal absorption and
renal tubular reabsorption of lysine, arginine, and
ornithine are impaired. Therefore, urinary excretion
of these amino acids is high, and their plasma levels
are low. Patients with this disorder suffer from
protein intolerance and episodes of hyperammone-
mia that result from having insufficient arginine and
ornithine for proper functioning of the urea cycle.
Other clinical features may include poor growth,
osteoporosis, immune deficiencies, alveolar protei-
nosis, pulmonary fibrosis, or mental retardation. The
occurrence of mental retardation is most likely
related to the severity of the episodes of hyperam-
monemia. Treatment involves a moderate dietary
protein restriction and replacement of urea cycle
intermediates through oral citrulline administration.
Amino acid transport mechanisms may also be
specific to certain subcellular organelles. For exam-
ple, cystinosis is a lysosomal storage disease caused
by mutations in a lysosomal membrane protein.
These mutations result in decreased efflux of cystine
from lysosomes. The major clinical manifestation of
cystinosis is renal failure. The diagnosis of cystinosis
can be made by demonstrating an increased cystine
content in lymphocytes. Treatment with cysteamine
helps remove cystine from lysosomes through the
formation of mixed disulfides and slows progression
of the disease, but kidney transplantation is often
necessary. Later, extrarenal manifestations may
occur, including ocular problems, hypothyroidism,
diabetes, myopathy, or encephalopathy.
Hartnup’s disorder is inherited as an autosomal
recessive trait with a prevalence of approximately 1
in 30,000 people. These patients have decreased
 AMINO ACID DISORDERS 111

Table 4 SELECTED DISORDERS OF AMINO ACID TRANSPORTa

Disorder Amino acid(s) Transporter Major sites involved Clinical features

Cystinosis Cystine Cystine transporter Lysosomal Renal failure; late endocrine, ocular,
membranes and neuromuscular manifestations
Cystinuria Cystine, arginine, Shared cystine and Renal tubules, Cystine renal stones
lysine, ornithine dibasic amino acid intestinal mucosa
transporter
Lysinuric protein intolerance Arginine, lysine, Dibasic amino acid Renal tubules, PI, hyperammonemia, MR, poor
ornithine transporter intestinal mucosa growth, osteoporosis,
hepatosplenomegaly
Dicarboxylic aminoaciduria Aspartate, Dicarboxylic amino Renal tubules, Asymptomatic
glutamate acid transporter intestinal mucosa
Hartnup disorder Most neutral Neutral amino acid Renal tubules, Most asymptomatic, intermittent
amino acids transporter intestinal mucosa ataxia and rash possible
Histidinuria Histidine Histidine transporter Renal tubules, Possible MR, possible seizures
intestinal mucosa
Iminoglycinuria Glycine, Shared glycine and Renal tubules, Asymptomatic
hydroxyproline, amino acid intestinal mucosa
proline transporter
Methionine malabsorption Methionine Methionine Intestinal mucosa MR, seizures, hyperpnea, white hair,
transporter a-hydroxy butyricaciduria
a
Abbreviations used: PI, protein intolerance; MR, mental retardation.

intestinal absorption and decreased renal tubular
reabsorption of many neutral amino acids, including
tryptophan. Symptoms of episodic ataxia and a
‘‘pellagra-like’’ rash are seen in some patients.
Mental retardation has been reported in a few.
However, population screening suggests that the vast
majority of patients with Hartnup’s disorder remain
asymptomatic. Human cells require nicotinamide,
which may be synthesized from either tryptophan or
niacin. Niacin deficiency produces pellagra. Treat-
ment with niacin has been reported to improve the
symptoms of Hartnup’s disorder in some patients,
and it is likely that sufficient dietary niacin intake is
one of the factors that accounts for the lack of
symptoms in most Hartnup patients.
DISORDERS OF AMINO ACID DERIVATIVES
Neurotransmitter Disorders
Many neurotransmitters, including serotonin, g-
aminobutyric acid, dopamine, epinephrine, and
norepinephrine, are derived from amino acids.
Defects in the metabolism of these compounds are
discussed elsewhere in this encyclopedia.
Creatine-Deficiency Syndromes
Recently, three interesting disorders of the metabo-
lism of creatine have been described. The incidence
and the clinical variability of these disorders have not
yet been determined. However, each of these defects
has been associated with severe neurological symp-
toms in at least a few patients. Two of the three
disorders appear to be treatable with oral creatine.
Creatine is formed from glycine, arginine, and S-
adenosylmethionine (Fig. 4). Creatine synthesis oc-
curs primarily in the liver, pancreas, and kidneys.
Other organs, especially the brain and muscles, take
up creatine from the blood. Inside cells, creatine is
phosphorylated and serves as a reservoir of high-
energy phosphate groups, allowing more rapid
regeneration of adenosine triphosphate and thus
supporting many energy-requiring reactions.
A deficiency of either arginine:glycine amidino-
transferase or guanidinoacetate methyltransferase
impairs the production of creatine. Patients with
these autosomal recessive disorders have shown
variable neurological symptoms, including mental
retardation, seizures, hypotonia, and/or dystonia.
Cerebral magnetic resonance spectroscopy (MRS) in
affected individuals shows absence of the usual peaks
corresponding to creatine and phosphocreatine.
Treatment with oral creatine gradually restores brain
creatine concentrations to nearly normal levels and
results in some clinical improvement. Similar symp-
toms and MRS findings have also been described in
patients with mutations in the X-linked gene encod-
ing the transporter that allows creatine to enter brain
112 AMINO ACIDS
Figure 4
Creatine and creatinine metabolism. 1, Arginine:glycine
amidinotransferase; 2, guanidinoacetate methyltransferase; 3,
creatine phosphokinase; S-AdoMet, S-adenosylmethionine; S-
AdoHcy, S-adenosylhomocysteine.
and muscle cells. As might be predicted, patients
with such transporter defects have not responded to
treatment with oral creatine.
—Edward G. Neilan and Vivian E. Shih
See also–Amino Acids
Further Reading
Baumgartner, M. R., Hu, C. A., Almashanu, S., et al. (2000).
Hyperammonemia with reduced ornithine, citrulline, arginine
and proline: A new inborn error caused by a mutation in the
gene encoding D1-pyrroline-5-carboxylate synthase. Hum. Mol.
Genet. 9, 2853–2858.
Fernandes, J., Saudubray, J.-M., van den Berghe, G. (Eds.) (2000).
Inborn Metabolic Diseases: Diagnosis and Treatment, pp. 171–
291, 439–444. Springer, Berlin.
Item, C. B., Stockler-Ipsiroglu, S., Stromberger, C., et al. (2001).
Arginine:glycine amidinotransferase deficiency: The third in-
born error of creatine metabolism in humans. Am. J. Hum.
Genet. 69, 1127–1133.
Palmieri, L., Pardo, B., Lasorsa, F. M., et al. (2001). Citrin and
aralar1 are Ca2 þ -stimulated aspartate glutamate transporters
in mitochondria. EMBO J. 20, 5060–5069.
Salomons, G. S., van Dooren, S. J., Verhoeven, N. M., et al.
(2001). X-linked creatine-transporter gene (SLC6A8) defect: A
new creatine-deficiency syndrome. Am. J. Hum. Genet. 68,
1497–1500.
Scriver, C. R., Sly, W., Childs, B., et al. (Eds.) (2001). The
Metabolic and Molecular Bases of Inherited Disease, 8th ed.,
pp. 1667–2163, 4909–4981, 5085–5108. McGraw-Hill,
New York.
Stöckler, S., Isbrandt, D., Hanefeld, F., et al. (1996). Guanidinoa-
cetate methyltransferase deficiency: The first inborn error of
creatine metabolism in man. Am. J. Hum. Genet. 58, 914–922.
Amino Acids
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALTHOUGH it has been proposed that the first living
things on Earth may have been self-replicating
polymers of ribonucleic acids, amino acids are now
equally indispensable to all known forms of life. The
genetic code carried in nucleic acids is translated into
proteins composed of linear polymers of amino
acids. It is largely these proteins that carry out the
work of the living cell. Thus, amino acids play a
critical role in nature as the building blocks of
proteins. In addition, amino acids serve living things
as sources of metabolic energy, as neurotransmitters,
and as required substrates for the biosyntheses of a
variety of other important molecules.
STRUCTURE OF AMINO ACIDS
The term amino acid usually refers to an a-
aminocarboxylic acid in which the a carbon atom
adjacent to a carboxylic acid moiety (-COOH)
carries three other substituents: an amino group
(-NH2), a hydrogen atom (-H), and a variable side
chain conventionally symbolized as ‘‘-R’’ (Fig. 1).
These four substituents are arranged around the a
carbon in a tetrahedral fashion. Two nonoverlapping
arrangements are possible. By convention, these
optically active, mirror-image stereoisomers are
designated the l and d forms. Except in the case of
glycine, in which R is a second hydrogen atom, the
four substituents are different, making the a carbon
atom a center of chirality.
Only the l-isomers of amino acids are commonly
found in proteins. The biosynthetic pathways that
Figure 1
The structure of amino acids. Most are optically active and exist as
mirror-image l- or d-isomers.
112 AMINO ACIDS
Figure 4
Creatine and creatinine metabolism. 1, Arginine:glycine
amidinotransferase; 2, guanidinoacetate methyltransferase; 3,
creatine phosphokinase; S-AdoMet, S-adenosylmethionine; S-
AdoHcy, S-adenosylhomocysteine.
and muscle cells. As might be predicted, patients
with such transporter defects have not responded to
treatment with oral creatine.
—Edward G. Neilan and Vivian E. Shih
See also–Amino Acids
Further Reading
Baumgartner, M. R., Hu, C. A., Almashanu, S., et al. (2000).
Hyperammonemia with reduced ornithine, citrulline, arginine
and proline: A new inborn error caused by a mutation in the
gene encoding D1-pyrroline-5-carboxylate synthase. Hum. Mol.
Genet. 9, 2853–2858.
Fernandes, J., Saudubray, J.-M., van den Berghe, G. (Eds.) (2000).
Inborn Metabolic Diseases: Diagnosis and Treatment, pp. 171–
291, 439–444. Springer, Berlin.
Item, C. B., Stockler-Ipsiroglu, S., Stromberger, C., et al. (2001).
Arginine:glycine amidinotransferase deficiency: The third in-
born error of creatine metabolism in humans. Am. J. Hum.
Genet. 69, 1127–1133.
Palmieri, L., Pardo, B., Lasorsa, F. M., et al. (2001). Citrin and
aralar1 are Ca2 þ -stimulated aspartate glutamate transporters
in mitochondria. EMBO J. 20, 5060–5069.
Salomons, G. S., van Dooren, S. J., Verhoeven, N. M., et al.
(2001). X-linked creatine-transporter gene (SLC6A8) defect: A
new creatine-deficiency syndrome. Am. J. Hum. Genet. 68,
1497–1500.
Scriver, C. R., Sly, W., Childs, B., et al. (Eds.) (2001). The
Metabolic and Molecular Bases of Inherited Disease, 8th ed.,
pp. 1667–2163, 4909–4981, 5085–5108. McGraw-Hill,
New York.
Stöckler, S., Isbrandt, D., Hanefeld, F., et al. (1996). Guanidinoa-
cetate methyltransferase deficiency: The first inborn error of
creatine metabolism in man. Am. J. Hum. Genet. 58, 914–922.
Amino Acids
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALTHOUGH it has been proposed that the first living
things on Earth may have been self-replicating
polymers of ribonucleic acids, amino acids are now
equally indispensable to all known forms of life. The
genetic code carried in nucleic acids is translated into
proteins composed of linear polymers of amino
acids. It is largely these proteins that carry out the
work of the living cell. Thus, amino acids play a
critical role in nature as the building blocks of
proteins. In addition, amino acids serve living things
as sources of metabolic energy, as neurotransmitters,
and as required substrates for the biosyntheses of a
variety of other important molecules.
STRUCTURE OF AMINO ACIDS
The term amino acid usually refers to an a-
aminocarboxylic acid in which the a carbon atom
adjacent to a carboxylic acid moiety (-COOH)
carries three other substituents: an amino group
(-NH2), a hydrogen atom (-H), and a variable side
chain conventionally symbolized as ‘‘-R’’ (Fig. 1).
These four substituents are arranged around the a
carbon in a tetrahedral fashion. Two nonoverlapping
arrangements are possible. By convention, these
optically active, mirror-image stereoisomers are
designated the l and d forms. Except in the case of
glycine, in which R is a second hydrogen atom, the
four substituents are different, making the a carbon
atom a center of chirality.
Only the l-isomers of amino acids are commonly
found in proteins. The biosynthetic pathways that
Figure 1
The structure of amino acids. Most are optically active and exist as
mirror-image l- or d-isomers.

Figure 2
Amino acids in solution are dipolar ions.
produce amino acids are stereospecific, and most
generate only l-isomers. Therefore, l-isomers are
present at much higher concentrations in human
tissues and bodily fluids. d-Amino acids, although
less common than l-amino acids, do have some
important roles in nature. For example, they have
long been known to be components of the cell walls
of certain bacteria. Recently, d-aspartate and d-serine
have been found to exist in significant concentrations
in mammalian brains. In fact, evidence suggests that
d-serine acts as a genuine neurotransmitter.
When dissolved in aqueous solutions at neutral
pH, the carboxylic acid groups of amino acids are
deprotonated, while their amino groups are proto-
nated (Fig. 2). This makes each amino acid molecule
a dipolar ion or zwitterion (from the German zwitter,
meaning mongrel).
Twenty amino acids are commonly found in
proteins (Fig. 3). Most of these have neutral side
chains. However, the carboxylic acid groups in the
side chains of aspartate and glutamate are deproto-
nated and negatively charged at physiological pH,
whereas the side chains of arginine and lysine are
protonated and positively charged. The imidazole
ring in histidine’s side chain has a pK of 6.0 and may
either be positively charged or neutral in physiolo-
gical solutions, depending on the exact pH and on
local interactions with surrounding atoms.
The sizes, shapes, and chemical properties of the
amino acid side chains in a protein determine that
protein’s unique three-dimensional folding pattern
and its specific functions. One major determinant of
protein folding is the hydrophobicity of the amino
acid side chains. Asparagine, glutamine, and the five
charged amino acids are hydrophilic. Patterns of
AMINO ACIDS 113
protein folding that leave these amino acids exposed
to water are thermodynamically favored. Five amino
acids—phenylalanine, methionine, isoleucine, leucine,
and valine—are hydrophobic. They are generally
either buried within protein interiors or exposed to
lipids along the transmembrane segments of integral
membrane proteins. The eight remaining amino acids
have intermediate affinities for water and may easily
occupy a variety of positions within proteins.
The properties of a few amino acids have
especially important consequences for protein fold-
ing and function. For example, proline is unique
among the amino acids because it is a secondary
amine rather than a primary amine. The nitrogen
atom of proline is part of a five-membered ring
structure. This prevents rotation between the nitro-
gen atom and the adjacent a carbon atom. Therefore,
the occurrence of proline in a polypeptide chain
tends to cause a ‘‘bend’’ in its three-dimensional
course. Cysteine is also unique among amino acids.
The sulfhydral group (-SH) of one cysteine may form
a disulfide bond (-S–S-) with another cysteine, thus
creating a covalent bond between two different
proteins or between two different points along same
polypeptide. These disulfide bonds are often essential
to the proper folding and function of the proteins
that contain them. Finally, the ‘‘catalytic’’ atoms
crucial to enzymatic activity are often provided by
the side chains of specific amino acids.
DIETARY INTAKE AND ABSORPTION OF
AMINO ACIDS
Microorganisms and plants are able to synthesize
each of the 20 common amino acids from simpler
molecules. Human beings, however, are only able to
synthesize the following 12: alanine, arginine,
asparagine, aspartate, cysteine, glutamate, gluta-
mine, glycine, histidine, proline, serine, and tyrosine.
The other 8 amino acids must be obtained from a
person’s diet; these are therefore called essential
amino acids (Table 1). Of note, arginine and histidine
are essential to the diets of rapidly growing children,
who may be unable to synthesize enough of these
amino acids to meet their needs.
The proteins in the foods we eat are digested into
free amino acids by the sequential actions of a variety
of proteases. The enzyme pepsin begins this process
in the stomach. Then trypsin, chymotrypsin, and
carboxypeptidase act on proteins in the lumen of the
small intestine. Next, a variety of aminopeptidases
and dipeptidases attached to the apical surface (or
114 AMINO ACIDS

Aspartate Glutamate Histidine Lysine Arginine

(Asp, D) (Glu, E) (His, H) (Lys, K) (Arg, R)
_ _ _ _ _
COO COO COO COO COO
+ + + C H + C H
+
H3N C H H3N C H H3N C H H3N H3N

CH2 CH2 CH2 CH2 CH2

_ +
COO CH2 C NH CH2 CH2
_
Acidic COO NH CH2 CH2

CH2 NH
+ +
NH3 C NH2
Basic
Asparagine Glutamine NH2
(Asn, N) (Gln, Q)
_ _
COO COO
Tyrosine Tryptophan Proline
+ C H + C H (Tyr, Y) (Trp, W) (Pro, P)
H3N H3N
_ _ _
COO COO COO
CH2 CH2
+ C H + C H + C H
C O CH2 H3N H3N H2N

C O CH2 CH2
NH2
NH2
Hydrophilic N
H
OH

Glycine Alanine Serine Threonine Cysteine

(Gly, G) (Ala, A) (Ser, S) (Thr, T) (Cys, C)
_ _ _ _ _
COO COO COO COO COO
+ C H + C H + C H + C H + C H
H3N H3N H3N H3N H3N
H CH3 CH2 HC CH3 CH2
Intermediate OH OH SH

Phenylalanine Methionine Isoleucine Leucine Valine

(Phe, F) (Met, M) (IIe, I) (Leu, L) (Val, V)
_ _ _ _ _
COO COO COO COO COO
+ C H + C H + H + C H + C H
H3N H3N H3N C H3N H3N
CH2 CH2 HC CH3 CH2 HC CH3

CH2 CH2 HC CH3 CH3

S CH3 CH3
Hydrophobic
CH3

Figure 3
The 20 amino acids commonly found in proteins. Those which are charged, hydrophilic, or hydrophobic are indicated, as are the standard
three-letter and single-letter abbreviations.

brush border) of intestinal epithelial cells cleave the
remaining protein fragments to either single amino
acids or di- or tripeptides. These are then transported
across the cell membrane into the cytoplasm of an
intestinal epithelial cell, where virtually all the
remaining peptide bonds are cleaved. The resulting
single amino acids are then transported across the
basolateral portion of the cell membrane to enter the
bloodstream.
The concentrations of amino acids in the blood
increase only slightly after a meal because the excess
amino acids are rapidly absorbed into cells through-
out the body, especially in the liver. Amino acids
move into cells via active transport or facilitated
diffusion through one of several specific transmem-
brane transporters. Although our bodies are able to
store excess carbohydrates as glycogen and excess
lipids as triglycerides, no similar mass storage of
amino acids occurs. Instead, an equilibrium exists
between the free amino acids in the bodily fluids and
the more labile proteins of the body. Under most
conditions, the amino acid concentrations in the
blood are maintained within fairly narrow ranges. To
achieve this, some degradation and recycling of

Table 1 AMINO ACIDS ESSENTIAL TO THE HUMAN DIET
Essential Nonessential
a
Arginine Alanine
Histidinea Asparagine
Isoleucine Aspartate
Leucine Cysteine
Lysine Glutamate
Methionine Glutamine
Phenylalanine Glycine
Threonine Proline
Tryptophan Serine
Valine Tyrosine
a
Essential for growing children.
endogenous proteins are necessary when free amino
acids are in short supply, especially when essential
amino acids are lacking.
AMINO ACID BIOSYNTHESIS
The nitrogen needed for amino acid synthesis
ultimately comes from atmospheric nitrogen gas
(N2). However, the triple bond that holds a molecule
of nitrogen gas together is very stable and resists
alteration. Only certain microorganisms, including
‘‘nitrogen-fixing’’ bacteria and blue-green algae, have
the capability to reduce atmospheric nitrogen. In an
energy-consuming process, these organisms are able
to convert N2 to ammonium ions (NH4þ ).
In higher organisms, including human beings,
NH4þ can be used by the enzyme glutamate
dehydrogenase to synthesize the amino acid l-
glutamate from a-ketoglutarate, a citric acid cycle
intermediate. A second ammonium ion can then be
combined with l-glutamate by glutamine synthetase
to make l-glutamine. The amino groups (-NH2) of
the other amino acids are then derived from those of
l-glutamate or l-glutamine by transamination, as in
the synthesis of alanine from pyruvate. As is true for
glutamate, glutamine, and alanine, the carbon-rich
‘‘backbones’’ of the other amino acids are also
derived from intermediates of major metabolic
pathways, such as the citric acid cycle, glycolysis,
and the pentose phosphate pathway.
The enzymatic reactions used by human beings to
synthesize most of the nonessential amino acids are
similar to those used by plants and microorganisms
(Fig. 4). However, we use alternative pathways to
produce cysteine, tyrosine, and arginine. We make
these from other amino acids: cysteine from methio-
AMINO ACIDS 115
nine, tyrosine from phenylalanine, and arginine from
proline (via conversion of proline to ornithine). In
lower organisms, histidine is synthesized from ribose
5-phosphate, a product of the pentose phosphate
pathway. The extent and route of histidine biosynth-
esis in human beings are unclear.
AMINO ACID CATABOLISM
Because the body is unable to store excess amino
acids, surplus amino acids must be degraded. The a-
amino groups are removed to form a-ketoacids,
which are then metabolized further to yield major
metabolic intermediates such as pyruvate, acetyl-
CoA, or citric acid cycle intermediates. Thus, amino
acids can be used to generate energy, glucose, and/or
fatty acids (Fig. 5).
The a-amino group of glutamate can be removed
by deamination, forming a-ketoglutarate and NH4þ .
Analogous reactions also allow serine and threonine
to be directly deaminated. However, the a-amino
groups of most amino acids are removed by
transamination of a-ketoglutarate, which produces
glutamate. Deamination of the resulting glutamate
then produces NH4þ ions. Excess NH4þ ions are
potentially toxic and must be eliminated from the
body. Most excess NH4þ is converted into urea
through the urea cycle and then excreted in the urine.
ALTERNATIVE ROLES FOR AMINO ACIDS
AND THEIR DERIVATIVES
Evolution has found a variety of uses for amino
acids, some of which have little or nothing to do with
protein synthesis. Interestingly, many of these alter-
native roles for amino acids are vital to the
functioning of the human nervous system. Some
Figure 4
De novo synthesis of amino acids in human beings from
intermediates of the citric acid cycle or glycolysis. The number of
enzymatic steps in each synthesis is indicated with a numeral
adjacent to the corresponding arrow.
116 AMOEBAE

See also–Amino Acid Disorders;

Neurotransmitters, Overview

Further Reading
Guyton, A. C., and Hall, J. E. (2000). Textbook of Medical
Physiology, 10th ed. Saunders, Philadelphia.
McMurry, J. (2000). Organic Chemistry, 5th ed. Brooks/Cole,
Pacific Grove, CA.
Scriver, C. R., Beaudet, A. L., Sly, W. S., et al. (Eds.) (2001). The
Metabolic and Molecular Bases of Inherited Disease, 8th ed.
McGraw-Hill, New York. See especially Part 8, Amino Acids,
pp. 1667–2105.
Snyder, S. H. (2000). d-Amino acids as putative neurotransmitters:
Focus on d-serine. Neurochem. Res. 25, 460–553.
Stryer, L. (1995). Biochemistry, 4th ed. Freeman, New York.
Zubay, G. L. (1993). Biochemistry, 3rd ed. Brown, Dubuque, IA.
Figure 5
Amino acid catabolism. The nonnitrogenous portions of amino
acids are converted to major metabolic intermediates from which
energy, glucose, and/or fatty acids are derived.
Amoebae (Free-Living
amino acids, such as l-glutamate and glycine, serve
directly as neurotransmitters. Several other neuro- and Parasitic)
transmitters are derived from amino acids. For Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
example, dopamine, epinephrine, and norepinephr-
ine are all derivatives of tyrosine. Serotonin is formed
FREE-LIVING amoebae belonging to the genus Nae-
from tryptophan, and g-aminobutyric acid (GABA) is
gleria, Acanthamoeba, and Balamuthia are known to
formed from glutamate.
cause lethal central nervous system (CNS) disease in
Amino acids are also required for the biosynthesis
humans and other animals. The disease produced by
of many essential compounds whose roles are not
Naegleria fowleri is called primary amebic menin-
limited to the nervous system, including purine and
goencephalitis (PAM), usually affecting young adults
pyrimidine nucleotides, melanin, thyroxine, hista-
and children with a recent history of water-sport
mine, creatine, and heme. The amino acids glycine,
activities. Several species of Acanthamoeba (e.g., A.
aspartate, and glutamine are necessary substrates for
castellanii, A. culberstoni, and A. polyphaga) and the
the synthesis of the purine nucleotides, donating six
only known species of Balamuthia, B. mandrillaris,
of the nine atoms in the purine ring. Similarly, during
cause a chronic CNS disease—granulomatous ame-
biosynthesis of pyrimidine nucleotides, aspartate
bic encephalitis (GAE)—in debilitated, malnourished
contributes four of the six atoms in the pyrimidine
persons, in those with the acquired immunodefi-
ring. The many forms of melanin pigment are derived
ciency syndrome (AIDS), or in patients undergoing
through a complex set of reactions that begin with
immunosuppressive therapy to avoid organ rejection
the hydroxylation and oxidation of tyrosine by the
after transplantation. Acanthamoeba spp. are also
enzyme tyrosinase to form dopaquinone. Thyroxine
known to cause Acanthamoeba keratitis, a painful
(thyroid hormone) is also a derivative of tyrosine.
infection of the human cornea.
Histamine, a vasoactive mediator of inflammation, is
Entamoeba histolytica, which is a common gastro-
produced through enzymatic decarboxylation of
intestinal parasite, can produce ulcerations of the
histidine. The amino acids arginine and glycine are
colonic mucosa called intestinal or colonic amebiasis.
used to synthesize creatine. Creatine is then phos-
Liver, pulmonary, and brain abscesses are secondary
phorylated and serves as a reservoir of high-energy
complications as a result of hematogenous spread
phosphate groups, allowing the more rapid regen-
from a primary focus in the colon.
eration of adenosine triphosphate. Finally, the
porphyrin ring of heme, which is essential to the
oxygen carrying capacity of our blood and the AMOEBAE AND THEIR LIFE CYCLES
function of many enzymes, is synthesized from Amoebae are protozoans. Familiarity with their
succinyl-CoA and the amino acid glycine. morphology is required for diagnoses. Trophozoite
—Edward G. Neilan and Vivian E. Shih forms may be found in the cerebrospinal fluid (CSF);
116 AMOEBAE

See also–Amino Acid Disorders;

Neurotransmitters, Overview

Further Reading
Guyton, A. C., and Hall, J. E. (2000). Textbook of Medical
Physiology, 10th ed. Saunders, Philadelphia.
McMurry, J. (2000). Organic Chemistry, 5th ed. Brooks/Cole,
Pacific Grove, CA.
Scriver, C. R., Beaudet, A. L., Sly, W. S., et al. (Eds.) (2001). The
Metabolic and Molecular Bases of Inherited Disease, 8th ed.
McGraw-Hill, New York. See especially Part 8, Amino Acids,
pp. 1667–2105.
Snyder, S. H. (2000). d-Amino acids as putative neurotransmitters:
Focus on d-serine. Neurochem. Res. 25, 460–553.
Stryer, L. (1995). Biochemistry, 4th ed. Freeman, New York.
Zubay, G. L. (1993). Biochemistry, 3rd ed. Brown, Dubuque, IA.
Figure 5
Amino acid catabolism. The nonnitrogenous portions of amino
acids are converted to major metabolic intermediates from which
energy, glucose, and/or fatty acids are derived.
Amoebae (Free-Living
amino acids, such as l-glutamate and glycine, serve
directly as neurotransmitters. Several other neuro- and Parasitic)
transmitters are derived from amino acids. For Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
example, dopamine, epinephrine, and norepinephr-
ine are all derivatives of tyrosine. Serotonin is formed
FREE-LIVING amoebae belonging to the genus Nae-
from tryptophan, and g-aminobutyric acid (GABA) is
gleria, Acanthamoeba, and Balamuthia are known to
formed from glutamate.
cause lethal central nervous system (CNS) disease in
Amino acids are also required for the biosynthesis
humans and other animals. The disease produced by
of many essential compounds whose roles are not
Naegleria fowleri is called primary amebic menin-
limited to the nervous system, including purine and
goencephalitis (PAM), usually affecting young adults
pyrimidine nucleotides, melanin, thyroxine, hista-
and children with a recent history of water-sport
mine, creatine, and heme. The amino acids glycine,
activities. Several species of Acanthamoeba (e.g., A.
aspartate, and glutamine are necessary substrates for
castellanii, A. culberstoni, and A. polyphaga) and the
the synthesis of the purine nucleotides, donating six
only known species of Balamuthia, B. mandrillaris,
of the nine atoms in the purine ring. Similarly, during
cause a chronic CNS disease—granulomatous ame-
biosynthesis of pyrimidine nucleotides, aspartate
bic encephalitis (GAE)—in debilitated, malnourished
contributes four of the six atoms in the pyrimidine
persons, in those with the acquired immunodefi-
ring. The many forms of melanin pigment are derived
ciency syndrome (AIDS), or in patients undergoing
through a complex set of reactions that begin with
immunosuppressive therapy to avoid organ rejection
the hydroxylation and oxidation of tyrosine by the
after transplantation. Acanthamoeba spp. are also
enzyme tyrosinase to form dopaquinone. Thyroxine
known to cause Acanthamoeba keratitis, a painful
(thyroid hormone) is also a derivative of tyrosine.
infection of the human cornea.
Histamine, a vasoactive mediator of inflammation, is
Entamoeba histolytica, which is a common gastro-
produced through enzymatic decarboxylation of
intestinal parasite, can produce ulcerations of the
histidine. The amino acids arginine and glycine are
colonic mucosa called intestinal or colonic amebiasis.
used to synthesize creatine. Creatine is then phos-
Liver, pulmonary, and brain abscesses are secondary
phorylated and serves as a reservoir of high-energy
complications as a result of hematogenous spread
phosphate groups, allowing the more rapid regen-
from a primary focus in the colon.
eration of adenosine triphosphate. Finally, the
porphyrin ring of heme, which is essential to the
oxygen carrying capacity of our blood and the AMOEBAE AND THEIR LIFE CYCLES
function of many enzymes, is synthesized from Amoebae are protozoans. Familiarity with their
succinyl-CoA and the amino acid glycine. morphology is required for diagnoses. Trophozoite
—Edward G. Neilan and Vivian E. Shih forms may be found in the cerebrospinal fluid (CSF);

trophozoites and cysts can occur in brain biopsy
specimens.
The life cycle of N. fowleri includes three stages: a
feeding trophozoite stage, a transient flagellate stage,
and a resistant cyst stage. The trophozoite, which
measures 10–25 mm, normally feeds on bacteria and
multiplies by binary fission. Under certain conditions
the trophozoite transforms into a transitory pear-
shaped biflagellated stage. During unfavorable con-
ditions, the trophozoite differentiates into a resistant
cyst stage. All three stages are uninucleate and the
spherical nucleus contains a centrally placed large,
dense nucleolus. The cyst ranges in size from 7 to 14
mm and is usually spherical; the dense cyst wall has
one or more flat pores. The life cycle of Acantha-
moeba spp. and B. mandrillaris includes a feeding or
vegetative trophozoite stage and a resistant cyst stage
but no flagellate stage. The trophozoites of Acantha-
moeba also feed on bacteria and multiply by binary
fission. They measure approximately 15–45 mm in
diameter and are uninucleate; the nucleus has a large,
centrally placed dense nucleolus. The cysts of
Acanthamoeba sp. measure 10–25 mm and are double
walled. The outer wall, or the ectocyst, is wrinkled
and the inner wall, or the endocyst, is usually stellate,
polygonal, oval, or spherical. Pores are present at the
point of contact between the ecto- and the endocyst
and each pore is covered by an operculum. Cysts are
uninucleate and possess a centrally placed dense
nucleolus. The trophozoites of B. mandrillaris are
irregular in shape, range in size from 12 to 60 mm,
and have a nucleus containing a large, dense, centrally
placed nucleolus. Occasionally, two or three nucleolar
bodies may be seen within the nucleolus. Cysts are
more or less spherical and measure 12–30 mm. At
light microscopy, the cysts appear to be double
walled, with a wavy ectocyst and a dense endocyst.
Ultrastructurally, however, the cyst is tripartite with
an outer thin and irregular ectocyst, an inner thick
endocyst, and a middle amorphous mesocyst.
The life cycle of E. histolytica consists of an
infective cyst stage and an invasive trophozoite stage.
The trophozoite of E. histolytica measures from 15
to 60 mm, with a mean of 25–30 mm. The cyst is
spherical, contains four nuclei, and measure from 10
to 20 mm, with a mean of 12–13 mm.
EPIDEMIOLOGY, GEOGRAPHIC
DISTRIBUTION, AND TRANSMISSION
Naegleria fowleri is ubiquitous and has been isolated
from fresh water, thermal discharges of power plants,
AMOEBAE 117
heated swimming pools, hydrotherapy and remedial
pools, aquaria, sewage, and even nasal passages and
throats of healthy persons. Typical cases of PAM
occur in the hot summer months when large numbers
of people engage in aquatic activities in fresh bodies
of water such as lakes, ponds, and swimming pools
that may harbor these amebas.
Acanthamoeba spp. have been isolated from soil;
fresh and brackish water; bottled water; cooling
towers of electric and nuclear power plants; phy-
siotherapy pools; jacuzzis; heating and ventilating
and air conditioning units; dialysis machines; dust in
air; bacterial, fungal, and mammalian cell cultures;
contact lens paraphernalia; the noses and throats of
people; and human and animal tissues. Additionally,
Acanthamoeba is known to harbor Legionella sp.
and Mycobacteria, thus indicating the public health
importance of these amebas.
Balamuthia mandrillaris has recently been isolated
from the environment. It has been isolated from
human and other animal tissues. Cases of GAE may
occur at any time of the year and therefore have no
relation to climatological changes.
Entamoeba histolytica is prevalent in developing
countries with tropical and subtropical climates. It is
also prevalent in countries in which unsanitary
conditions prevail and proper public health measures
are not implemented. The cysts are excreted in the
feces, and when food and water contaminated with
cysts of E. histolytica are ingested, the cysts will
excyst and the trophozoites will invade the colonic
mucosa. The cyst is resistant to gastric acidity and
desiccation but can survive in a moist environment
for several weeks.
PATHOGENESIS
Naegleria fowleri
The olfactory neuroepithelium is the portal of entry
into the CNS. The amebic trophozoites pierce the
cribriform plate and penetrate into the subarachnoid
space and the brain parenchyma. The incubation of
period of PAM varies from 2 to 15 days.
Acanthamoeba spp. and B. mandrillaris
GAE, whether caused by Acanthamoeba spp. or B.
mandrillaris, usually occurs in chronically ill, debili-
tated persons. Many have undergone immunosup-
pressive therapy or have AIDS, or they are recipients
of broad-spectrum antibiotics or chemotherapeutic
medications. The incubation period is unknown, and
118 AMOEBAE
several weeks or months may elapse before the
disease becomes apparent. The route of invasion and
penetration into the brain is hematogenous, probably
as a result of spread from the primary focus, such as
the lower respiratory tract or the skin.
Acanthamoeba keratitis (AK) is a chronic inflam-
mation of the cornea and is associated with contact
lens wear, corneal abrasion or hypoxic trauma, and
exposure to contaminated water. Contact lens wear
and use of contaminated homemade, nonsterile
saline solution may allow the invasion and destruc-
tion of the corneal stoma by the ameba.
Amebiasis
The cysts of E. histolytica present in contaminated
vegetables, food, and water are the infective forms.
The cysts excyst and the resultant trophozoites invade
the colonic mucosa and cause ulceration. Invasion of
the colonic mucosa is facilitated by the adhesion of
the trophozoites to colonic mucin glycoproteins via a
galactose and N-acetyl-d-galactosamine-specific lec-
tin. The trophozoites infrequently may reach the
brain via hematogenous dissemination from a pri-
mary focus in the colon or liver.
CLINICAL SIGNS AND SYMPTOMS
PAM caused by N. fowleri is an acute and fulminant
illness characterized by sudden onset of bifrontal and
bitemporal headaches, fever, nausea, vomiting,
photophobia, and stiff neck. Symptoms progress
rapidly, with the development of lethargy, confusion,
coma, and death within 48–96 hr.
GAE, whether produced by Acanthamoeba spp. or
B. mandrillaris, is characterized by a long and
protracted clinical course. The clinical picture
mimics single- or multiple-space-occupying lesions,
with the occurrence of hemiparesis and seizure in the
early course of infection. Mental status abnormal-
ities, headache, sporadic low-grade fever, stiff neck,
cranial nerve palsies, nausea, vomiting, and lethargy
may also be present. Cerebellar ataxia, diplopia, and
coma may indicate imminent death. Pneumonitis
with the presence of trophozoites and cysts within
pulmonary alveoli has been described. The direct
cause of death is usually acute bronchopneumonia,
liver or renal failure, and septicemia.
Chronic inflammation of the cornea, painful
recurrent corneal ulceration, a 3601 stromal infil-
trate, and refractoriness to the usual antibacterial,
antifungal, and antiviral medications are the hall-
marks of AK.
Cerebral abscess caused by E. histolytica is caused
by a late complication of the intestinal, pulmonary,
or hepatic amebiasis and is usually fatal. Clinically,
the patients develop nonspecific signs and symptoms
of meningoencephalitis or encephalitis, with mani-
festation of space-occupying mass. Severe headaches
are the most characteristic symptom. The clinical
manifestations of amebic colitis may be confused
with those of ulcerative colitis.
PATHOLOGICAL FINDINGS
PAM
The cerebral hemispheres in PAM are usually
markedly swollen and edematous. The arachnoid is
severely congested, with scant purulent exudate. The
olfactory bulbs and the orbitofrontal cortices are
usually necrotic and hemorrhagic. The leptomeninges
show a fibrinopurulent exudate composed largely of
polymorphonuclear leukocytes, eosinophils, a few
macrophages, and lymphocytes. Amebic trophozoites
are usually seen within perivascular spaces, some-
times phagocytosed by polymorphonuclear leuko-
cytes and macrophages. Cysts are not present.
GAE
The cerebral hemispheres in GAE usually contain
areas of cortical softening with hemorrhages and also
variable necrosis. Hemorrhagic necrosis may also be
seen in the basal ganglia, midbrain, brainstem, and
cerebellum. Multiple ulcerations of the skin may be
seen, mainly in patients with AIDS with acute and
chronic inflammation. The ulcerated skin may serve
as the portal of entry for the amebas or it may
represent terminal dissemination of the infection.
The histopathological changes consist of necrotizing
granulomatous encephalitis with multinucleated
giant cells in the cerebral hemispheres, midbrain,
basal ganglia, and cerebellum. In patients with AIDS,
the lesions may be mostly necrotic, with minimal or
negligible inflammation.
AK
The damaged corneal tissue may show annular
infiltrate and congested conjunctiva or a dendriti-
form epitheliopathy and patchy stromal infiltrate
with lacunar areas. In the early stages of AK the
anterior cornea is destroyed by the invading
Acanthamoeba trophozoites. Amebic trophozoites
and cysts are seen infiltrating between the lamellae of
the cornea. During the later stage of the disease

process, AK is characterized by severe pain and
ulceration of the cornea.
Entamoeba histolytica
Cerebral abscesses caused by E. histolytica are rare.
They are characterized clinically by a depressed level
of consciousness because of an increased level of
cranial pressure and as a consequence of a space-
occupying mass. The abscesses may vary in size and
number and may extend into the leptomeninges.
Amebic abscesses of the liver may penetrate the
diaphragm, producing emphysema and pulmonary
abscesses. If they affect the pericardium, a suppura-
tive amebic pericarditis may be produced.
CLINICAL AND LABORATORY METHODS
AND DIFFERENTIAL DIAGNOSIS
PAM
There are no distinctive clinical features to differ-
entiate PAM from acute pyogenic or bacterial
meningoencephalitis. CSF examination reveals char-
acteristic pleocytosis with a predominance of poly-
morphonuclear leukocytes and no bacteria. The CSF
pressure is elevated (300–600 mm H2O). Glucose
concentration may be slightly reduced or normal, but
the protein content is elevated. Amebic trophozoites
may be detected by their movement in a drop of CSF
when examined under a microscope or may be
identified in CSF smears stained with Wright or
Giemsa. Computed tomography (CT) scan shows
obliteration of the cisterns around the midbrain and
the subarachnoid space over the cerebral hemi-
spheres.
GAE
CSF examination reveals lymphocytic pleocytosis
with mild elevation of proteins and normal glucose.
Unlike N. fowleri, Acanthamoeba spp. and B.
mandrillaris have not been readily found in the
CSF. Brain and skin biopsies are important diagnostic
procedures antemortem; if present within subacute
or chronic encephalitic lesions, amebic trophozoites
and cysts are easily identified by light microscopic
examination of the tissue sections. In most cases of
GAE, however, final diagnosis has been made at
autopsy. In general, Acanthamoeba sp. and B.
mandrillaris are difficult to differentiate in tissue
sections by light microscopy because of their similar
morphology. However, they can be differentiated by
immunofluorescence and electron microscopic ana-
AMOEBAE 119
lysis. The morphology of the trophozoites with two
or more nuclear elements and cysts with tripartite
walls are particularly useful in the identification of B.
mandrillaris. CT and magnetic resonance imaging
(MRI) scans of the head show single or multiple
heterogeneous, hypodense, nonenhancing, space-
occupying lesions involving basal ganglia, cerebral
cortex, subcortical white matter, cerebellum, and
pons. These features may mimic a brain abscess,
brain tumor, or intracerebral hematoma.
AK
Deep corneal scraping and biopsy are recommended
for the identification of Acanthamoeba trophozoites
and/or cysts. The scraped material should be
processed for staining with Giemsa–Wright or
hemacolor or Wheatley’s trichrome stain and culture.
Other procedures that have been used to identify
Acanthamoeba spp. are calcofluor white and im-
munofluorescence staining.
Entamoeba histolytica
Differential diagnosis should include infectious
etiologies, such as shigella, salmonella, and campy-
lobacter, as well as noninfectious inflammatory
bowel disease. Colonoscopy is preferable to sigmoi-
doscopy for the diagnosis of amebic colitis because
most ulcerations are located in the ascending colon
and cecum. Sharply defined borders and pseudo-
membranes characterize ulcers in the colon. Biopsy
of the colonic mucosa should be taken from the edge
of the ulcers. Periodic acid Schiff stains the amebic
trophozoite with a magenta color. Ultrasound, CT,
and MRI studies of the liver may be useful to detect
amebic liver abscesses, but these techniques cannot
differentiate an amebic abscess from a pyogenic
abscess. Stool antigen detection is the method of
choice for the diagnosis. Detection of serum anti-
bodies to the amebas can be useful in the diagnosis,
particularly in the case of liver abscesses.
ISOLATION AND CULTURE
Naegleria fowleri can be easily isolated from the CSF
or brain tissue and grown on nonnutrient plates
coated with Gram-negative bacteria such as Escher-
ichia coli as well as axenically (as pure culture) in
liquid media and also on mammalian cell culture.
Acanthamoeba, like N. fowleri, can be grown on
nonnutrient plates covered with bacteria, axeni-
cally in a chemical medium, and also on mammalian
tissue cultures. Balamuthia mandrillaris, unlike
120 AMOEBAE
Acanthamoeba and N. fowleri, cannot be grown on
nonnutrient agar plates with bacteria but can be
grown axenically in a complete chemical medium as
well as on mammalian tissue culture. The agar plate
should be incubated at either 301C, if the specimens
originate from cornea or skin, or 371C, if the
specimens are from brain, lungs, or other internal
organs, and examined under a microscope every day
for at least 2 weeks. Balamuthia mandrillaris cannot
be isolated into culture using this method because
this ameba does not grow on bacterized agar plates.
However, B. mandrillaris can be cultured by inocu-
lating macerated biopsy materials into mammalian
cell culture. Generic identification of the amebas is
based on characteristic morphology of the tropho-
zoites and cysts and enflagellation experiments.
Entamoeba histolytica can also be isolated and
established in either polyxenic or axenic culture.
TREATMENT AND PROGNOSIS
PAM
Only a few patients have survived this disease.
Intrathecal and intravenous administration of am-
photericin B and miconazole and oral rifampin
appear to be the drugs of choice.
GAE
There is no effective treatment of CNS and lung
infections caused by Acanthamoeba. In vitro experi-
ments, however, suggest that pentamidine, paromo-
mycin, ketoconazole, itraconazole, and 5-fluoro-
cytosine may be of some use in the treatment of
Acanthamoeba.
The prognosis of patients with disseminated skin
infections without CNS involvement is good. Recent
studies suggest that Balamuthia is sensitive to
pentamidine isethionate in vitro and treatment with
this drug may be beneficial to patients with
Balamuthia GAE.
AK
During the past few years, the treatment of choice for
AK has been the topical application of polyhexa-
methylene biguanide or chlorhexidine gluconate. In
some cases, treatment with propamidine isethionate
(Brolene), in association with neosporin, has con-
trolled the infection. Corneal transplantation is
another option in chronic cases.
Entamoeba histolytica
Treatment for amebic colitis includes paramomycin,
diloxanide furoate, and iodoquinol. Metronidazole is
the drug of choice for liver abscess. Treatment with
chloroquin and/or percutaneous drainage of the liver
abscess is another option for patients that do not
respond to metronidazole. The prognosis of amebic
colitis is good if treated adequately. Brain abscesses
with E. histolytica, however, have an ominous
prognosis.
PREVENTION AND CONTROL
PAM
Since N. fowleri is susceptible to chlorine at one part
per million, it is necessary that swimming pools be
maintained properly with adequate chlorination.
Since it is impossible to chlorinate natural bodies of
water, such as lakes and ponds, it is recommended
that posters be displayed at strategic places around
these bodies of water to inform the public of the
presence of pathogenic free-living amebas and the
danger to one’s health because of them.
GAE
The disease produced by Acanthamoeba spp. and B.
mandrillaris has almost always occurred in persons
with weakened immune systems. Due to the usually
poor prognosis in patients infected with these
amebas, new approaches in treatment modalities
and preventive measures are required.
AK
Contact lenses and contact lens paraphernalia should
be kept meticulously clean. Health care professionals
should educate their patients about the proper care
of their lenses.
Entamoeba histolytica
The prevention of infection with E. histolytica is
dependent on the interruption of the fecal–oral cycle.
Drinking water should be boiled in places where
unhygienic practices are routine. Furthermore, vege-
tables and other foodstuffs should be properly
cooked before consumption. Additionally, infected
persons should follow strict hygienic measures
(particularly after using the toilet) and should wash
their hands well before handling any food, glassware,
and utensils used in the kitchen. The development of

a vaccine to prevent the amebic infection is the next
logical step.
—Augusto Julio Martinez and Govinda S. Visvesvara
See also–Parasites and Neurological Diseases,
Overview; Tropical Neurology
Further Reading
De Villiers, J. P., and Durra, G. (1998). Amoebic abscess of the
brain. Clin. Radiol. 53, 307–309.
John, D. T. (1993). Opportunistically pathogenic free-living
amebae. In Parasitic Protozoa (J. P. Kreier and J. R. Baker
Eds.), 2nd ed., Vol. 3, pp. 143–246. Academic Press, San Diego.
Martinez, A. J., and Visvesvara, G. S. (1997). Free-living,
amphizoic and opportunistic ameba. Brain Pathol. 7, 583–598.
Murakawa, G. J., McCalmont, T., Altman, J., et al. (1995).
Disseminated acanthamebiasis in patients with AIDS. A report
of five cases and a review of the literature. Arch. Dermatol. 131,
1291–1296.
Petri, W. A., and Singh, U. (1999). Diagnosis and management of
amebiasis. Clin. Infect. Dis. 29, 1117–1125.
Schuster, F. L., and Visvesvara, G. S. (1998). Efficacy of novel
antimicrobials against clinical isolates of opportunistic amebas.
J. Euk. Microbiol. 45, 612–618.
Seidel, J. S., Harmatz, P., Visvesvara, G. S., et al. (1982). Successful
treatment of primary amebic meningoencephalitis. N. Engl. J.
Med. 306, 346–348.
Seto, R. K., and Rockey, D. C. (1999). Amebic liver abscess:
Epidemiology, clinical features and outcome. West. J. Med. 170,
104–109.
Slater, C. A., Sickel, J. Z., Visvesvara, G. S., et al. (1994).
Successful treatment of disseminated Acanthamoeba infection
in an immunocompromised patient. N. Engl. J. Med. 331,
85–87.
Visvesvara, G. S., Schuster, F. L., and Martinez, A. J. (1993).
Balamuthia mandrillaris, N. G., N. Sp., agent of amebic
meningoencephalitis in humans and other animals. J. Euk.
Microbiol. 40, 504–514.
Amphetamine Toxicity
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMPHETAMINES have been used for several decades
to promote weight loss and to enhance attentiveness
in such conditions as attention deficit disorder and
narcolepsy. They have also been used occasionally as
an adjunct treatment in depression. During the 1960s
and early 1970s, amphetamines were widely abused
as a street drug, but cocaine had become more
popular than amphetamines by the 1990s. Never-
theless, prescribed amphetamines remain a signifi-
AMPHETAMINE TOXICITY 121
cant source of neurotoxicity. Recently, drugs such as
methamphetamine (i.e., meth and Ice) and methyl-
enedioxymethamphetamine (MDMA; Ecstasy) have
seen a major resurgence among adolescents and
those in their early twenties. MDMA has become a
major public heath issue in some communities. Meth
has also resurged in California and in some
midwestern states, where it is synthesized in home-
based laboratories. It has been predicted that these
drugs may displace cocaine as the major drugs of
abuse. In Japan, meth abuse has been particularly
frequent.
The amphetamine analogs produce a typical array
of toxic signs and symptoms. Positive sensations
include hyperalertness, euphoria, and greater physi-
cal endurance. Higher doses of these drugs, however,
cause depression, headaches, and confusion. Unlike
cocaine, these drugs can produce a prolonged ‘‘rush’’
when taken intravenously. Inhalation of meth can
sometimes cause a very rapid rush that is well-known
among drug users. This rapid and prolonged rush
effect is believed to be chemically based on the long
half-life of amphetamine derivatives compared to
cocaine. In the midst of the psychological excitation,
however, meth can induce psychotic symptomatol-
ogy that is often indistinguishable from an acute
schizophrenic breakdown. This behavioral crisis is
commonly reported in Japan.
Tics and Tourette’s syndrome can be exacerbated
and at first signs precipitated by central stimulant
drugs such as amphetamines, methylphenidate, or
pemoline. In most cases, tics return to their baseline
level when these drugs are stopped. Stereotypic,
repetitive movements (pundling) can develop in
subjects with chronic amphetamine use, and bruxism
and choreiform movements have been described as
well. These movement disorders may relate to
amphetamine effects on the neurochemical system
involving dopamine. Because amphetamines also
activate the neurochemical pathways involving the
transmitter norepinephrine, tremors may be en-
hanced, especially postural tremors.
Strokes are also frequent complications of amphe-
tamine abuse, and bleeding into the brain substance
(intracerebral hematomas) has been reported after
either nasal or intravenous use of these drugs. Often,
strokes are preceded by complaints of severe head-
aches, and among subjects seen in emergency rooms
or medical offices, blood pressure is usually markedly
elevated. Neuroimaging studies including computer
tomography (CT) scans have shown intracerebral
hematomas, hemorrhage into the ventricular system,

a vaccine to prevent the amebic infection is the next
logical step.
—Augusto Julio Martinez and Govinda S. Visvesvara
See also–Parasites and Neurological Diseases,
Overview; Tropical Neurology
Further Reading
De Villiers, J. P., and Durra, G. (1998). Amoebic abscess of the
brain. Clin. Radiol. 53, 307–309.
John, D. T. (1993). Opportunistically pathogenic free-living
amebae. In Parasitic Protozoa (J. P. Kreier and J. R. Baker
Eds.), 2nd ed., Vol. 3, pp. 143–246. Academic Press, San Diego.
Martinez, A. J., and Visvesvara, G. S. (1997). Free-living,
amphizoic and opportunistic ameba. Brain Pathol. 7, 583–598.
Murakawa, G. J., McCalmont, T., Altman, J., et al. (1995).
Disseminated acanthamebiasis in patients with AIDS. A report
of five cases and a review of the literature. Arch. Dermatol. 131,
1291–1296.
Petri, W. A., and Singh, U. (1999). Diagnosis and management of
amebiasis. Clin. Infect. Dis. 29, 1117–1125.
Schuster, F. L., and Visvesvara, G. S. (1998). Efficacy of novel
antimicrobials against clinical isolates of opportunistic amebas.
J. Euk. Microbiol. 45, 612–618.
Seidel, J. S., Harmatz, P., Visvesvara, G. S., et al. (1982). Successful
treatment of primary amebic meningoencephalitis. N. Engl. J.
Med. 306, 346–348.
Seto, R. K., and Rockey, D. C. (1999). Amebic liver abscess:
Epidemiology, clinical features and outcome. West. J. Med. 170,
104–109.
Slater, C. A., Sickel, J. Z., Visvesvara, G. S., et al. (1994).
Successful treatment of disseminated Acanthamoeba infection
in an immunocompromised patient. N. Engl. J. Med. 331,
85–87.
Visvesvara, G. S., Schuster, F. L., and Martinez, A. J. (1993).
Balamuthia mandrillaris, N. G., N. Sp., agent of amebic
meningoencephalitis in humans and other animals. J. Euk.
Microbiol. 40, 504–514.
Amphetamine Toxicity
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMPHETAMINES have been used for several decades
to promote weight loss and to enhance attentiveness
in such conditions as attention deficit disorder and
narcolepsy. They have also been used occasionally as
an adjunct treatment in depression. During the 1960s
and early 1970s, amphetamines were widely abused
as a street drug, but cocaine had become more
popular than amphetamines by the 1990s. Never-
theless, prescribed amphetamines remain a signifi-
AMPHETAMINE TOXICITY 121
cant source of neurotoxicity. Recently, drugs such as
methamphetamine (i.e., meth and Ice) and methyl-
enedioxymethamphetamine (MDMA; Ecstasy) have
seen a major resurgence among adolescents and
those in their early twenties. MDMA has become a
major public heath issue in some communities. Meth
has also resurged in California and in some
midwestern states, where it is synthesized in home-
based laboratories. It has been predicted that these
drugs may displace cocaine as the major drugs of
abuse. In Japan, meth abuse has been particularly
frequent.
The amphetamine analogs produce a typical array
of toxic signs and symptoms. Positive sensations
include hyperalertness, euphoria, and greater physi-
cal endurance. Higher doses of these drugs, however,
cause depression, headaches, and confusion. Unlike
cocaine, these drugs can produce a prolonged ‘‘rush’’
when taken intravenously. Inhalation of meth can
sometimes cause a very rapid rush that is well-known
among drug users. This rapid and prolonged rush
effect is believed to be chemically based on the long
half-life of amphetamine derivatives compared to
cocaine. In the midst of the psychological excitation,
however, meth can induce psychotic symptomatol-
ogy that is often indistinguishable from an acute
schizophrenic breakdown. This behavioral crisis is
commonly reported in Japan.
Tics and Tourette’s syndrome can be exacerbated
and at first signs precipitated by central stimulant
drugs such as amphetamines, methylphenidate, or
pemoline. In most cases, tics return to their baseline
level when these drugs are stopped. Stereotypic,
repetitive movements (pundling) can develop in
subjects with chronic amphetamine use, and bruxism
and choreiform movements have been described as
well. These movement disorders may relate to
amphetamine effects on the neurochemical system
involving dopamine. Because amphetamines also
activate the neurochemical pathways involving the
transmitter norepinephrine, tremors may be en-
hanced, especially postural tremors.
Strokes are also frequent complications of amphe-
tamine abuse, and bleeding into the brain substance
(intracerebral hematomas) has been reported after
either nasal or intravenous use of these drugs. Often,
strokes are preceded by complaints of severe head-
aches, and among subjects seen in emergency rooms
or medical offices, blood pressure is usually markedly
elevated. Neuroimaging studies including computer
tomography (CT) scans have shown intracerebral
hematomas, hemorrhage into the ventricular system,
122 AMUSIA
or subarachnoid hemorrhage. Because many of these
forms of stroke relate to drug-induced inflammation
of the cerebral blood vessels (vasculitis), cerebral
angiography may show irregular narrowing of distal
cerebral vessels, along with evidence of occlusion or
‘‘beading.’’
The management of intoxicated subjects depends
on their primary symptoms. In patients with acute
psychotic behavior, antipsychotic or neuroleptic
drugs used in other medical situations such as for
schizophrenia are indicated. It is very important to
pay close attention to blood pressure and body
temperature because amphetamines can cause hy-
perthermia and hypertension. Intoxicated patients
might be prone to develop a particular syndrome
found in association with neuroleptic drug treatment
known as neuroleptic malignant syndrome. In such
cases in which high fevers, muscle rigidity, and signs
of instability of the autonomic nervous system (blood
pressure and pulse control) predominate, patients are
placed in a quiet, cool room. In the case of
amphetamine-induced strokes, the management is
the same as that for other causes.
Whether amphetamines can cause permanent
psychiatric or cognitive disturbance after chronic
exposure is uncertain. Ten users of amphetamines
reported decreased memory or poor concentration
after achieving abstinence. There are also reports of
lasting psychosis or dementia. However, formal
studies of cognitive performance in chronic amphe-
tamine abusers have not been systematically per-
formed.
—Christopher G. Goetz
See also–Alcohol-Related Neurotoxicity;
Cocaine; Eating Disorders; Hallucinogens;
Heroin; Intoxication; Marijuana; Substance
Abuse
Further Reading
Bonthala, C. M., and West, A. (1983). Pemoline induced chorea
and Gilles de la Tourette’s syndrome. Br. J. Psychiatry 143,
300–302.
Kaku, D. A., and Lowenstein, D. H. (1991). Emergence of
recreational drug abuse as a major risk factor for stroke in
young adults. Ann. Intern. Med. 113, 821–827.
Petitti, D. B., Sidney, S., and Quesenberry, C. (1998). Stroke and
cocaine or amphetamine use. Epidemiology 9, 596–600.
Rothrock, J. F., Rubenstein, R., and Lyden, P. D. (1988). Ischemic
stroke associated with methamphetamine inhalations. Neurol-
ogy 38, 589–592.
Amusia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMUSIA can be defined as the loss of a preexisting
musical talent. The deficit may manifest as an
inability to perceive differences in the elements of
music, to sing a song, or to play an instrument.
Various classifications of the amusias have been
developed based on motor versus sensory deficits,
higher versus lower cognitive functions, or anatomi-
cal areas.
As one of the five primary senses, the perception of
sound plays key roles in communication via speech
or the appreciation of music. Any sound can be
defined by its fundamental components: pitch,
intensity, and timbre. Respectively, these are the
sound’s frequency, loudness, and overtone. Musical
notes have additional properties that make them
unique. A note is played or sung for a certain period
of time, thus conferring the element of duration.
Several musical notes combined simultaneously
become a melody. Consecutive notes or melodies
form a harmony. Finally, rhythm is the temporal
sequence of musical notes or melodies.
Although sounds have bilateral representation in
the cerebral cortex, some functions of the brain are
unique to a particular hemisphere. For example, the
dominant hemisphere controls comprehension and
production of speech. However, the anatomical areas
responsible for processing music are less defined.
Various methods have been used to localize the
process of musical perception and performance.
Intraoperative electrical stimulation of the brain
by Penfield produced auditory hallucinations of
voices or songs and caused some subjects to sing.
The points of stimulation specific to music were
found to be in the superior temporal gyrus of either
hemisphere. Milner described impaired perception
for timbre and poor tonal memory following right
temporal lobectomies. Employing the dichotic listen-
ing technique in which different melodies were
presented simultaneously in each ear, Kimura con-
cluded that the left ear and right hemisphere were
more effective in melodic perception.
Bever and Chiarello found a left hemispheric
superiority for melody analysis in persons with
musical experience when compared to musically
naive listeners. They suggested that musical training
increases the left hemisphere’s contribution and
develops a more detailed schema in melody analysis.
122 AMUSIA
or subarachnoid hemorrhage. Because many of these
forms of stroke relate to drug-induced inflammation
of the cerebral blood vessels (vasculitis), cerebral
angiography may show irregular narrowing of distal
cerebral vessels, along with evidence of occlusion or
‘‘beading.’’
The management of intoxicated subjects depends
on their primary symptoms. In patients with acute
psychotic behavior, antipsychotic or neuroleptic
drugs used in other medical situations such as for
schizophrenia are indicated. It is very important to
pay close attention to blood pressure and body
temperature because amphetamines can cause hy-
perthermia and hypertension. Intoxicated patients
might be prone to develop a particular syndrome
found in association with neuroleptic drug treatment
known as neuroleptic malignant syndrome. In such
cases in which high fevers, muscle rigidity, and signs
of instability of the autonomic nervous system (blood
pressure and pulse control) predominate, patients are
placed in a quiet, cool room. In the case of
amphetamine-induced strokes, the management is
the same as that for other causes.
Whether amphetamines can cause permanent
psychiatric or cognitive disturbance after chronic
exposure is uncertain. Ten users of amphetamines
reported decreased memory or poor concentration
after achieving abstinence. There are also reports of
lasting psychosis or dementia. However, formal
studies of cognitive performance in chronic amphe-
tamine abusers have not been systematically per-
formed.
—Christopher G. Goetz
See also–Alcohol-Related Neurotoxicity;
Cocaine; Eating Disorders; Hallucinogens;
Heroin; Intoxication; Marijuana; Substance
Abuse
Further Reading
Bonthala, C. M., and West, A. (1983). Pemoline induced chorea
and Gilles de la Tourette’s syndrome. Br. J. Psychiatry 143,
300–302.
Kaku, D. A., and Lowenstein, D. H. (1991). Emergence of
recreational drug abuse as a major risk factor for stroke in
young adults. Ann. Intern. Med. 113, 821–827.
Petitti, D. B., Sidney, S., and Quesenberry, C. (1998). Stroke and
cocaine or amphetamine use. Epidemiology 9, 596–600.
Rothrock, J. F., Rubenstein, R., and Lyden, P. D. (1988). Ischemic
stroke associated with methamphetamine inhalations. Neurol-
ogy 38, 589–592.
Amusia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMUSIA can be defined as the loss of a preexisting
musical talent. The deficit may manifest as an
inability to perceive differences in the elements of
music, to sing a song, or to play an instrument.
Various classifications of the amusias have been
developed based on motor versus sensory deficits,
higher versus lower cognitive functions, or anatomi-
cal areas.
As one of the five primary senses, the perception of
sound plays key roles in communication via speech
or the appreciation of music. Any sound can be
defined by its fundamental components: pitch,
intensity, and timbre. Respectively, these are the
sound’s frequency, loudness, and overtone. Musical
notes have additional properties that make them
unique. A note is played or sung for a certain period
of time, thus conferring the element of duration.
Several musical notes combined simultaneously
become a melody. Consecutive notes or melodies
form a harmony. Finally, rhythm is the temporal
sequence of musical notes or melodies.
Although sounds have bilateral representation in
the cerebral cortex, some functions of the brain are
unique to a particular hemisphere. For example, the
dominant hemisphere controls comprehension and
production of speech. However, the anatomical areas
responsible for processing music are less defined.
Various methods have been used to localize the
process of musical perception and performance.
Intraoperative electrical stimulation of the brain
by Penfield produced auditory hallucinations of
voices or songs and caused some subjects to sing.
The points of stimulation specific to music were
found to be in the superior temporal gyrus of either
hemisphere. Milner described impaired perception
for timbre and poor tonal memory following right
temporal lobectomies. Employing the dichotic listen-
ing technique in which different melodies were
presented simultaneously in each ear, Kimura con-
cluded that the left ear and right hemisphere were
more effective in melodic perception.
Bever and Chiarello found a left hemispheric
superiority for melody analysis in persons with
musical experience when compared to musically
naive listeners. They suggested that musical training
increases the left hemisphere’s contribution and
develops a more detailed schema in melody analysis.

This was later supported by functional imaging.
Subjects using a nonanalytical strategy for tonal
memory had greater right than left asymmetry. Those
using an analytical strategy had increased metabolism
in the left posterior superior temporal lobe.
Relatively few studies have dealt with the execu-
tion of music. Smith showed that singing was
possible after resection of the left hemisphere. Bogen
and Gordon injected amobarbital into the carotid
artery to selectively depress either hemisphere and
then assessed the quality of singing melodies without
lyrics. Right hemispheric anesthesia produced mono-
tone singing but did not affect the rhythm of singing
or speech. Of the two patients that received left
carotid injection, one produced melodic but slurred
singing and the other could sing without difficulty.
The nondominant hemisphere appears to be more
important in the production of correct pitch and
melody. They also suggested that singing may result
from contributions of both hemispheres.
Oral-expressive or vocal amusia is perhaps the
most frequently described motor amusia. Various
permutations of the partial form may be seen: correct
production of a tone but inability to carry a melody,
correct production of a melody but inability to
produce a tone, or production of a tune with inability
to sing the words. Excluding those with aphasia,
most cases of oral-expressive amusia result from
anterior right hemispheric pathology. A singer was
unable to sing or whistle after traumatic injury to the
right frontal lobe. Following ligation of the right
common carotid artery, a musician could not sing,
whistle, or read a score. In both cases, the recogni-
tion of pitch and melody was intact.
Instrumental amusia is the loss of the ability to
play a musical instrument. Key to this definition is
the absence of dyspraxia for other motor skills. Botez
and Wertheim reported on a 26-year-old man who
had been playing the accordion since age 9. Follow-
ing removal of an oligodendroglioma in the right
frontal lobe, he could not accurately produce notes
or songs on the accordion but did not show any
motor apraxias. Also demonstrating oral-expressive
amusia, he had difficulty singing or whistling in tune,
but his perception of music was unaffected.
Musical agraphia is another form of motor
amusia. In the primary form, a trained musician
loses the skill to transcribe notes that are heard.
Impaired copying of a score has also been reported as
a form of musical agraphia. However, in most cases,
musical agraphia may represent impaired visual–
spatial skills rather than an amusia.
AMUSIA 123
A commonly described sensory amusia is receptive
amusia. In the most basic form, one cannot differ-
entiate notes of various pitch and timbre. Tone-deaf
persons often have difficulty with melodic apprecia-
tion. Reflecting the fact that receptive amusia may
result from an auditory agnosia, there is a close
association with understanding spoken language.
Musical alexia, another type of sensory amusia,
afflicts musicians trained to read musical scores. An
1892 article described a singer who could not read a
single note but was able to sing. Other patients with
musical alexia also had receptive aphasias or other
amusias.
The mixed motor and sensory amusias demon-
strate impairments of both the execution and percep-
tion of music. Musical amnesia refers to the inability
to name a tune or produce a melody. For example,
musicians cannot write the score or singers cannot
sing the tune when given the name of a familiar
melody. Another mixed amusia is the disorder of
rhythm, either impaired reproduction or discrimina-
tion of rhythmic patterns. Poor rhythm production is
often the result of general motor apraxia.
As with many neurological functions, the loss of
musical ability results primarily from destructive
lesions, such as traumatic injury, tumors, and
surgical resection. Ischemic stroke has also been
reported to cause amusia. Infarction of the right
temporal lobe has produced impaired tonal and
timbre discrimination. In another case, an infarct in
the right superior temporal and supramarginal gyri
caused expressive and receptive amusia. The organist
patient could sing and imitate nonmusical rhythms
but had difficulty reproducing rhythms on the organ
and identifying familiar melodies. A stroke in the left
parietal area resulted in disturbed melody and
rhythm production and recognition.
In contrast to structural and vascular damage,
recent case reports suggest that musical functions are
generally preserved in Alzheimer’s-type dementia.
Beatty described a musician who was able to play the
trombone despite dementia that was diagnosed as
Alzheimer’s disease at autopsy.
—Craig E. Hou
Further Reading
Benton, A. L. (1977). The amusias. In Music and the Brain (M.
Critchley and R. A. Henson, Eds.), pp. 378–397. Thomas,
Springfield, IL.
Bogen, J. E., and Gordon, H. W. (1971). Musical tests for
functional lateralization with intracarotid amobarbital. Nature
230, 523–525.
124 AMYGDALA

Damasio, A. R., and Damasio, H. (1977). Musical faculty and

cerebral dominance. In Music and the Brain (M. Critchley and
R. A. Henson, Eds.), pp. 141–155. Thomas, Springfield, IL.
Kimura, D. (1964). Left–right differences in the perception of
melodies. Q. J. Exp. Psychol. 16, 355–358.
Mazziotta, J. C., Phelps, M. E., Carson, R. E., et al. (1982).
Tomographic mapping of human cerebral metabolism: Audi-
tory stimulation. Neurology 32, 921–937.
Penfield, W., and Perot, P. (1963). The brain’s record of auditory
and visual experience. Brain 86, 595–696.

Amygdala
Encyclopedia of the Neurological Sciences Figure 1
Copyright 2003, Elsevier Science (USA). All rights reserved. (A) Coronal section through the human brain at the level of the
amygdala (only the right half of the brain is shown; the amygdala
THE AMYGDALA is an almond-shaped cluster of brain is actually found on both sides of the brain). Note that the
amygdala (shaded area) is located in the anteromedial part of the
nuclei located in the anteromedial part of the temporal lobe. (B) Enlargement of the amygdala at the level shown
temporal lobe. It is an anatomically complex region in A, illustrating the locations of the main amygdalar nuclei. AC,
that has connections with numerous brain areas. The anterior commissure; GP, globus pallidus.
amygdala is involved in a wide range of functions,
including emotion, biologically based behaviors,
attention, memory, and learning. It exhibits patho- fore, here the amygdalar nuclei will be divided into
logical and pathophysiological changes in several three main groups: the basolateral nuclear group, the
important neurological and psychiatric diseases, cortical nuclear group, and the centromedial nuclear
including temporal lobe epilepsy, Alzheimer’s disease, group. In addition, attenuated portions of the
schizophrenia, anxiety disorders, and depression. centromedial nuclear group extend forward (along
the main fiber pathways associated with the amyg-
dala) to become continuous with a brain region
GENERAL ANATOMY
The amygdala in human and nonhuman primates is
located in the anteromedial part of the temporal
lobe, where it lies ventral to the putamen and globus
palllidus, and anterior to the ventral portion of the
hippocampal formation (Figs. 1 and 2). It has a
similar position in nonprimates, such as the rat and
cat, in which the temporal lobes are not as well
developed. The amygdala in all mammals is anato-
mically complex, consisting of numerous nuclei that
often merge with their neighbors as well as with
adjacent nonamygdalar regions. It is customary to
categorize the amygdalar nuclei into groups that
exhibit distinctive anatomical or functional charac-
teristics. Traditionally, two major amygdalar nuclear
groups were recognized: a superficial ‘‘corticome-
dial’’ group (which included the cortical, medial, and Figure 2
central nuclei) and a deeper ‘‘basolateral’’ group Lateral view of the human brain illustrating the anatomy of the
(which included the lateral, basal, and accessory main cortical pathways conveying sensory information to the
amygdala. Note that somatosensory, auditory, and visual
basal nuclei). Recent studies, however, indicate that
information is transmitted to the amygdala over polysynaptic
the central and medial nuclei exhibit anatomical and cortical pathways; only higher order cortical areas involved in
histochemical characteristics that are distinct from processing the most complex sensory information in these
those of the rest of the corticomedial group. There- modalities have projections to the amygdala.
124 AMYGDALA

Damasio, A. R., and Damasio, H. (1977). Musical faculty and

cerebral dominance. In Music and the Brain (M. Critchley and
R. A. Henson, Eds.), pp. 141–155. Thomas, Springfield, IL.
Kimura, D. (1964). Left–right differences in the perception of
melodies. Q. J. Exp. Psychol. 16, 355–358.
Mazziotta, J. C., Phelps, M. E., Carson, R. E., et al. (1982).
Tomographic mapping of human cerebral metabolism: Audi-
tory stimulation. Neurology 32, 921–937.
Penfield, W., and Perot, P. (1963). The brain’s record of auditory
and visual experience. Brain 86, 595–696.

Amygdala
Encyclopedia of the Neurological Sciences Figure 1
Copyright 2003, Elsevier Science (USA). All rights reserved. (A) Coronal section through the human brain at the level of the
amygdala (only the right half of the brain is shown; the amygdala
THE AMYGDALA is an almond-shaped cluster of brain is actually found on both sides of the brain). Note that the
amygdala (shaded area) is located in the anteromedial part of the
nuclei located in the anteromedial part of the temporal lobe. (B) Enlargement of the amygdala at the level shown
temporal lobe. It is an anatomically complex region in A, illustrating the locations of the main amygdalar nuclei. AC,
that has connections with numerous brain areas. The anterior commissure; GP, globus pallidus.
amygdala is involved in a wide range of functions,
including emotion, biologically based behaviors,
attention, memory, and learning. It exhibits patho- fore, here the amygdalar nuclei will be divided into
logical and pathophysiological changes in several three main groups: the basolateral nuclear group, the
important neurological and psychiatric diseases, cortical nuclear group, and the centromedial nuclear
including temporal lobe epilepsy, Alzheimer’s disease, group. In addition, attenuated portions of the
schizophrenia, anxiety disorders, and depression. centromedial nuclear group extend forward (along
the main fiber pathways associated with the amyg-
dala) to become continuous with a brain region
GENERAL ANATOMY
The amygdala in human and nonhuman primates is
located in the anteromedial part of the temporal
lobe, where it lies ventral to the putamen and globus
palllidus, and anterior to the ventral portion of the
hippocampal formation (Figs. 1 and 2). It has a
similar position in nonprimates, such as the rat and
cat, in which the temporal lobes are not as well
developed. The amygdala in all mammals is anato-
mically complex, consisting of numerous nuclei that
often merge with their neighbors as well as with
adjacent nonamygdalar regions. It is customary to
categorize the amygdalar nuclei into groups that
exhibit distinctive anatomical or functional charac-
teristics. Traditionally, two major amygdalar nuclear
groups were recognized: a superficial ‘‘corticome-
dial’’ group (which included the cortical, medial, and Figure 2
central nuclei) and a deeper ‘‘basolateral’’ group Lateral view of the human brain illustrating the anatomy of the
(which included the lateral, basal, and accessory main cortical pathways conveying sensory information to the
amygdala. Note that somatosensory, auditory, and visual
basal nuclei). Recent studies, however, indicate that
information is transmitted to the amygdala over polysynaptic
the central and medial nuclei exhibit anatomical and cortical pathways; only higher order cortical areas involved in
histochemical characteristics that are distinct from processing the most complex sensory information in these
those of the rest of the corticomedial group. There- modalities have projections to the amygdala.

called the bed nucleus of the stria terminalis, which is
located in the septal region adjacent to the anterior
commissure. The term ‘‘extended amygdala’’ has
been used to designate the centromedial group and
its forward extensions.
CELL TYPES AND NEUROTRANSMITTERS
The cell types in the basolateral and cortical nuclear
groups are very similar to each other. Most of the
neurons in both groups are termed pyramidal cells
because they resemble the pyramidal neurons in the
cerebral cortex. They have large pyramidal-shaped
cell bodies and dendrites that exhibit a dense
covering of dendritic spines. The latter structures
are in synaptic contact with incoming axons from the
cerebral cortex and thalamus. The pyramidal cells
are the main ‘‘projection neurons’’ of these nuclear
groups (i.e., their axons project out of the amygdala
and allow the amygdala to activate other brain
regions). In addition, local branches of pyramidal cell
axons synapse with neighboring pyramidal and
nonpyramidal neurons. Pyramidal cells are thought
to utilize the amino acid glutamate as an excitatory
neurotransmitter.
The remaining cell types in the basolateral and
cortical nuclear groups are nonpyramidal neurons.
These cells, which are morphologically heteroge-
neous, have ovoid, fusiform, or multipolar cell bodies
and also dendrites that lack spines. The axons of
these cells establish synaptic contacts with neighbor-
ing amygdalar neurons but do not extend beyond the
amygdala (i.e., they are interneurons). They utilize g-
aminobutyric acid (GABA) as an inhibitory neuro-
transmitter. Subpopulations of these interneurons
contain different neuropeptides (e.g., somatostatin,
CCK, and neuropeptide Y) that are thought to
function as modulators of neurotransmission.
Unlike the nuclei of the basolateral and cortical
nuclear groups, the cell types of the centromedial
group do not resemble those of the cerebral cortex.
Neurons in the lateral part of the central nucleus
have ovoid cell bodies and dendrites with an
extremely dense covering of dendritic spines. They
closely resemble the medium-sized spiny neurons of
the adjacent caudate and putamen. Neurons in the
medial nucleus and medial part of the central nucleus
are spiny, but they have a lower spine density than
neurons in the lateral central nucleus. Although most
of the spiny neurons in the centromedial amygdala
are probably projection neurons that send axons to
other brain regions, other aspiny neurons have been
AMYGDALA 125
seen that may function as interneurons. Most of the
neurons in the centromedial nuclear group contain
neuropeptides and/or GABA. Neurons in the more
rostral parts of the extended amygdala (e.g., the bed
nucleus of the stria terminalis) are similar to the cell
types found in the central and medial amygdalar
nuclei.
FUNCTIONAL ANATOMY
OF THE AMYGDALA
In a classic study performed in 1939, Kluver and
Bucy found that lesions of the amygdalar region
rendered monkeys remarkably tame and hypoemo-
tional. These animals also exhibited inappropriate
sexual and feeding behavior. In general, it appeared
that these amygdalectomized monkeys exhibited a
specific type of visual agnosia characterized by the
inability to recognize the emotional or behavioral
significance of sensory stimuli. Subsequent studies
revealed that animals with amygdalar lesions also did
not respond appropriately to auditory, somatosen-
sory, and olfactory cues. Thus, it appears that the
amygdala is critical for producing appropriate
behavioral responses to biologically relevant sensory
stimuli and events in the external world. In fact, the
amygdala is thought to constitute an essential link
between brain regions that process sensory informa-
tion (e.g., the cerebral cortex and thalamus) and
brain regions responsible for eliciting emotional and
motivational responses (i.e., the hypothalamus,
brainstem, and striatum). For this reason, the
amygdala has been called the ‘‘sensory gateway to
the emotions.’’
Connections with the Cerebral Cortex
The amygdala has extensive reciprocal connections
with the olfactory cortex and with higher order
sensory association areas in the cerebral cortex. The
cortical and medial nuclei receive olfactory informa-
tion from the olfactory cortex and from the main and
accessory olfactory bulbs. The latter structure is part
of the vomeronasal system, which is involved in
detecting special odors (pheromones) that are pro-
duced by individuals of the same species. Phero-
mones elicit hormonal and behavioral responses
involved in species-specific reproductive and social
activities. The amygdala receives visual and auditory
information from the temporal lobe, somatosensory
and viscerosensory (including gustatory) information
from the insular lobe, and polysensory information
from the prefrontal cortex and hippocampal region
126 AMYGDALA
(including the subiculum, cornu ammonis, and the
entorhinal and perirhinal cortices). These nonolfac-
tory inputs primarily target the basolateral and, to a
lesser extent, the centromedial amygdala. The
basolateral but not the centromedial amygdalar
nuclei have reciprocal projections back to these same
cortical regions. It has been suggested that these
amygdalocortical projections may be important for
attention to emotionally and behaviorally significant
stimuli and for the storage of emotional memories.
Connections with Subcortical Brain Regions
The amygdala has connections with several subcor-
tical regions, including the basal forebrain, dience-
phalon, and brainstem. Some of these fibers course in
the ventral amygdalofugal pathway, which runs
ventral to the globus pallidus (Fig. 3). Others course
in a thin fiber bundle termed the stria terminalis,
which takes a more circuitous route dorsal to the
internal capsule. Projections from the dorsal thala-
mus to the amygdala arise mainly from the midline
thalamic nuclei and from the medial part of medial
geniculate nucleus and adjacent posterior thalamic
nuclei. These projections, which terminate primarily
in the basolateral and central amygdalar nuclei,
convey auditory, somatosensory, viscerosensory, and
visual information to the amygdala. Amygdalotha-
lamic projections are more limited and consist of
Figure 3
Medial view of the human brain illustrating the connections of the
amygdala (AMYG) with subcortical brain regions. All connections
are reciprocal except those to the caudate and nucleus accumbens,
which do not have projections back to the amygdala. HT,
hypothalamus; LC, locus ceruleus; PAG, periaqueductal gray;
VTA, ventral tegmental area.
projections from the central nucleus to the midline
thalamic nuclei and from the basolateral amygdala to
the mediodorsal thalamic nucleus. Since the latter
nucleus has extensive reciprocal connections with the
prefrontal cortex, it provides an indirect link by
which the amygdala can influence the activity of the
prefrontal region.
There are extensive reciprocal connections between
the medial portions of the preoptic/hypothalamic
region and the amygdala, particularly the medial
amygdalar nucleus, the cortical nuclei, and medial
portions of the basolateral amygdala. Consistent with
these connections, stimulation and lesion studies in
experimental animals have shown that the amygdala
is involved in behavior related to biological drives
and motivation, including arousal, orienting, and
sleep; fight or flight; feeding and drinking; and social,
reproductive, and maternal behavior. In humans,
these behaviors are typically associated with emo-
tional feelings (e.g., fear with flight and anger and
rage with fighting and defensive behavior). In each of
these affective states, the amygdala appears to elicit a
coordinated response consisting of autonomic, endo-
crine, and behavioral components by way of its
projections to various subcortical regions, especially
the hypothalamus. The endocrine responses produced
by amygdalar stimulation are due to its activation of
the hypothalamic–pituitary axis. Interestingly, many
of the hormones secreted by the glands targeted by
pituitary hormones can affect the activity of the
amygdala via receptors expressed by amygdalar
neurons. Thus, there is a very high density of estrogen
and androgen receptors in the medial and cortical
nuclei. Glucocorticoid receptors are located in all
portions of the amygdala, but particularly high levels
are found in the centromedial nuclear group.
Another significant subcortical target of the
amygdala that is important for producing behavioral
responses is the striatum (caudate, putamen, and
nucleus accumbens) (Fig. 3). This projection, which
is very robust, originates mainly in the basolateral
nuclear group and terminates primarily in the ventral
and medial portions of the striatum, including the
nucleus accumbens. There is no significant projection
of the striatum back to the amygdala. Lesion studies
indicate that the projections of the basolateral
amygdala to the striatum are important for control-
ling behavior related to the reinforcing properties of
sensory stimuli.
The central nucleus is the main amygdalar region
exhibiting connections with the brainstem and basal
forebrain. Among these targets are several brainstem

areas involved in visceral function, including the
parabrachial nucleus, dorsal vagal nucleus, and
nucleus solitarius. It also has projections to the
periaqueductal gray and reticular formation, which
are important for pain modulation and behavioral
responses to stress. In addition, the central nucleus
innervates several brain regions that give rise to
neurotransmitter-specific fiber systems that target the
amygdala and other forebrain areas. These regions
include the locus ceruleus (which provides a nora-
drenergic innervation of the amygdala and cortex),
the substantia nigra and ventral tegmental area
(which provide a dopaminergic innervation of the
amygdala and striatum), the raphe nuclei (which
provides a serotonergic innervation of the amygdala
and cortex), and the nucleus basalis (which provides
a cholinergic innervation of the amygdala and
cortex). The latter region is also innervated by
portions of the basolateral nuclear group. These
transmitter-specific systems are activated in certain
behavioral states, particularly during stress, and can
modulate amygdalar activities related to emotion,
attention, and memory.
FUNCTIONAL AND CLINICAL SIGNIFICANCE
OF THE HUMAN AMYGDALA
Consistent with results of animal experiments, recent
investigations of the human amygdala have shown
that it is critical for the recognition of the emotional
significance of auditory, visual, and olfactory stimuli,
including facial expressions, vocal intonation, and
expressive body movements. These findings derive
from studies of patients who have had the amygdalar
region surgically removed to control epilepsy, patients
who have a rare disease (Urbach–Wiethe disease) that
exhibits selective destruction of the amygdala, and
normal individuals who have been studied using
function magnetic resonance imaging. It has also been
demonstrated that electrical stimulation of the human
amygdala elicits fear, rage, or other emotions.
Investigations in humans have shown that the
amygdala is important for learning conditioned
emotional responses (usually fear) to sensory stimuli
and events. These findings are in agreement with
results of numerous animal studies showing that the
amygdala is essential for classic Pavlovian fear
conditioning to simple sensory cues and to complex
sensory representations, such as the context in which
an emotional event has occurred. Additional inves-
tigations in humans and animals have demonstrated
that the release of noradrenaline in the amygdala is
AMYGDALA 127
essential for the formation and recall of memories
involving emotional events.
Clinical interest in the amygdala stems from its
involvement in temporal lobe epilepsy, Alzheimer’s
disease, and emotional disorders. Temporal lobe
epilepsy (TLE) is the most common type of epilepsy
and is often characterized by psychiatric distur-
bances. The amygdala exhibits cell loss and gliosis
in TLE, and altered activity has been noted in
recording studies. Studies in the rat have shown that
the amygdala has the lowest threshold for ‘‘kind-
ling,’’ a phenomenon that has attracted a consider-
able amount of interest as a model of TLE. The
amygdala is also a major target of the classic
neuropathological changes seen in Alzheimer’s dis-
ease, and it has been suggested that degeneration of
the amygdala may be responsible for the emotional
lability seen in this disease.
The amygdala exhibits degeneration in schizophre-
nia, and recording studies have detected abnormal
activity in the amygdala in this condition. There is
evidence that dopamine levels are increased in the
amygdala in schizophrenia and that this brain region
may be one of the main sites of action of atypical
antipsychotic drugs (e.g., clozapine). Consistent with
numerous rodent studies implicating the amygdala in
fear and anxiety, there is evidence that anxiety dis-
orders in humans, such as posttraumatic stress, are
associated with excessive activity in the amygdala.
Moreover, studies in animals and humans have
shown that the amygdala has very high levels of
benzodiazepine receptors, which is critical for the
anxiolytic actions of these drugs. Recent positron
emission tomography investigations have demon-
strated that there is increased activity in the human
amygdala in major depression and that administra-
tion of antidepressive medication, which modulates
levels of noradrenaline and serotonin in the amygda-
la, causes a decrease in amygdalar activity that is
associated with amelioration of depressive symptoms.
—Alexander J. McDonald
See also–Aggression;
Amygdalohippocampectomy; Brain Anatomy;
Cerebral Cortex: Architecture and Connections;
Emotion, Neural Mechanisms of; Epilepsy,
Temporal Lobe; Post-Traumatic Stress Disorder
(PTSD); Temporal Lobe
Further Reading
Aggleton, J. P. (Ed.) (1992). The Amygdala: Neurobiological
Aspects of Emotion, Memory, and Mental Dysfunction. Wiley–
Liss, New York.
128 AMYGDALOHIPPOCAMPECTOMY
Gloor, P. (1997). The Temporal Lobe and Limbic System. Oxford
Univ. Press, New York.
LeDoux, J. (1996). The Emotional Brain. Simon & Schuster,
New York.
McGinty, J. F. (1999). Advancing from the Ventral Striatum to the
Extended Amygdala. Ann. N. Y. Acad. Sci. 877, xii–xv.
Price, J. L., Russchen, F. T., and Amaral, D. G. (1987). The limbic
region. II: The amygdaloid complex. In Handbook of Chemical
Neuroanatomy (A. Björklund, T. Hökfelt, and L. W. Swanson,
Eds.), Vol. 5, pp. 279–388. Elsevier, Amsterdam.
Amygdalohippocampectomy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMYGDALOHIPPOCAMPECTOMY is a selective form
of temporal lobectomy in which the mesial temporal
structures are removed with little or no resection of
the lateral temporal gyri. Amygdalohippocampec-
tomy is a refinement of temporal lobectomy that
seeks to minimize the traditional risks of visual and
language loss by preserving the functionality of the
lateral temporal gyri. Meanwhile, the mesial tempo-
ral structures responsible for generating seizures are
resected. The hippocampus, located in an area
known as Ammon’s horn, contains neurons with
specific properties that result in an especially low
threshold for neuronal damage. When damaged,
these cells become the focus of temporal lobe seizures
in a condition known as mesial temporal sclerosis
(MTS), even when the original damaging events to
the hippocampus may have abated. This concept is
the rationale underlying amygdalohippocampect-
omy. To date, the procedure has been associated
with excellent outcomes. In the hands of experienced
surgeons, seizures are controlled in up to 90% of
cases.
As early as 1958, a transventricular approach via
the middle temporal gyrus was used to remove the
amygdala and anterior 3 cm of the hippocampus.
Seizure control, encephalographic waveforms, and
neuropsychological outcomes associated with this
procedure were favorable. In the era preceding the
advent of microneurosurgical techniques, the techni-
cal difficulty of the procedure led to its abandonment
and the continued popularity of the standard
temporal lobectomy. In the 1970s, Yasargil intro-
duced a selective amygdalohippocampectomy per-
formed via a Sylvian fissure approach. Again, due to
its technical difficulty, this procedure and its poten-
tial for damaging vessels in the Sylvian fissure gained
only modest popularity. Although the lateral mesial
structures were not removed, they were functionally
disconnected because access through the Sylvian
fissure required transection of the temporal stem. In
the 1990s, Hori and Park described subtemporal
approaches for amygdalohippocampectomy. Both
procedures involved selective resection of mesial
temporal structures without lateral temporal resec-
tion or disconnection. However, the risks of the
subtemporal approach include excessive retraction
injury to both the temporal lobe and the vein of
Labbé.
One of the authors (KAS) has performed a novel
minimal-access, wand-guided amygdalohippocam-
pectomy via a transventricular approach in more
than 50 patients and has obtained excellent seizure
control. Under frameless stereotactic guidance, a
linear incision is centered over the most appropriate
sulcus (usually the inferior temporal sulcus) for
approaching the mesial temporal structures. A 2.5-
to 3-cm temporal craniotomy is made, and the sulcus
is opened with a microsurgical technique, sparing the
vessels and the pial surface of the gyri. The temporal
horn is entered, and the ependymal surface, choroid
plexus, and the landmarks of the hippocampus and
choroidal fissure are visualized. The uncus, amygda-
la, hippocampus, and parahippocampal gyrus are
then resected. A complete 4-cm hippocampal resec-
tion is thus possible, with no risk to the vein of Labbé
and almost no risk to Meyer’s loop. Because the
craniotomy is so small, the length of postoperative
recovery is markedly decreased compared to that of
other approaches. The preliminary results from a
study comparing the pre- and postoperative cognitive
function of these patients with that of patients
undergoing standard temporal lobectomy are en-
couraging. Consequently, minimal access selective
amygdalohippocampectomy has become our proce-
dure of choice for all patients with refractory
temporal lobe epilepsy caused by MTS.
—Ming Cheng and Kris A. Smith
See also–Amygdala; Aqueduct of Sylvius;
Hippocampus; Lobectomy, Temporal
Further Reading
Smith, K. A. (1997). Metastic brain tumors: gamma knife
radiosurgery or microsurgical resction? BNI Q. 13, 22–39.
Spencer, D. D., and Fried, I. (1993). Surgical aspects. In The
Treatment of Epilepsy. Principle and Practice (E. Wyllie, Ed.),
pp. 1079–1083. Lea & Febiger, Philadelphia.
128 AMYGDALOHIPPOCAMPECTOMY
Gloor, P. (1997). The Temporal Lobe and Limbic System. Oxford
Univ. Press, New York.
LeDoux, J. (1996). The Emotional Brain. Simon & Schuster,
New York.
McGinty, J. F. (1999). Advancing from the Ventral Striatum to the
Extended Amygdala. Ann. N. Y. Acad. Sci. 877, xii–xv.
Price, J. L., Russchen, F. T., and Amaral, D. G. (1987). The limbic
region. II: The amygdaloid complex. In Handbook of Chemical
Neuroanatomy (A. Björklund, T. Hökfelt, and L. W. Swanson,
Eds.), Vol. 5, pp. 279–388. Elsevier, Amsterdam.
Amygdalohippocampectomy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMYGDALOHIPPOCAMPECTOMY is a selective form
of temporal lobectomy in which the mesial temporal
structures are removed with little or no resection of
the lateral temporal gyri. Amygdalohippocampec-
tomy is a refinement of temporal lobectomy that
seeks to minimize the traditional risks of visual and
language loss by preserving the functionality of the
lateral temporal gyri. Meanwhile, the mesial tempo-
ral structures responsible for generating seizures are
resected. The hippocampus, located in an area
known as Ammon’s horn, contains neurons with
specific properties that result in an especially low
threshold for neuronal damage. When damaged,
these cells become the focus of temporal lobe seizures
in a condition known as mesial temporal sclerosis
(MTS), even when the original damaging events to
the hippocampus may have abated. This concept is
the rationale underlying amygdalohippocampect-
omy. To date, the procedure has been associated
with excellent outcomes. In the hands of experienced
surgeons, seizures are controlled in up to 90% of
cases.
As early as 1958, a transventricular approach via
the middle temporal gyrus was used to remove the
amygdala and anterior 3 cm of the hippocampus.
Seizure control, encephalographic waveforms, and
neuropsychological outcomes associated with this
procedure were favorable. In the era preceding the
advent of microneurosurgical techniques, the techni-
cal difficulty of the procedure led to its abandonment
and the continued popularity of the standard
temporal lobectomy. In the 1970s, Yasargil intro-
duced a selective amygdalohippocampectomy per-
formed via a Sylvian fissure approach. Again, due to
its technical difficulty, this procedure and its poten-
tial for damaging vessels in the Sylvian fissure gained
only modest popularity. Although the lateral mesial
structures were not removed, they were functionally
disconnected because access through the Sylvian
fissure required transection of the temporal stem. In
the 1990s, Hori and Park described subtemporal
approaches for amygdalohippocampectomy. Both
procedures involved selective resection of mesial
temporal structures without lateral temporal resec-
tion or disconnection. However, the risks of the
subtemporal approach include excessive retraction
injury to both the temporal lobe and the vein of
Labbé.
One of the authors (KAS) has performed a novel
minimal-access, wand-guided amygdalohippocam-
pectomy via a transventricular approach in more
than 50 patients and has obtained excellent seizure
control. Under frameless stereotactic guidance, a
linear incision is centered over the most appropriate
sulcus (usually the inferior temporal sulcus) for
approaching the mesial temporal structures. A 2.5-
to 3-cm temporal craniotomy is made, and the sulcus
is opened with a microsurgical technique, sparing the
vessels and the pial surface of the gyri. The temporal
horn is entered, and the ependymal surface, choroid
plexus, and the landmarks of the hippocampus and
choroidal fissure are visualized. The uncus, amygda-
la, hippocampus, and parahippocampal gyrus are
then resected. A complete 4-cm hippocampal resec-
tion is thus possible, with no risk to the vein of Labbé
and almost no risk to Meyer’s loop. Because the
craniotomy is so small, the length of postoperative
recovery is markedly decreased compared to that of
other approaches. The preliminary results from a
study comparing the pre- and postoperative cognitive
function of these patients with that of patients
undergoing standard temporal lobectomy are en-
couraging. Consequently, minimal access selective
amygdalohippocampectomy has become our proce-
dure of choice for all patients with refractory
temporal lobe epilepsy caused by MTS.
—Ming Cheng and Kris A. Smith
See also–Amygdala; Aqueduct of Sylvius;
Hippocampus; Lobectomy, Temporal
Further Reading
Smith, K. A. (1997). Metastic brain tumors: gamma knife
radiosurgery or microsurgical resction? BNI Q. 13, 22–39.
Spencer, D. D., and Fried, I. (1993). Surgical aspects. In The
Treatment of Epilepsy. Principle and Practice (E. Wyllie, Ed.),
pp. 1079–1083. Lea & Febiger, Philadelphia.
 AMYLOIDOSIS 129

structures. As shown in Table 1, their precursor

Amyloidosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMYLOIDOSIS AND AMYLOID PROTEINS
THE TERM amyloidosis refers to a heterogeneous
group of disorders characterized by the extracellular
deposition of insoluble fibrils in different tissues and
organs leading to cellular damage, organ dysfunc-
tion, and eventually death. From the clinical stand-
point, amyloid diseases can be classified as systemic,
when several organs are affected by amyloid
deposits, or localized, when amyloid lesions are
restricted to a single organ or tissue. In both
instances, hereditary conditions have been identified.
Amyloid fibrils are composed of self-assembled, low-
molecular-weight peptides usually representing frag-
ments of larger precursor molecules normally present
in body fluids. In humans, 24 different proteins are
known to self-assemble and form fibrillar amyloid
molecules are totally unrelated proteins codified in
different chromosomes and exhibiting a wide variety
of biological functions (i.e., immune system-related
molecules, apolipoproteins, transport and regulatory
components, coagulation factors, enzymes, protease
inhibitors, hormones, cytoskeletal proteins, cell
adhesion molecules, and infectious agents). Despite
these differences, all amyloid proteins share a
number of biochemical and structural properties.
Collectively, they are products of normal genes,
although several amyloid precursors have been
shown to contain abnormal amino acid substitutions
that can impose an increased potential for self-
aggregation. All amyloid peptides are molecules in
the mass range of 4 to 30 kDa, and many of them are
heterogeneous at the amino- and/or carboxyl-term-
inal ends. In general, amyloids are rich in b-pleated
sheet secondary structure, a conformation largely
responsible for their high tendency to aggregate and
polymerize and for their tinctoreal characteristics
with Congo red or thioflavin S. All these molecules

Table 1 HUMAN AMYLOID PROTEINS

Precursor function Precursor molecule Chromosome Amyloid protein Systemic/localized CNS involvement

Immune system-related molecules Ig l light chain 22 AL S, L No

Ig k light chain 2 AL S, L No
Ig heavy chain 14 AH S, L No
b2-microglobulin 15 Ab2M S No
Apolipoproteins ApoSAA 11 AA S No
apoAI 11 AApoAI S No
apoAII 1 AApoAII S No
Regulatory proteins Gelsolin 9 AGel S Yes
Transport proteins Transthyretin 18 ATTR S Yes
Lactoferrin 3 ALac L No
Coagulation factors Fibrinogen a chain 4 AFib S No
Hormones (Pro)calcitonin 11 ACal L No
Prolactin 6 Apro L No
Atrial natriuretic factor 1 AANF L No
Islet amyloid polypeptide 12 AIAPP L No
Insulin 11 Ains L No
Enzymes Lysozyme 12 Alys S No
Protease inhibitors Cystatin C 20 Acys S Yes
Infectious agents Prion protein 20 AprPsc L Yes
Unknown function Lactadherin 15 Medin L? No
Ab protein precursor 21 Ab L Yes
ABri protein precursor 13 ABri S Yes
ADan protein precursor 13 ADan L? Yes
Cell adhesion? Keratoepithelin 5 AKE L No
Cytoskeletal proteins Keratin 12,17 AKer L No
130 AMYLOIDOSIS

self-assemble into long, unbranched, B8-nm-wide

twisted fibrils that are highly insoluble and show
poor antigenic properties—features that preclude
their effective physiological removal by macrophages.

CEREBRAL AMYLOIDOSIS
Only seven of the amyloid proteins listed in Table 1
are known to cause fibrillar deposits in the central
nervous system (CNS), resulting in neurological
disorders associated with cognitive deficits, demen-
tia, stroke, cerebellar and extrapyramidal signs, or a
combination of these (Table 2). Amyloid lesions in
the CNS are found in the form of (i) cerebral amyloid
angiopathy, consisting of Congo red/thioflavin S-
positive fibrillar deposits affecting the media and
adventitia of medium and small cerebral arteries and
arterioles as well as many cerebral capillaries; (ii)
parenchymal preamyloid lesions, immunohisto-
chemically identified by their reactivity with specific
anti-amyloid antibodies, their lack of staining with
Congo red or thioflavin S, and their amorphous
nonfibrillar structure when observed under the
electron microscope; and (iii) parenchymal amyloid
deposits, usually adopting the form of plaques
containing extensive Congo red/thioflavin S-positive
fibrillar material immunoreactive with specific anti-
amyloid antibodies.

Ab-RELATED CEREBRAL AMYLOIDOSIS

Late-onset or sporadic Alzheimer’s disease (AD) is
the most common form of dementia in humans older
than age 60. The major neuropathological features
that characterize AD are shown in Fig. 1. Amyloid
deposits affect leptomeningeal and cerebral vessel
walls (Figs. 1A and 1B), whereas parenchymal
amyloid lesions are present as preamyloid lesions

Table 2 HUMAN CEREBRAL AMYLOIDOSIS RELATED TO Figure 1

DEMENTIA AND/OR STROKE Neuropathological lesions in Alzheimer’s disease. (A)
Amyloid Associated disorders Cerebrovascular Ab deposits detected in leptomeningeal vessels by
anti-Ab antibodies [4G8 (anti-Ab17–24) immunohistochemistry;
Ab Sporadic and familial Alzheimer’s disease, Down’s original magnification  40]. (B) Congo red staining of a parallel
syndrome, sporadic congophilic angiopathy, section observed under polarized light (original magnification
normal aging  40). (C) Hippocampal neuritic plaques containing a central core
APrPsc Creutzfeldt–Jacob disease, Gerstmann–Sträussler– (4G8 immunohistochemistry; original magnification  70). (D)
Scheinker disease, fatal familial insomnia, kuru Purified amyloid fibrils extracted from leptomeningeal vessels
observed under the electron microscope (uranyl acetate negative
ACys HCHWA-Icelandic type
staining; original magnification  100,000). (E) Neurofibrillary
ATTR Meningovascular amyloidosis tangles in the temporal cortex (hyperphosphorylated-tau
AGel Familial amyloidosis Finish type immunohistochemistry; original magnification  70). (F) Purified
ABri Familial British dementia paired helical filaments observed under the electron microscope
ADan Familial Danish dementia (uranyl acetate negative staining; original magnification
 120,000).
 AMYLOIDOSIS 131

(or diffuse plaques, not shown) and neuritic plaques
that often show a compact central core (Fig. 1C).
Cerebrovascular and parenchymal lesions are com-
posed of fibrillar self-aggregates of Ab protein
(Fig. 1D). Ab is a degradation product of a larger
precursor AbPP codified by a single gene on
chromosome 21. Although morphologically indis-
tinguishable, vascular Ab is two residues shorter than
parenchymal Ab (Ab40 vs Ab42). The reasons for
this selectivity as well as its importance for the
etiopathogenesis of the disease are not known. Ab
deposits are also typical in trisomy 21 (Down’s
syndrome), in sporadic congophilic angiopathy, and
in normal aging. An additional pathological marker
of AD is the presence of neurofibrillary tangles,
which are intraneuronal cytoplasmic deposits of
hyperphosphorylated tau (Fig. 1E) in the form of
paired helical filaments (Fig. 1F).
Early onset (o60 years) familial AD accounts for
less than 5% of the total AD cases. Mutations in
three different genes codifying for AbPP (chromo-
some 21), presenilin 1 (PS1; chromosome 14), and
presenilin 2 (PS2; chromosome 1) have been linked
to familial AD. PS1 and PS2 mutations affect the
levels of Ab production, whereas nucleotide changes
in the AbPP molecule either affect the levels of Ab (if
the mutations are located immediately outside the Ab
sequence) or produce a mutated Ab peptide. The
genetic variants that concentrate in the middle of the
Ab molecule (positions 21–23, corresponding to
codons 692–694 of AbPP) are invariably associated
with extensive cerebrovascular pathology. Figure 2
illustrates the known mutations in the AbPP mole-
cule. The first mutation described in the AbPP gene
was found in a condition known as hereditary
cerebral hemorrhage with amyloidosis, Dutch type
(HCHWA-Dutch), which is an autosomal dominant
disorder clinically defined by recurrent strokes,
vascular dementia, and fatal cerebral bleeding in
the fifth to sixth decades of life. Histologically, the
disease is characterized by a massive amyloid
deposition in the walls of leptomeningeal and
cortical arteries and arterioles as well as in vessels
in the brainstem and cerebellum. In addition to the
vascular involvement, there are a moderate number
of parenchymal amyloid deposits resembling the
diffuse preamyloid plaques seen in AD, whereas
dense plaque cores and neurofibrillary tangles are

Figure 2
Ab mutants: genetic defects and phenotypic expression. Schematic representation of the segment 665–723 of the AbPP molecule (numbers
above the sequence). The N and C termini of the Ab peptide are indicated with numbers below the sequence. Target amino acids are shown in
open circles and their respective mutants in open squares. Open arrows indicate a phenotype predominately related to cerebral hemorrhage
followed by late-onset dementia, whereas solid arrows indicate clinically early-onset dementia phenotypes.
132 AMYLOIDOSIS
consistently absent. The amyloid subunit in
HCHWA-Dutch is homologous to Ab, bearing a
single nucleotide change (G for C) at codon 693 of
AbPP resulting in a single amino acid substitution
(Gln for Glu) at position 22. The Flemish mutation, a
C to G transversion at codon 692, results in an Ala to
Gly substitution at position 21 and a clinical
phenotype of presenile dementia and cerebral he-
morrhage. At position 22 of Ab, in addition to the
Dutch mutant, two other genetic variants have been
described: The Arctic mutation (A to G at codon
693, resulting in the replacement of Glu for Gly)
presents as an early onset AD with prominent
vascular symptomatology, and the Italian mutation
(G to A at codon 693, bearing Lys for Glu) is
characterized by presenile dementia with cerebral
hemorrhage. At position 23, the Iowa mutation has
been recently described, in which a G to A transition
at codon 694 results in the substitution of the
normally occurring Asp residue for Asn and a clinical
manifestation of aphasic dementia, severe CAA, and
leukoencephalopathy.
Many of the pathogenic missense mutations
described outside the amyloid Ab sequence cluster
closer to the amino acids recognized by the b- and g-
secretases that release the amyloidogenic peptide
from the precursor molecule. In general, these
mutations seem to affect AbPP processing and result
in an increased selective production of the amyloido-
genic Ab species. At codons 670 and 671, at the b-
secretase processing site, the Swedish double-muta-
tion shows Lys to Met and Asn to Leu substitutions,
respectively. Other pathogenic mutations occur close
to the g-secretase site. An Ile to Val substitution at
codon 716 and various missense mutations occurring
at codon 717 have been described. In this last
instance, the substitutions correspond to the change
of the normally occurring Val for Ile, Phe, or Gly and
have been associated with familial AD in Anglo-
Saxon, Italian, and Japanese kindred.
PRION-RELATED CEREBRAL AMYLOIDOSIS
A unique category in the amyloid disorders is
constituted by the prion-related diseases, in which
the etiology is thought to be related to the conver-
sion, by a posttranslational process, of the normal
prion protein PrPC into an infectious and pathogenic
form PrPSC. The infectious etiological agent is devoid
of nucleic acids and was called prion to denote its
proteinaceous nature and distinguish it from viruses
and viroids. The infective protein PrPSC differs from
the normal counterpart only in the conformational
folding, in which a high b-sheet content results in its
high propensity to aggregation and its relative
resistance to proteolysis. This group of diseases
includes Creutzfeldt–Jakob disease (CJD), kuru,
Gerstmann–Sträussler–Scheinker disease (GSS), and
fatal familial insomnia in humans as well as scrapie,
chronic wasting disease, and bovine spongiform
encephalopathy in animals. Extensive cortical spon-
giform change, gliosis, and neuronal loss are
common although not invariable features of these
disorders. The parenchymal amyloid load, character-
istic of the autosomal dominant GSS, is only present
in approximately 10% of the CJD cases, whereas
amyloid angiopathy is virtually absent in all of them.
Several mutations of the PrP gene are known to
cause inherited or familial prion-related diseases. The
point mutations associated with CJD and spongiform
degeneration result from amino acid substitutions at
positions 178 (Asp to Asn), 180 (Val to Ile), 200 (Glu
to Lys), 210 (Val to Ile), and 232 (Met to Arg). Some
of the point mutations associated with GSS correlate
with the invariable presence of multicentric plaques
and are located at codons 102 (Pro to Leu), 105 (Pro
to Leu), and 117 (Ala to Val). Other amino acid
substitutions in GSS are associated with the presence
of plaques and neurofibrillary tangles such as those
corresponding to codons 145 (Tyr to Stop), 198 (Phe
to Ser), and 217 (Glu to Arg). The Tyr to Stop
mutation at codon 145 constitutes the only case
described in which PrP amyloid deposition occurs in
leptomeningeal and parenchymal blood vessels.
CYSTATIN C-RELATED CEREBRAL
AMYLOIDOSIS
Hereditary cerebral hemorrhage with amyloidosis,
Icelandic type (HCHWA-Icelandic), is an autosomal
dominant disorder characterized by massive amyloid
deposition within small arteries and arterioles of
leptomeninges, cerebral cortex, basal ganglia, brain-
stem, and cerebellum. Seven pedigrees have been
described in small rural communities of western
Iceland. Although brain involvement is the main
clinicopathological feature, silent amyloid deposits
are also present in peripheral tissues, such as skin,
lymph nodes, spleen, salivary glands, and seminal
vesicles. The main clinical hallmark of the disease is
cerebral hemorrhage with fatal outcome in the third
to fourth decade of life in approximately 50% of the
cases. Strokes are rare after the age of 50, and
cognitive decline followed by dementia may occur in

those cases that survive the hemorrhagical episodes.
The constituent protein of the amyloid deposits in
HCHWA-Icelandic is a genetic variant of cystatin C
(ACys-Q68), a ubiquitously expressed inhibitor of
cysteine proteases codified by a single gene on
chromosome 20. The 110-residue-long ACys-Q68
amyloid subunit is degraded at the N terminus,
starting at position 11 of the normal cystatin C, and
bears a single amino acid substitution (Gln for Leu)
as a result of a point mutation (A for T) at codon 68.
TRANSTHYRETIN-RELATED
CEREBRAL AMYLOIDOSIS
Familial transthyretin (TTR) amyloidosis is usually
associated with peripheral neuropathy and involve-
ment of visceral organs, whereas signs of CNS
involvement are exceptional. Cerebral amyloid de-
posits consisting of TTR variants ATTR-G18 and
ATTR-G30 have been reported in two unrelated
families carrying different point mutations in the
TTR gene mapped to chromosome 18. In the kindred
of Hungarian origin (56 members spanning four
generations), the major clinical symptoms include
short-term memory decline, hearing loss, cerebellar
dysfunction with ataxia, and bilateral pyramidal
dysfunction with progressive spasticity. The onset of
symptoms varies from ages 36 to 53, with death
occurring between ages 51 and 60. Extensive
amyloid deposition is present in meningeal vessels
and subpial areas; although not associated to the
clinical symptoms, small systemic deposits are
present in kidney, skin, ovaries, and peripheral
nerves. A single nucleotide change (A for G) at
codon 18 results in the presence of Gly instead of
Asp. In the kindred of German ancestry identified in
Ohio (59 members spanning four generations), the
main clinical symptoms are slowly progressive
dementia, seizures, ataxia, hemiparesis, decreased
vision, and mutism. The age of onset is 46–56 years
and the duration of the disease varies between 3 and
26 years. Amyloid deposits are present in the
arachnoid and arachnoid blood vessels in the brain
and spinal cord, with small and medium-sized vessels
being the most severely affected. Interestingly,
vascular amyloid is not detectable after the vessels
penetrate into the brain parenchyma. Amyloid
deposits are also present in choroid plexus, ventri-
cular regions, and, infrequently, vessels of virtually
all visceral organs, skin, and skeletal muscle. In this
family, a T for G mutation at codon 30 results in the
substitution of Val for Gly in the TTR molecule.
AMYLOIDOSIS 133
GELSOLIN-RELATED CEREBRAL
AMYLOIDOSIS
Familial amyloidosis, Finnish type (FAF) is an
autosomal dominant systemic form of amyloidosis
characterized by progressing cranial and peripheral
neuropathy, dry and itchy skin, intermittent protei-
nuria, and cardiac abnormalities. Patients have
typical faces with droopy eyelids and protruding
lips. Corneal lattice dystrophy, lace-like deposition of
amyloid within the stroma, is the earliest clinical
finding of the syndrome. Amyloid deposition in the
spinal and cerebral blood vessel walls, meninges, and
spinal nerve roots and sensory ganglia is an essential
feature of this form of systemic amyloidosis that
contributes to the CNS symptoms. The amyloid
fibrils (AGel) are formed by a 7-kDa internal
degradation product of human gelsolin, a ubiquitous
regulatory protein involved in actin polymerization.
AGel spans from position 173 to residue 243 of the
gelsolin protein, bearing an amino acid substitution
at position 187 (Asn instead of Asp) due to a single G
to A transition at position 654, the first nucleotide at
codon 187. FAF cosegregates with the mutation, and
the disease is particularly severe in those homozy-
gously affected. The mutation has been detected in
Finnish, Dutch, American, and Japanese families. A
different amino acid substitution at codon 187 has
been described in patients of Danish and Czech
origin suffering the same disorder. In these cases,
a transition of G to T at the same codon results in
the presence of a Tyr instead of the normally occur-
ring Asp.
ABRI-RELATED CEREBRAL AMYLOIDOSIS
Familial British dementia (FBD) is an autosomal
dominant disorder characterized by progressive
dementia, spastic tetraparesis, and cerebellar ataxia,
with an age of onset in the fourth or fifth decade.
This extensive pedigree of British origin (343
individuals over nine generations dating back to
B1780), originally described by Worster-Drought in
1933, is the first known cerebral amyloidosis
published in the Western world. Personality changes
are the earliest manifestations, with the patients
becoming either irritable or depressed. The spastic
paralysis is by far more profound than that seen in
GSS or in AD. Pseudo-bulbar palsy and dysarthria
are universal and all patients progress to a chronic
vegetative state: They become mute, unresponsive,
quadriplegic, and incontinent. Neuropathologically,
134 AMYLOIDOSIS
patients with FBD present severe and widespread
amyloid angiopathy of the brain and spinal cord,
with perivascular amyloid plaque formation; peri-
ventricular white matter changes resembling Bins-
wanger’s leukoencephalopathy; neuritic and
nonneuritic amyloid plaques affecting cerebellum,
hippocampus, amygdala, and, occasionally, cerebral
cortex; and neurofibrillary degeneration of hippo-
campal neurons. Due to the extensive cerebrovascu-
lar involvement, the disorder was previously
designated familial cerebral amyloid angiopathy–
British type and cerebrovascular amyloidosis–British
type. Despite extensive amyloid deposition of the
CNS vasculature, large intracerebral hemorrhage is a
rare feature of the disease. Amyloid fibrils are
composed of a 4-kDa peptide (ABri), a degradation
product of a larger 277-amino acid transmembrane
protein codified by a single gene BRI2 (also known
as ITM2B) located on the long arm of chromosome
13. In patients with FBD, a single nucleotide
substitution (T to A, codon 267) results in the
presence of an Arg residue in place of the stop codon
normally occurring in the wild-type precursor
molecule and a longer open-reading frame of 277
amino acids instead of 266. The ABri amyloid
peptide is formed by the 34 C-terminal amino acids
of the mutated precursor protein, and it is the first
example of an amyloid molecule synthesized de novo
as a result of a point mutation in the stop codon of its
corresponding precursor protein.
ADAN-RELATED CEREBRAL AMYLOIDOSIS
Familial Danish dementia (FDD), also known as
heredopathia ophthalmo-oto-encephalica, is an early
onset autosomal dominant disorder originating in the
Djürsland peninsula, Denmark. The disease, identi-
fied in nine cases spanning three generations of a
single family, is clinically characterized by the
development of cataracts at Bage 20, deafness at
Bage 30, followed by progressive cerebellar ataxia
before the age of 40, and paranoid psychosis and
dementia 10 years later. Most patients die in their
fifth or sixth decade of life. The disease is neuro-
pathologically characterized by diffuse brain atro-
phy, with a particularly severe involvement of the
cerebellum, cerebral cortex, and white matter, as well
as by the presence of very thin and almost demye-
linated cranial nerves. Neuropathologically, there is a
widespread amyloid angiopathy in the blood vessels
of the cerebrum, choroid plexus, cerebellum, spinal
cord, and retina. The presence of parenchymal
plaques and neurofibrillary tangles is the major
histological finding in the hippocampus, whereas
the cerebral white matter also shows some ischemic
lesions. Amyloid deposits in FDD are composed of a
4-kDa peptide (ADan) with N-terminal homology to
the ABri, the peptide producing amyloid deposits in
FBD. Molecular genetic analysis of the BRI2 gene in
the Danish kindred showed a different defect, namely
the presence of a 10-nucleotide duplication (795–
796ins-TTTAATTTGT) between codons 265 and
266, three nucleotides before the normal stop codon
267. The decamer duplication mutation produces a
frame shift generating a larger-than-normal precur-
sor protein, of which the amyloid subunit ADan
comprises the last 34 C-terminal amino acids. The
first 22 amino acids of the ADan and ABri peptides
are identical, whereas the last 12 residues are
completely different.
CONCLUSIONS
Several unrelated molecules are known to produce
amyloid deposits in the CNS. In many instances,
amyloid deposition manifests as cerebral hemor-
rhage, whereas in other cases it is associated with
memory loss and dementia. Clinical, biochemical,
and genetic studies revealed that different pheno-
types may occur among pedigrees with a similar
genetic defect and that distinct genetic alterations can
produce a similar phenotypic expression. The mole-
cular mechanisms associated with this dichotomy are
not well understood. The finding that, in addition to
Ab, other amyloid peptides can lead to neuronal loss
and dementia has strengthened the hypothesis that
amyloid proteins are important in the initiation of
neurodegeneration.
—Agueda Rostagno and Jorge Ghiso
See also–Alzheimer’s Disease; Creutzfeldt–Jakob
Disease (CJD); Dementia; Gerstmann–Straussler–
Scheinker Syndrome; Neuropathies, Amyloid
Further Reading
Clark, C., and Trojanowski, J. (Eds.) (2000). Neurodegenerative
Dementias. McGraw-Hill, New York.
Esiri, M., and Morris, J. (Eds.) (1997). The Neuropathology of
Dementia. Cambridge Univ. Press, Oxford.
Growdon, J., Wurtman, R., Corkin, S., and Nitsch, R. (Eds.)
(2000). The molecular basis of dementia. Ann. N. Y. Acad. Sci.
920.
Kalaria, R., and Ince, P. (Eds.) (2000). Vascular factors in
Alzheimer’s disease. Ann. N. Y. Acad. Sci. 903.

Prusiner, S. B. (1998). Prions. Proc. Natl. Acad. Sci. USA 95,
13363–13383.
St. George-Hyslop, P. (2000). Molecular genetics of Alzheimer’s
disease. Biol. Psychiatry 47, 183–199.
Amyotrophic Lateral
Sclerosis (ALS)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMYOTROPHIC LATERAL SCLEROSIS (ALS) is the most
common form of motor neuron disease. Originally
described by Charcot in 1874, the disease is defined
by clinical, electrophysiological, or neuropathic
evidence of progressive pathology affecting the
anterior horn cell in the spinal cord [lower motor
neuron (LMN)] and the pyramidal motor neuron in
the brain [upper motor neuron (UMN)] (Table 1).
ALS remains a diagnosis of exclusion and the
workup must be sufficient to rule out other disease
processes that might explain the same clinical and
electrophysiological signs. The clinical signs and
symptoms of upper verses lower motor neuron
involvement are distinct. Although the manifestation
of these signs varies in individual patients, accurate
diagnosis is dependent on the combination of specific
findings on the neurological examination (Table 1)
and exclusion of other disorders (Table 2).
In 1998, the World Federation of Neurology
proposed the first formal grading of diagnostic
criteria, referred to as the El Escorial criteria for
ALS. These were reviewed and modified by the
World Federation of Neurology at the Airlie House
Conference in Warrington, Virginia. The resulting
clinical guidelines were established primarily to
Table 1 CLINICAL SYMPTOMS AND SIGNS RELATED TO UPPER AND LOWER MOTOR NEURON DYSFUNCTION IN AMYOTROPHIC
LATERAL SCLEROSIS
Upper motor neuron Lower motor neuron
Moderate weakness Severe weakness
Hyperreflexia Hyporeflexia
Pathological reflexes Muscle atrophy
Pseudobulbar effect Fasciculations
Spasticity Muscle cramps
Loss of dexterity Muscle hypotonicity or flaccidity
Slowed movements
AMYOTROPHIC LATERAL SCLEROSIS 135
provide the selection of a more homogeneous group
of patients for participation in clinical trials. These
published criteria have categorized the clinical
diagnosis of ALS into various levels of certainty
depending on the presence and extent of LMN and
UMN signs together in the same topographical
anatomical region in the bulbar, cervical, thoracic,
or lumbosacral spinal cord (Fig. 1).
The spectrum of motor neuron disease is vast. ALS
represents only one type of motor neuron disease
affecting the UMN and LMN in several areas along
the neuraxis. Other motor neuron diseases selectively
affect isolated populations of motor neurons and,
consequently, may result from a different pathophy-
siology and have a different prognosis (Table 3).
EPIDEMIOLOGY
The overall incidence of ALS has been estimated in
the range of 2–5 cases per 100,000 population with a
slight male predominance. Disease prevalence has
been estimated at approximately 9 or 10 per 100,000
population. Obtaining such estimates has been
challenging due to the lack of a single reporting
mechanism for new diagnoses. Historically, patients
have been given a grim prognosis and, consequently,
many may not have presented for regular follow-up.
Recently, aggressive symptomatic management and
clinical trials have likely resulted in an increase in the
population of actively treated ALS patients. Newly
developed monitoring protocols, including a national
database, may eventually provide better estimates of
incidence and prevalence.
Sporadic ALS, in which the etiology remains
unknown, accounts for 90–95% of cases. Five to
10% of all patients have a family history of ALS,
usually inherited in an autosomal dominant pattern
Neuropathological and electrodiagnostic evidence
Motor neuron loss in the motor cortex and spinal cord
Accumulation of phosphorylated neurofilaments
Mitochondrial swelling
Ubiquitin inclusions
Bunina bodies
Denervation atrophy on muscle biopsy
Active (increased spontaneous activity) and chronic (motor unit
remodeling, decreased recruitment) signs on electrodiagnostic testing

Prusiner, S. B. (1998). Prions. Proc. Natl. Acad. Sci. USA 95,
13363–13383.
St. George-Hyslop, P. (2000). Molecular genetics of Alzheimer’s
disease. Biol. Psychiatry 47, 183–199.
Amyotrophic Lateral
Sclerosis (ALS)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AMYOTROPHIC LATERAL SCLEROSIS (ALS) is the most
common form of motor neuron disease. Originally
described by Charcot in 1874, the disease is defined
by clinical, electrophysiological, or neuropathic
evidence of progressive pathology affecting the
anterior horn cell in the spinal cord [lower motor
neuron (LMN)] and the pyramidal motor neuron in
the brain [upper motor neuron (UMN)] (Table 1).
ALS remains a diagnosis of exclusion and the
workup must be sufficient to rule out other disease
processes that might explain the same clinical and
electrophysiological signs. The clinical signs and
symptoms of upper verses lower motor neuron
involvement are distinct. Although the manifestation
of these signs varies in individual patients, accurate
diagnosis is dependent on the combination of specific
findings on the neurological examination (Table 1)
and exclusion of other disorders (Table 2).
In 1998, the World Federation of Neurology
proposed the first formal grading of diagnostic
criteria, referred to as the El Escorial criteria for
ALS. These were reviewed and modified by the
World Federation of Neurology at the Airlie House
Conference in Warrington, Virginia. The resulting
clinical guidelines were established primarily to
Table 1 CLINICAL SYMPTOMS AND SIGNS RELATED TO UPPER AND LOWER MOTOR NEURON DYSFUNCTION IN AMYOTROPHIC
LATERAL SCLEROSIS
Upper motor neuron Lower motor neuron
Moderate weakness Severe weakness
Hyperreflexia Hyporeflexia
Pathological reflexes Muscle atrophy
Pseudobulbar effect Fasciculations
Spasticity Muscle cramps
Loss of dexterity Muscle hypotonicity or flaccidity
Slowed movements
AMYOTROPHIC LATERAL SCLEROSIS 135
provide the selection of a more homogeneous group
of patients for participation in clinical trials. These
published criteria have categorized the clinical
diagnosis of ALS into various levels of certainty
depending on the presence and extent of LMN and
UMN signs together in the same topographical
anatomical region in the bulbar, cervical, thoracic,
or lumbosacral spinal cord (Fig. 1).
The spectrum of motor neuron disease is vast. ALS
represents only one type of motor neuron disease
affecting the UMN and LMN in several areas along
the neuraxis. Other motor neuron diseases selectively
affect isolated populations of motor neurons and,
consequently, may result from a different pathophy-
siology and have a different prognosis (Table 3).
EPIDEMIOLOGY
The overall incidence of ALS has been estimated in
the range of 2–5 cases per 100,000 population with a
slight male predominance. Disease prevalence has
been estimated at approximately 9 or 10 per 100,000
population. Obtaining such estimates has been
challenging due to the lack of a single reporting
mechanism for new diagnoses. Historically, patients
have been given a grim prognosis and, consequently,
many may not have presented for regular follow-up.
Recently, aggressive symptomatic management and
clinical trials have likely resulted in an increase in the
population of actively treated ALS patients. Newly
developed monitoring protocols, including a national
database, may eventually provide better estimates of
incidence and prevalence.
Sporadic ALS, in which the etiology remains
unknown, accounts for 90–95% of cases. Five to
10% of all patients have a family history of ALS,
usually inherited in an autosomal dominant pattern
Neuropathological and electrodiagnostic evidence
Motor neuron loss in the motor cortex and spinal cord
Accumulation of phosphorylated neurofilaments
Mitochondrial swelling
Ubiquitin inclusions
Bunina bodies
Denervation atrophy on muscle biopsy
Active (increased spontaneous activity) and chronic (motor unit
remodeling, decreased recruitment) signs on electrodiagnostic testing
136 AMYOTROPHIC LATERAL SCLEROSIS

Table 2 MOTOR NEURON DISEASE: DIFFERENTIAL DIAGNOSES AND LABORATORY EVALUATION

Clinical phenotype Differential diagnoses Laboratory evaluation

‘‘Routine’’ studies
‘‘Classic’’ ALS Hyperthyroidism, hyperparathyroidism, MRI brain and/or cervical spine, electrodiagnostic studies, CBC
lymphoma, cervical spondylosis, heavy and chemistry panel, thyroid function tests, parathyroid
metal intoxication, combined systems hormone level, vitamin B12 level, immunophoresis, lyme, 24-hr
degeneration, brainstem tumor, syrinx urine for heavy metals (if history of exposure)

‘‘Additional’’ studies (when clinically indicated)

Pure lower motor Multifocal motor neuropathy, GM1 antibody, erthrocyte sedimentation rate, anti-nuclear
neuron syndrome polyradiculopathy, mononeuropathy antibody, rheumatoid factor, serum hexosaminidase A level,
multiplex, hexosaminidase A deficiency, DNA studies for SMA and Kennedy’s, muscle biopsy, creatine
polyneuropathy, inclusion body myositis, kinase, acetylcholine receptor antibody titers, repetitive nerve
chronic inflammatory demyelinating stimulation, muscle biopsy
polyneuropathy, adult-onset spinal
muscular atrophy, progressive muscular
atrophy, Kennedy’s syndrome,
plexopathy, polymyositis, post-polio
syndrome, limb–girdle muscular
dystrophy, myasthenia gravis
Pure upper motor Primary lateral sclerosis, spinal cord Serum long-chain fatty acids, CSF oligoclonal bands, myelin basic
neuron syndrome lesions, adrenoleukodystrophy, multiple protein and IgG synthesis rate; visual, auditory, and
sclerosis, familial spastic paraparesis, somatosensory evoked potentials; HIV antibody, HTLV-1
stroke, Arnold–Chiari malformation, antibody
HIV or HTLV-1 myelopathy

(chromosome 21). Approximately 20% of familial environmental exposure initiate motor neuron de-
ALS (FALS) patients possess one of 90 known generation. To date, this remains an area of
mutations in the copper–zinc superoxide dismutase continued speculation largely due to the continued
(SOD1) gene on chromosome 21. recognition of endemic areas and common predis-
Environmental factors have also been implicated posing factors.
in ALS; endemic areas have been identified. Numer-
ous anecdotal case reports and retrospective reviews
ETIOLOGY
explore the possibility that trauma, stress, or
The number of hypotheses pertaining to the patho-
physiology of motor neuron degeneration in ALS has
escalated steadily during the past 10 years. The
Weakness / Atrophy / Hyper-reflexia / Spasticity
Progression over time search for a cause of motor neuron disease has
EMG / NCV / Neuroimaging / Biopsy
Neuropathology become one of the most active areas of investigation
LMN signs only LMN + UMN
in neurology and neuroscience laboratories world-
>/= 1 region
UMN signs only
LMN + UMN
1 region
1 region
or UMN
LMN + UMN
2 regions
LMN + UMN
3 regions
wide. Current areas of investigation include a search
>/= 1 region >/= 1 region for environmental factors, viral infections, autoim-
Suspected Possible EMG acute
Probable Definite mune mechanisms, oxidative stress, excitotoxicity,
denervation
ALS ALS >/= 2 limbs ALS ALS abnormalities of the motor neuron cytoskeleton, and
Identified Probable ALS
the loss of neurotrophic support. In addition,
DNA
gene
Laboratory implantation of stem cells with the potential to
supported
function as replacements for the degenerated neurons
Definite has become the newest area of investigation.
familial ALS
Laboratory Individual hypotheses, which were introduced in-
supported
dependently, are now thought to interact or overlap,
Figure 1 providing new insight into novel combinations of
Revised El Escorial diagnostic criteria for ALS. therapeutic agents worthy of testing.
Table 3 CLINICAL FEATURES OF ADULT MOTOR NEURON DISEASESa

Progressive Brachial
Amyotrophic lateral muscular Spinal muscular Primary lateral Kennedy’s Progressive bulbar Monomelic amyotrophic
sclerosis atrophy atrophy sclerosis disease palsy amyotrophy diplegia

Typical distribution Asymmetrical distal Asymmetrical Symmetrical Asymmetric Symmetrical Initially limited to Asymmetrical Symmetrical
of weakness distal proximal or distal proximal bulbar muscles Restricted to 1 or proximal
distal 2 extremities Upper
extremities
UMN signs Present Absent Absent Present Absent Present Absent Absent
LMN signs Present Present Present Absent Present Present Present Present
Sensory loss Absent Absent Absent Absent Modest Absent 20% Absent
Genetics AD (10%) SOD ? AR, AD SMN ? XLR CAG ? ? ?
mutation (2%) gene repeats 440
implicated
Distinct features UMN and LMN Pure LMN Pure LMN Pure UMN Gynecomastia, Weakness initially Progression over 2 Preservation of
signs usually with disorder disorder disorder with diabetes limited to bulbar or 3 years with respiratory
rapid progression usually with usually with indolent mellitus, muscles; may subsequent and bulbar
indolent progressive course impotence, progress rapidly to stabilization; functions with
course proximal infertility ALS or be typically young slow
weakness over relatively indolent age of onset progression
decades
a
Abbreviations used: AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; SMN, survival motor neuron; SOD, superoxide dismutase; CAG, cytosine–
adenine–quanine nucleotidase; UMN, upper motor neuron; LMN, lower motor neuron.
138 AMYOTROPHIC LATERAL SCLEROSIS
Viral Hypothesis
Since the eradication of the polio virus, multiple viral
agents have been implicated as the cause of the
selective motor neuron degeneration seen in patients
with ALS. However, a single viral pathogen has not
been consistently identified in affected patients.
Recently, enterovirus nucleic acid sequences were
identified in autopsy tissue in 15 of 17 ALS patients
compared to only 1 of 29 control spinal cord
samples. This observation must be replicated, and
the implication for patients currently affected by the
disease is unclear. Multiple viral agents have been
similarly implicated in ALS without subsequent
verification and treatment, including picornavirus,
adenovirus, herpesvirus, coxsackie virus, echovirus,
and retrovirus. The possibility remains that a viral
pathogen may be responsible for inducing motor
neuron degeneration in some ALS patients. Viral
infection may also induce vulnerability to other
mechanisms of motor neuron degeneration discussed
later.
Glutamate Excitotoxicity
Glutamate is the major excitatory neurotransmitter
throughout the central nervous system. A selective
defect in the reuptake of glutamate from the synaptic
cleft has been reported in ALS patients. The
persistent effect of glutamate on the motor neuron
is toxicity leading to cell death. Excitotoxicity in ALS
patients is thought to result from a specific deficiency
of at least one glutamate transporter protein on the
presynaptic cell as well as on surrounding glial cells.
Abnormal mRNA for the glutamate transporter on
glial cells has been found in 65% of patients with
sporadic ALS. Similar observations may also be
found in some patients with other neurodegenerative
disease processes, suggesting a common pathophy-
siological mechanism. The selectivity of the gluta-
mate transporter abnormality on the glial cell may be
specific to ALS patients.
Excitotoxicity results in a cascade of intracellular
events that terminate in cell death. Calcium influx,
enhanced production of oxidative free radicals, and
subsequent damage to the structural proteins, lipids,
DNA, and intracellular organelles are all thought to
result from an excitotoxic insult to the motor
neuron.
Autoimmunity
Serum from ALS patients is toxic to motor neurons
grown in culture. Specifically, IgG from ALS patients
has been shown to be lethal in in vitro preparations
of motor neurons. Calcium appears to have a
fundamental role in IgG-mediated cytotoxicity. The
importance of IgG-mediated calcium toxicity in ALS
is of particular interest because abnormal calcium
influx has been implicated in cytoskeletal abnormal-
ities, excitotoxic injury, and oxidative damage.
Specific antibodies to calcium channels are found in
the sera of ALS patients, further implicating auto-
immunity in the pathophysiology of motor neuron
disease. Despite these strong implications, treatment
with immunosuppresant or immunomodulating
drugs did not appear to be effective in clinical trials.
Cytoskeletal Abnormalities
An abnormal accumulation of neurofilaments is
found in the cell body and proximal axon of motor
neurons in patients with ALS. The selectivity of
neurofilament abnormalities in affected motor neu-
rons implicates these cytoskeletal abnormalities as a
cause of motor neuron death in ALS. Transgenic
mouse models have been developed in which altera-
tions in individual neurofilament subunits have
resulted in a phenotype characterized by abnormal
gait and progressive weakness. The importance of
cytoskeletal abnormalities in ALS is also supported
by the recent observation that a small subset of
familial ALS patients have mutations in one of the
neurofilament proteins. Furthermore, commonly im-
plicated mechanisms of excitotoxicity, abnormal
calcium influx, and oxidative injury can induce
neurofilament pathology, possibly leading to cell
death.
Oxidative Injury
Multiple hypotheses of motor neuron degeneration
implicate oxidative injury contributing to cell death.
Excess production of oxidative free radicals or
deficiency in antioxidant proteins have been sug-
gested. Oxidative injury may also be a final common
pathway for multiple sources of cell death, suggest-
ing the use of antioxidants as a treatment modality.
In some patients with familial ALS, there is evidence
of an abnormality in one of the essential antioxidant
proteins. At least 90 different mutations affecting the
superoxide dismutase-1 protein (SOD-1) have been
found, although cell death in these instances does not
seem to be related to the lack of antioxidant activity.
Evidence suggests that the mutant SOD-1 protein has
a toxic effect on surviving motor neurons. The
mutated form of the protein may be serving as a
source of toxic free radicals rather than as a

scavenger for them. Mutant SOD-1 protein may also
promote the formation of reactive nitronium ions
that may selectively involve the breakdown of
neurofilaments and other proteins, promoting the
formation of neurofilament accumulations often
found in affected motor neurons. Transgenic mice
possessing the mutated, toxic SOD-1 protein have
been developed and are one of the best models of
ALS for experimental study.
Neurotrophic Factors
Motor neurons are dependent on neurotrophic
factors for survival and maintenance during devel-
opment and throughout life. The use of neurotrophic
factors in human disease may promote both survival
and sprouting of healthy motor neurons, thereby
retarding the degeneration of vulnerable cells. More
than 12 neurotrophic factors with survival-promot-
ing effects on motor neurons have been identified.
Despite significant laboratory evidence of their
survival-promoting effects, clinical efficacy has been
modest. In individual patients there have been
anecdotal reports of documented improvement,
suggesting the possibility of selective benefits in a
subset of patients.
A newer class of neurotrophic factors, the neu-
roimmunophillins, have been identified and may
offer additional promise in the clinic. These small
molecules share both properties of neurotrophic
factors and immune modulation.
Exogenous Toxins
ALS is not likely caused by a single entity. Multiple
theories have been proposed to account for isolated
increases in selective populations in whom ALS
appears endemic. In a survey of the Italian popula-
tion from 1964 to 1982, Granieri et al. found disease
to be more common in agricultural workers, with an
even greater prevalence in more rural areas. This has
since been confirmed in an Italian study as well as in
Sweden and among farmers and shepherds in
Sardinia. Other studies have found a greater in-
cidence among factory workers, maids, athletes, and
manual laborers. Exposure to areas dominated by
major chemical industry has also been suggested as a
cause of greater disease prevalence.
Many reports suggest a link with specific exogen-
ous or environmental factors, but these are often
limited by few patient reports and poor statistical
resolution. Lead and mercury, solvents, milk, em-
ployment in the textile industry, and exposure to
welding have all been associated with ‘‘outbreaks’’ of
AMYOTROPHIC LATERAL SCLEROSIS 139
ALS. Despite these associations, there remains no
consistent association with any environmental agent.
The most significant example of an exogenous
toxin implicated as a causative agent in a variant of
ALS was discovered in the western Pacific with the
ingestion of the neurotoxic seed of the cycad nut.
Trace levels of a-amino-b-methylaminopropionic
acid and cycasin were thought to be responsible for
the neuronal degeneration seen in this variant of
motor neuron disease that also resulted in a type of
dementia and parkinsonism. Subsequently, there has
been a controversy regarding whether the cycad nut
may ultimately be responsible for the neurotoxicity
seen in this patient population.
Apoptosis
Apoptosis refers to a process of programmed (or
genetically determined) cell death. Many reports
have provided evidence for apoptosis in the nervous
system of ALS patients. Unique antigens, specific for
damaged DNA and a by-product of the apoptotic
process, can be detected with immunostaining in the
brain and spinal cord of ALS patients. Specific
proteins that promote apoptosis (BAX and inter-
leukin-1b converting enzyme) are also strongly
expressed in tissues of ALS patients, suggesting that
they may have a primary role in motor neuron
degeneration.
Oxidative mechanisms may also be related to
inducing apoptosis in ALS. Mutated forms of SOD
promote apoptosis. Increased production of reactive
oxygen molecules also induces apoptosis, and over-
expression of antioxidant proteins (superoxide dis-
mutase) inhibits apoptosis. Furthermore, deprivation
of neurotrophic factors can induce apoptosis, and
this process can be rescued by the overexpression of
antioxidant proteins.
Inhibitors of specific proteins in the apoptotic
pathway have been proposed as a mechanism of
treating motor neuron death in ALS patients. In
animal models, inhibition of caspase-1 slowed
disease progression in a mouse model (G93A)
possessing a mutated SOD protein. The caspase
proteins are a favorable target for therapeutic
intervention because they represent a final common
pathway in the apoptotic process and are induced by
a variety of stimuli.
TREATMENT
The most significant effects in slowing disease
progression have been achieved due to our under-
140 AMYOTROPHIC LATERAL SCLEROSIS
standing of aggressive symptomatic therapy. Preser-
vation of respiratory function and nutritional status
have resulted from the aggressive use of noninvasive
ventilation (BiPAP and VPAP) and enteral feeding,
respectively. Both measures have been associated
with improved prognosis and enhanced quality of
life. The use of symptomatic medications for control
of hypersialorrhea, spasticity, and constipation has
also had a significant impact on patients’ quality of
life. Improved technology for assistive communica-
tion enables patients who have limited or no motor
function to lead more fulfilling lives by maintaining
communication ability and access to the Internet. A
large variety of adaptive equipment exists to assist
patients with all aspects of daily living, both at home
and at work. Aggressive implementation of this
equipment should be emphasized as a means for
continued independence rather than as a marker of
disease progression. The same philosophy is opti-
mally applied to physical therapy and devices to
ensure safe ambulation. Range of motion exercise
should also be used to offset the formation of painful
contractures and ultimately lessen morbidity.
TREATMENT TRIALS
The number and diversity of experimental treatment
trials for ALS during the past 10 years have been
unprecedented. Multiple drugs and a variety of
delivery systems have been tested (Table 4). There
is a large disparity between the number of agents
found to promote motor neuron survival in the
laboratory and those found in clinical trials. Many
explanations for the apparent lack of efficacy in prior
clinical trials have been identified:
* The drug may not be effective.
* The delivery method of the drug may not reach
the intended motor neuron target.
* Our current method of detecting clinical benefit
(improved strength, improved respiratory function,
and survival) may not be sensitive enough consider-
ing the diversity of clinical presentation in patients
with ALS.
* ALS may be a syndrome with multiple etiologies
resulting in the same clinical appearance.
* A multiple drug combination may be required
for synergy and ultimate efficacy.
Most of the proposed etiologies mentioned pre-
viously have resulted in the design of experimental
protocols that have been proposed or tested.
Antiglutamate Agents
The only US Food and Drug Administration (FDA)-
approved drug for the treatment of ALS is riluzole
(Rilutek). Riluzole inhibits the presynaptic release of
glutamate and reduces neuronal damage in a number
of experimental models. Riluzole was studied in two
large clinical trials with a primary endpoint of death
or ventilator dependence. The first study showed a
significant benefit in prolonging survival and im-
proving strength in patients with bulbar ALS. A
larger phase III study, however, showed only a
modest but statistically significant survival benefit
in patients with bulbar or limb-onset ALS. A quality
of life measure was not directly used, but a retro-
spective analysis suggested that patients taking
riluzole remained in a milder health state for a
longer period of time compared to patients taking
placebo. These results suggest that there may be an
advantage to taking riluzole in the earlier stages of
the disease compared to the late stages.
Gabapentin is another drug with antiglutamate
activity. It is currently approved for its efficacy as an
antiepilepsy agent and its use as an off-label
indication for ALS was once popular. In preclinical
studies, gabapentin resulted in prolonged survival in
the SOD-1 mouse model as well as prolonged
survival of motor neurons in tissue culture. A phase
II, double-blind, placebo-controlled trial of gabapen-
tin (800 mg three times a day) in 150 ALS patients
showed that a quantitative measure of arm strength
declined slower in patients receiving gabapentin
compared with patients receiving a placebo
(p ¼ 0.057). A phase III study using a higher dose
was recently completed, and no significant differ-
ences were detected in the treated group.
Topiramate, also currently FDA approved for the
treatment of epilepsy, may have a role in ALS
therapy due to its ability to block the action of
glutamate. A 1-year, 21-site placebo-controlled
clinical trial involving 300 patients has recently
been completed; it failed, however, to demonstrate
clinical efficacy.
An alternative mechanism to reduce glutamate
toxicity involves the selective block of the AMPA
receptor, a natural binding site for glutamate. A
newer AMPA receptor antagonist, Talampanel
(LY300164), was recently tested in a blinded,
placebo-controlled, 9-month phase II trial in 60
patients. The drug was well tolerated and further
studies are being considered to examine efficacy in a
larger phase III trial.
 AMYOTROPHIC LATERAL SCLEROSIS 141

Table 4 HYPOTHESES REGARDING THE PATHOGENESIS OF ALS AND RECENTLY PROPOSED TREATMENTSa

Hypothesis Medications Mechanisms Outcome

Glutamate Riluzole Inhibits presynaptic glutamate Significant survival benefit at 12 months; no

excitotoxicity release benefit in strength; FDA approved 1/96
Gabapentin Inhibits glutamate synthesis No benefit in strength, FVC, or symptoms
Dextramethorphan NMDA receptor inhibitor No benefit
BCAA Increases GDH level No benefit
Lamotrigine Inhibits glutamate No benefit
LY300164 AMPA receptor blocker Well tolerated; no significant improvement in
strength or FVC
Topiramate Glutamate inhibitor Ongoing

Autoimmune Prednisone Immunosuppression No benefit

Cyclophosphamide Immunosuppression No benefit
Total body irradiation Total immunosuppression No benefit
Cyclosporine Immunosuppression No benefit
Verapamil Calcium channel blocker No benefit
Nimodipine Calcium channel blocker No benefit

Free radical damage l-deprenyl Free radical scavenger No benefit

N-acetylcysteine Increase scavengers No benefit
Co-Q10 Antioxidant Ongoing
Creatine Enhance energy metabolism of Ongoing
muscle

Apoptosis CNTF Neurotrophic factor No benefit

IGF-1 Neurotrophic factor No benefit
SC BDNF Neurotrophic factor Modest benefit
IT BDNF Neurotrophic factor Ongoing
IV GDNF Neurotrophic factor Not tolerated
Xaliproden (SR5774GA) Neuroprotective by stimulating Data analysis pending
biosynthesis of endogenous
growth factors

Viral Pleconaril Antiviral

a
BCAA, branched-chain amino acids (valine, leucine, and isoleucine); NMDA, N-methyl-d-aspartate; FVC, forced vital capacity; SOD,
superoxide dismutase; GDH, glutamine dehydrogenase; BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor;
GDNF, glial-derived growth factor-1; IGF-1, insulin growth factor; IT, intrathecal; IV, intraventricular; SC, subcutaneous.

Antioxidant Agents have been performed. Trials with deprenyl and

Oxidative stress appears to be a common patho-
genic mechanism in multiple neurodegenerative
diseases including ALS. The accumulation of free
radicals, induced by multiple mechanisms, has a
toxic effect leading to neuronal degeneration. There
has been a great deal of interest in treating patients
with various antioxidant combinations. Unfortu-
nately, due to the accessibility of these over-the-
counter agents, very few controlled clinical trials
N-acetylcysteine failed to show any clinical benefit.
Co-Q10 is a powerful antioxidant and also serves to
enhance mitochondrial function. Co-Q10 has shown
efficacy in animal models of ALS. An open label
study of 18 patients has shown the drug to be
safe and well tolerated. Further studies are currently
being considered. Creatine has also shown evi-
dence of improved survival in animal. A multi-
center, placebo-controlled, 9-month trial is currently
under way.
142 AMYOTROPHIC LATERAL SCLEROSIS
Neurotrophic Agents
Neurotrophic factors have been the focus of the
majority of ALS clinical research during the past 10
years based on their promising results in laboratory
investigations. Ciliary neurotrophic factor was the
first growth factor tested. Unfortunately, two large
independent phase III placebo-controlled trials failed
to show efficacy. Insulin-like growth factor-1 (IGF-1)
was subsequently studied in two trials. One study
demonstrated a 34% slowing of disease progression
based on the Appel ALS scale, which was statistically
significant. The European IGF-1 actually showed an
increased mortality (15%) in the treatment group
compared to placebo (8%). IGF-1 was available to
patients through an ‘‘expanded access program’’ until
December 1999. An additional IGF-1 study has since
been completed in Japan, and it yielded negative
results.
A large phase III trial of subcutaneous brain-
derived neurotrophic factor (BDNF) showed no
significant benefit. A post hoc analysis of the data
showed significantly greater survival (p ¼ 0.001)
among 78 patients receiving BDNF who developed
diarrhea within the first 15 days of therapy. This
indicated a biological effect of the drug with
presumably higher serum levels in a selected sub-
population of patients. A dose-escalation subcuta-
neous BDNF was recently completed and found not
to be effective.
Another theory to explain why subcutaneous
administration of neurotrophic factors shows no
significant clinical effects involves impaired delivery
of the agent to the affected motor neurons. As a
result, an intrathecal BDNF study was performed
using the SynchroMed infusion system that is
currently FDA approved for intrathecal delivery of
baclofen and morphine. Unfortunately, this study
indicated that the BDNF was not of significant
clinical benefit.
Xaliproden (SR57746A) is a unique compound
whose mechanism is thought to mimic the activity or
stimulate the biosynthesis of a number of endogen-
ous growth factors, such as nerve growth factor and
BDNF. Based on limited laboratory data, the drug
may also have neuroprotective effects. A small phase
II trial showed a statistically significant reduction in
the rate of decline of FVC and a trend in favor of the
treatment group in the rate of decline of the limb
functional and muscle testing scores. A large phase
III trial was recently completed with two parallel
studies. In one study, the treatment group (1200
patients) taking riluzole and xaliproden was com-
pared with placebo patients. In the second study, a
treatment group (800 patients) taking only xalipro-
den was compared with patients taking a placebo.
The results yielded some favorable trends; however,
the data did not show a significant benefit in patients’
overall survival after taking the drug. Further studies
may be required before clear benefits are confirmed.
Antiviral Agents
Based on recent evidence suggesting an enteroviral
infection as a potential pathogenic mechanism to
either induce or propagate motor neuron degenera-
tion, there has been tremendous interest in studying
the effect of antiviral therapy in ALS. Pleconaril is an
antienteroviral drug currently awaiting FDA ap-
proval. It is available through a FDA investigational
new drug application program for compassionate use
in patients in whom enteroviral infection can be
documented in serum or cerebrospinal fluid cultures.
A controlled trial of Pleconaril in ALS is being
planned, pending confirmation of virus detection in
affected patients.
FUTURE DIRECTIONS
There has recently been an unprecedented amount of
research regarding the pathogenesis of motor neuron
disease that will continue to provide avenues for drug
development. In the meantime, the concomitant
development of aggressive treatment protocols has
had a significant impact on the course of the disease.
It is generally believed that the use of combinations
of drugs that have different mechanisms of action
will become the standard of care, similar to the
‘‘treatment cocktails’’ that have evolved for the
treatment of AIDS and cancer. Providing multi-
disciplinary care with aggressive symptomatic and
supportive therapies have the most significant effect
in reducing disability and enhancing quality of life in
patients with motor neuron disease.
—Jeffrey Rosenfeld
See also–Betz Cells; Charcot, Jean-Martin;
Degenerative Disorders; Lower Motor Neuron
Lesions; Neurotrophins; Neuromuscular Dis-
orders, Overview; Oxidative Metabolism; Spinal
Muscular Atrophy; Upper Motor Neuron Lesions
Further Reading
Andersen, P., Morita, M., and Brown, R. (2000). Genetics of
amyotrophic lateral sclerosis: An overview. In Amyotrophic

Lateral Sclerosis (R. Brown, V. Meininger, and M. Swash, Eds.),
pp. 223–250. Martin-Dunitz, London.
Brown, R., Meninger, V., and Swash, M. (Eds.) (2000). Amyo-
trophic Lateral Sclerosis. Martin-Dunitz, London.
Charcot, J. (1874). De la sclerose laterale amytrophique. Prog.
Med. 2, 325–327, 341–342, 453–455.
Doble, A. (1999). The role of excitotoxicity in neurodegenerative
disease: Implications for therapy. Pharmacol. Ther. 81, 163–
221.
Granieri, E., Carreras, M., Tola, R., et al. (1988). Motor neuron
disease in the province of Ferrara, Italy, in 1964–1982.
Neurology 38, 1604–1608.
Gurney, M., Pu, H., Chiu, A. Y., et al. (1994). Motor neuron
degeneration in mice that express a human Cu, Zn superoxide
dismutase mutation. Science 264, 1772–1775.
Iwami, O., Niki, Y., Watanabe, T., et al. (1993). Motor neuron
disease on the Kii peninsula of Japan: Cycad exposure.
Neuroepidemiology 12, 307–312.
Kieburtz, K. (1999). Antiglutamate therapies in Huntington’s
disease. J. Neural Transm. Suppl. 55, 97–102.
Miller, R. G., Anderson, F. A., Jr., Bradley, W. G., et al. (2000). The
ALS patient care database: Goals, design, and early results. ALS
C.A.R.E. Study Group. Neurology 54, 53–57.
Mitsumoto, H., Chad, D. A., and Pioro, E. P. (1998). Amyotrophic
Lateral Sclerosis: Contemporary Neurology Series, Vol. 49
Davis, Philadelphia.
Provinciali, L., and Giovagnoli, A. R. (1990). Antecedent events in
amyotrophic lateral sclerosis: Do they influence clinical onset
and progression? Neuroepidemiology 9, 255–262.
Rosen, D. R., Siddique, T., Patterson, D., et al. (1993). Mutations
in Cu/Zn superoxide dismutase are associated with familial
amyotrophic lateral sclerosis. Nature 362, 59–62.
World Federation of Neurology Research Group on Motor
Neuron Diseases (1998). El Escorial revisited: Revised criteria
for the diagnosis of amyotrophic lateral sclerosis. In
ALS Consensus Conference, Airlie House, Warrenton, VA
(B. Brooks, Ed.). World Federation of Neurology. Warrenton,
VA.
Zhang, Z. X., Anderson, D. W., Mantel, N., et al. (1996). Motor
neuron disease on Guam: Geographic and familial occurrence
1956–85. Acta Neurol. Scand. 94, 51–59.
Analgesia, Cancer Pain and
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ONE OF THE FUNDAMENTAL GOALS of medical care is
to provide palliative care to relieve patients’ pain and
suffering. This has been true since the birth of
medicine in ancient Greece. Hippocrates wrote in
The Art, ‘‘I will define what I conceive medicine to
be. In general terms, it is to do away with suffering of
the sick, to lessen the violence of their disease.’’
Hippocrates also said, ‘‘Divine is the effort to subdue
pain.’’
ANALGESIA, CANCER PAIN AND 143
Pain and symptom control is a central priority of
the cancer control program of the World Health
Organization (WHO). In 1982, the WHO convened
a consensus conference of experts in the management
of cancer pain. They suggested that attaining
satisfactory relief of pain in most cancer patients is
a realistic goal that may be achieved through the use
of a limited number of drugs. Draft guidelines were
developed in 1982 and published in the 1986
monograph Cancer Pain Relief. This WHO publica-
tion included an approach to drug selection for
cancer pain that has become known as the three-step
analgesic ladder (Fig. 1). The WHO analgesic ladder
represents an approach to the selection of doses and
type of drugs for effective pain management that is
based on pain intensity. This approach emphasized
that analgesic pharmacotherapy is the mainstay of
cancer pain management. Occasionally, other onco-
logical, psychological, or rehabilitative interventions
may be needed, and sometimes patients benefit from
invasive therapies. This approach has been widely
evaluated, adopted by clinicians in numerous coun-
tries, and endorsed by the U.S. Agency for Health
Care Policy and Research in their clinical practice
guidelines for the management of cancer pain.
In general, analgesics are administered by the
safest and least invasive route likely to produce
adequate relief. Extensive experience indicates that
the majority of patients can be effectively managed
using drugs administered by the oral route during
most of the course of their illness. For patients who
are unable to swallow, rectal, transdermal, subcuta-
neous, and intravenous routes are commonly used.
FREEDOM FROM CANCER PAIN
OPIOID FOR MODERATE TO SEVERE
PAIN
+/ NON-OPIOID
+/ ADJUVANT
PAIN PERSISTING
OR INCREASING OPIOID FOR MILD TO
MODERATE PAIN
+NON OPIOID
+/ ADJUVANT
PAIN PERSISTING
OR INCREASING
NON-OPIOID
+/ ADJUVANT
PAIN
Figure 1
The WHO three-step analgesic ladder (adapted from WHO,
1990).

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Analgesia, Cancer Pain and
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ONE OF THE FUNDAMENTAL GOALS of medical care is
to provide palliative care to relieve patients’ pain and
suffering. This has been true since the birth of
medicine in ancient Greece. Hippocrates wrote in
The Art, ‘‘I will define what I conceive medicine to
be. In general terms, it is to do away with suffering of
the sick, to lessen the violence of their disease.’’
Hippocrates also said, ‘‘Divine is the effort to subdue
pain.’’
ANALGESIA, CANCER PAIN AND 143
Pain and symptom control is a central priority of
the cancer control program of the World Health
Organization (WHO). In 1982, the WHO convened
a consensus conference of experts in the management
of cancer pain. They suggested that attaining
satisfactory relief of pain in most cancer patients is
a realistic goal that may be achieved through the use
of a limited number of drugs. Draft guidelines were
developed in 1982 and published in the 1986
monograph Cancer Pain Relief. This WHO publica-
tion included an approach to drug selection for
cancer pain that has become known as the three-step
analgesic ladder (Fig. 1). The WHO analgesic ladder
represents an approach to the selection of doses and
type of drugs for effective pain management that is
based on pain intensity. This approach emphasized
that analgesic pharmacotherapy is the mainstay of
cancer pain management. Occasionally, other onco-
logical, psychological, or rehabilitative interventions
may be needed, and sometimes patients benefit from
invasive therapies. This approach has been widely
evaluated, adopted by clinicians in numerous coun-
tries, and endorsed by the U.S. Agency for Health
Care Policy and Research in their clinical practice
guidelines for the management of cancer pain.
In general, analgesics are administered by the
safest and least invasive route likely to produce
adequate relief. Extensive experience indicates that
the majority of patients can be effectively managed
using drugs administered by the oral route during
most of the course of their illness. For patients who
are unable to swallow, rectal, transdermal, subcuta-
neous, and intravenous routes are commonly used.
FREEDOM FROM CANCER PAIN
OPIOID FOR MODERATE TO SEVERE
PAIN
+/ NON-OPIOID
+/ ADJUVANT
PAIN PERSISTING
OR INCREASING OPIOID FOR MILD TO
MODERATE PAIN
+NON OPIOID
+/ ADJUVANT
PAIN PERSISTING
OR INCREASING
NON-OPIOID
+/ ADJUVANT
PAIN
Figure 1
The WHO three-step analgesic ladder (adapted from WHO,
1990).
144 ANALGESIA, CANCER PAIN AND

SYSTEMIC ANALGESIC thesis due to inhibition of platelet aggregation,

PHARMACOTHERAPY gastroduodenopathy (including peptic ulcer disease),
and renal impairment being the most common. Less
Non-Opioid Analgesics
common adverse effects include confusion, precipita-
Non-opioid analgesics are used in the management tion of cardiac failure, and exacerbation of hyperten-
of mild to moderate pain and to augment the sion. Particular caution should be exercised when
analgesic effect of opioids in selected patients with these agents are administered to patients at increased
severe pain (Table 1). The non-opioid analgesics risk of adverse effects, such as the elderly, those with
constitute a heterogeneous group of compounds. blood-clotting disorders, predilection to peptic ul-
Some of these agents, such as aspirin and the ceration, and impaired renal function, and those
NSAIDs, inhibit the enzyme cyclooxygenase and receiving concurrent corticosteroid therapy.
consequently block the biosynthesis of prostaglan- The risk of gastrointestinal bleeding can be
dins, which are inflammatory mediators known to minimized by drug selection and the use of peptic
sensitize peripheral nociceptors. A central mechan- cytoprotective agents. There are at least two isoforms
ism has also been described and appears to pre- of cyclooxygenase with distinct roles in analgesia and
dominate in the analgesia generated by toxicity. Cyclooxygenase-1 is responsible for the
acetaminophen and dipyrone. Unlike opioid analge- synthesis of the protective prostaglandins that pre-
sics, the non-opioid analgesics have a ‘‘ceiling’’ effect serve the integrity of the stomach lining and maintain
for analgesia and produce neither tolerance nor normal renal function in a compromised kidney;
physical dependence. cyclooxygenase-2 is an inducible enzyme involved in
The safe administration of non-opioid analgesics inflammation, pain, and fever. Recently, a number of
requires familiarity with their potential adverse relatively selective cyclooxygenase-2 inhibitors, in-
effects. Aspirin and the other NSAIDs have a broad cluding meloxicam, nemesulide, rofecoxib, and
spectrum of potential toxicity, with bleeding dia- celecoxib, have been introduced and approved as
analgesics. Early data indicate that these agents are
associated with less gastrointestinal morbidity.
Data from randomized trials support the use of
Table 1 NON-OPIOID ANALGESICS
famotidine, omeprazole, or misoprostol as the
Chemical class Generic name preferred agents for the prevention of NSAID-related
peptic ulceration. In contrast, acetaminophen rarely
Nonacidic Acetaminophen
produces gastrointestinal toxicity and there are no
Nabumeton
adverse effects on platelet function. Hepatic toxicity
Nemesulid
is possible, however, and patients with chronic
Meloxicam
alcoholism and liver disease can develop severe
Acidic salicylates Aspirin
hepatotoxicity at the usual therapeutic doses of
Diflunisal
acetaminophen.
Choline magnesium trisalicylate
Salsalate Opioid Analgesics
Propionic acids Ibuprofen
Naproxen
Most patients with moderate or severe pain will
Fenoprofen
require opioid analgesics.
Ketoprofen General Principles of Opioid Pharmacology
Fluribiprofen
Classification: Opioid compounds can be categor-
Suprofen
ized into agonist, agonist–antagonist, and antagonist
Acetic acids Indometahacin
classes based on their interactions with the various
Tolmentin
opioid receptor subtypes. The pure agonists are most
Sulindac
commonly used in the management of cancer pain.
Diclofenac
On the other hand, the mixed agonist–antagonist
Ketrolac
opioids (pentazocine, nalbuphine, and butorphanol)
Oxicam Piroxicam
and the partial agonist opioids (buprenorphine and
Fenemates Mefenamic acid
probably dezocine) play a minor role in the manage-
Meclofenamic acid
ment of cancer pain due to the existence of a ceiling
 ANALGESIA, CANCER PAIN AND 145

effect for analgesia, the potential for precipitating
withdrawal in patients physically dependent on
opioid agonists (Table 2), and, in the case of mixed
agonist–antagonists, the problem of dose-dependent
psychomimetic side effects that exceed those of pure
agonist drugs.
Dose–Response Relationship: The pure agonist
opioids do not have a ceiling dose per se; as the
dose is increased, analgesic effects increase in a semi-
log-linear function until either analgesia is achieved
or the patient develops dose-limiting adverse effects,
such as nausea, vomiting, confusion, sedation,
myoclonus, or respiratory depression. In practice,
the efficacy of any particular drug in a specific patient
will be determined by the degree of analgesia
produced following dose escalation through a range
limited by the development of adverse effects.
Relative Potency and Equianalgesic Doses: Rela-
tive analgesic potency is the ratio of the dose of two
analgesics required to produce the same analgesic
effect. By convention, the relative potency of each of
the commonly used opioids is based on comparison
with 10 mg of parenteral morphine. Equianalgesic
dose information (Table 2) provides guidelines for
dose selection when the drug or route of adminis-
tration are changed and is generally useful as a
reference point.
Moderate Pain (Step 2 of the Analgesic Lad-
der): Traditionally, patients with moderate pain have
been treated with a combination product containing
acetaminophen or aspirin plus codeine, dihydroco-
deine, hydrocodone, oxycodone, or propoxyphene.
The doses of these combination products can be
increased until the maximum dose of the non-opioid
coanalgesic is attained (e.g., 4000 mg of acetamino-
phen); beyond this dose, the opioid in the combina-
tion product could be increased as a single agent or
the patient could be switched to an opioid con-
ventionally used for severe pain. In recent years, new
opioid formulations have been developed that may
improve the convenience of drug administration for
patients with moderate pain, including controlled-
release formulations of codeine, dihydrocodeine,
oxycodone, morphine, and tramadol.
Severe Pain (Step 3 of the Analgesic Ladder): By
convention, morphine is usually the initial drug of
choice for the management of severe pain. This
recommendation is not based on its superiority as a
pharmacological agent; rather, it is based on the wide
range of available formulations and widespread
clinical familiarity and availability. Morphine is
generally available orally (syrups and immediate-
and controlled-release tablets), parenterally, and
rectally.
During the past 10 years, alternative opioids have
become widely available and in some situations they
are preferred. Alternative opioids include hydromor-
phone, oxycodone, fentanyl, and methadone. Oxy-
codone is available in both immediate and
controlled-release formulations and is commonly
used in the management of severe pain for patients
who have previously used the drug for moderate
pain. Fentanyl is available as a transdermal patch

Table 2 OPIOID ANALGESICSa

Dose (mg) equianalgesic to 10 mg

morphine

Drug IM PO Comments

Codeine 130 200 Usually combined with non-opioid

Fentanyl 0.1 NA Patches available to deliver 25, 50, 75, or 100 mg/hr
Hydromorphone 2–3 7.5 Multiple routes available
Levorphanol 2 4 Plasma accumulation may lead to delayed toxicity
Meperidine 75 300 Normeperidine toxicity limits utility
Methadone 1–3 2–6 Plasma accumulation may lead to delayed toxicity; dosing should be
initiated on PRN basis
Morphine 10 30 Multiple routes available
Oxycodone 15 20–30 Combined with a non-opioid or as a controlled-release tablet
Propoxyphene 100 50 Usually combined with a non-opioid
a
Abbreviations used: IM, intramuscular; IV, intravenous; NA, not available.
146 ANALGESIA, CANCER PAIN AND
that delivers medication for 72 hr. Transdermal
fentanyl is commonly used for patients who are
unable to tolerate orally administered medication
and for those who are especially sensitive to the
constipatory effect of opioids. Hydromorphone is
available as both oral and parenteral formulations. It
is highly soluble and is particularly useful for
subcutaneous infusions. Methadone has a much
longer half-life than the other alternatives. Fear of
adverse effects with dose accumulation has discour-
aged the widespread use of this agent. In contrast to
the other opioids, methadone is best initiated on an
‘‘as needed’’ schedule that avoids the risk of dose
accumulation with a fixed schedule.
Scheduling Opioid Administration: Patients with
continuous or frequent pain generally benefit from
scheduled ‘‘around-the-clock’’ dosing, which can
provide continuous relief by preventing the pain
from recurring. Most patients who receive an
around-the-clock opioid regimen are also provided
a rescue dose, which is a supplemental dose offered
on an as-needed basis to treat pain that occurs
despite the regular schedule. The frequency with
which the rescue dose can be offered depends on the
route of administration and the time to peak effect
for the particular drug. Oral rescue doses are usually
offered up to every 1 or 2 hr and parenteral doses can
be offered as frequently as every 15–30 min. Clinical
experience suggests that the initial size of the rescue
dose should be equivalent to approximately 50–
100% of the dose administered every 4 hr for oral or
parenteral bolus medications or 50–100% of the
hourly infusion rate for patients receiving continuous
infusions. Alternatively, this may be calculated as 5–
15% of the 24-hr baseline dose. The integration of
around-the-clock dosing with rescue doses provides a
method for safe and rational stepwise dose escala-
tion, which is applicable to all routes of opioid
administration.
In some situations, opioid administration on an as-
needed basis, without an around-the-clock dosing
regimen, may be beneficial. In the opioid-naive
patient, as needed dosing may provide additional
safety during the initiation of opioid therapy,
particularly when rapid dose escalation is needed or
when therapy with a long half-life opioid, such as
methadone, is begun. As-needed dosing may also be
appropriate for patients who have rapidly decreasing
analgesic requirements or intermittent pain separated
by pain-free intervals.
Patient-controlled analgesia generally refers to a
technique of parenteral drug administration in which
the patient controls an infusion device that delivers a
bolus of analgesic drug on demand, according to
parameters set by the physician. Use of a patient-
controlled analgesia device allows the patient to
overcome variations in both pharmacokinetic and
pharmacodynamic factors by carefully titrating the
rate of opioid administration to meet individual
analgesic needs. Although the use of oral rescue
doses is, in fact, a form of patient-controlled
analgesia, the term is not commonly applied to this
situation.
Adverse Effects of Opioids: Successful opioid
therapy requires that the benefits of analgesia and
other desired effects clearly outweigh treatment-
related adverse effects. Common adverse effects of
opioid analgesics include constipation, drowsiness,
cognitive impairment, nausea, vomiting, urinary
retention, and myoclonous. Respiratory depression,
the most important adverse effect, results from severe
central nervous system depression and occurs in
patients who are severely obtunded. This is an
uncommon phenomenon when patients receiving
opioid are monitored for pain intensity and degree
of sedation confusion. The appearance of these
effects depends on a number of factors, including
patient’s age, the extent of disease, concurrent organ
dysfunction, other drugs, prior opioid exposure, and
the route of drug administration.
Gastrointestinal Side Effects: The gastrointestinal
adverse effects of opioids are common. In general,
they are characterized by a weak dose–response
relationship.
Constipation is the most common adverse effect of
chronic opioid therapy. The likelihood of opioid-
induced constipation is so great that for most
patients laxative medications should be prescribed
prophylactically.
Opioids may produce nausea and vomiting
through both central and peripheral mechanisms.
These drugs stimulate the medullary chemoreceptor
trigger zone, increase vestibular sensitivity, and have
effects on the gastrointestinal tract that include
increased gastric antral tone, diminished motility,
and delayed gastric emptying. In ambulatory pa-
tients, the frequency of nausea and vomiting is 10–
40%. The likelihood of these effects is greatest at the
start of opioid therapy. Tolerance typically develops
within weeks. Routine prophylactic administration
of an antiemetic is not necessary, except in patients

with a history of severe opioid-induced nausea and
vomiting; however, patients should have access to an
antiemetic at the start of therapy if the need for one
arises.
Central Nervous System Side Effects: The central
nervous system side effects of opioids are generally
dose related, with specific patterns influenced by
individual patient factors, duration of opioid ex-
posure, and dose.
Sedation: Initiation of opioid therapy or signifi-
cant dose escalation commonly induce sedation that
persists until tolerance to this effect develops, usually
within days to weeks. Some patients have a persistent
problem with sedation, particularly if other con-
founding factors exist, including the use of other
sedating drugs or coexistent diseases such as demen-
tia, metabolic encephalopathy, or brain metastases.
Both dextroamphetamine and methylphenidate have
been widely used in the treatment of opioid-induced
sedation. This approach is relatively contraindicated
among patients with cardiac arrhythmias, agitated
delirium, paranoid personality, and past ampheta-
mine abuse.
Confusion and Delirium: Mild cognitive impair-
ment is common following the initiation of opioid
therapy or dose escalation. Similar to sedation,
however, pure opioid-induced encephalopathy ap-
pears to be transient in most patients, lasting from
days to 1 or 2 weeks. Haloperidol in low doses may
improve or reduce mild opioid-induced delirium. If
drowsiness or delirium is severe or persistent,
consideration should be given to switching to an
alternative opioid.
Respiratory Depression: Respiratory depression is
potentially the most serious adverse effect of opioid
therapy. Clinically significant respiratory depression,
however, is always accompanied by other signs of
central nervous system depression, including seda-
tion and mental clouding. Respiratory compromise
accompanied by tachypnea and anxiety is never a
primary opioid event.
The ability to tolerate high doses of opioids is also
related to the stimulatory effect of pain on respira-
tion in a manner that is balanced against the
depressant opioid effect. Opioid-induced respiratory
depression can occur if pain is suddenly eliminated
(such as may occur following neurolytic procedures)
and the opioid dose is not reduced.
ANALGESIA, CANCER PAIN AND 147
When respiratory depression occurs in patients on
chronic opioid therapy, administration of the specific
opioid antagonist, naloxone, usually improves venti-
lation. This is true even if the primary cause of the
respiratory event was not the opioid but rather an
intercurrent cardiac or pulmonary process.
All opioid analgesics can produce involuntary
muscular contractions called myoclonus. Although
the mechanism of this effect is not known, patients
with advanced cancer often have multiple potentially
contributory factors. The opioid effect is dose related
and is most prominent with meperidine, presumably
as a result of metabolite accumulation. Mild and
infrequent myoclonus is common and may resolve
spontaneously with the development of tolerance to
this effect. In occasional patients, myoclonus can be
distressing or contribute to breakthrough pain that
occurs with the involuntary movement.
Adverse Drug Interactions: In patients with ad-
vanced cancer, side effects due to drug combinations
are common. The potential for additive side effects
and serious toxicity from drug combinations must be
recognized. The sedative effect of an opioid may add
to that produced by numerous other centrally acting
drugs, such as anxiolytics, neuroleptics, and anti-
depressants. Likewise, drugs with anticholinergic
effects probably worsen the constipatory effects of
opioids. A severe adverse reaction, including excita-
tion, hyperpyrexia, convulsions, and death, has been
reported after the administration of meperidine to
patients treated with a monoamine oxidase inhibitor.
Other Effects
Urinary Retention: Opioid analgesics increase
smooth muscle tone and can occasionally cause
bladder spasm or urinary retention (due to an
increase in sphincter tone). This is an infrequent
problem that is usually observed in elderly male
patients. Tolerance can develop rapidly but catheter-
ization may be necessary to manage transient
problems.
Pulmonary Edema: Noncardiogenic pulmonary
edema has been observed in patients treated with
high, escalating opioid doses. A clear cause-and-
effect relationship with opioid use has not been
established but is suspected. The mechanism, if
opioid related, is obscure.
Common Patient Concerns: Tolerance and Addic-
tion: The need for escalating doses is a complex
phenomenon. Most patients obtain a dose that
148 ANALGESIA, CANCER PAIN AND
remains constant for prolonged periods. When the
need for dose escalation arises, any of a variety of
processes may be involved. Clinical experience
suggests that disease progression and increasing
psychological distress are much more common than
true analgesic tolerance. In true pharmacological
tolerance, continued drug administration induces an
attenuation of effect.
The induction of true analgesic tolerance, which
could compromise the utility of treatment, can only
be said to occur if a patient manifests the need for
increasing opioid doses in the absence of other
factors (e.g., progressive disease) that would explain
the increase in pain. Consequently, concern about
tolerance should not impede the use of opioids early
in the course of the disease, and worsening pain
should be assessed as presumptive evidence of disease
progression or, less commonly, increasing psycholo-
gical distress.
Confusion about physical dependence and addic-
tion augments the fear of opioid drugs and con-
tributes substantially to the undertreatment of pain.
Physical dependence is defined by the development of
an abstinence (withdrawal) syndrome following
either abrupt dose reduction or administration of
an antagonist. Despite the observation that physical
dependence is most commonly observed in patients
taking large opioid doses for a prolonged period of
time, withdrawal has also been observed with low
doses or short duration of treatment. Physical
dependence rarely becomes a clinical problem if
patients are warned to avoid abrupt discontinuation
of the drug.
Addiction refers to a psychological and behavioral
syndrome characterized by a continued craving for an
opioid drug to achieve a psychic effect (psychological
dependence) and associated aberrant drug-related
behaviors, such as compulsive drug seeking, unsanc-
tioned use or dose escalation, and use despite harm to
self or others. Addiction should be suspected if
patients demonstrate compulsive use, loss of control
over drug use, and continuing use despite harm.
The medical use of opioids is very rarely associated
with the development of addiction. In a prospective
study of 550 cancer patients who were treated with
morphine for a total of 22,525 treatment days, only
one patient developed problems related to substance
abuse. Health care providers, patients, and families
often require vigorous and repeated reassurance that
the risk of addiction is extremely low.
The distress engendered in patients who have a
therapeutic dependence on analgesic pharmacother-
Table 3 ADJUVANT ANALGESICS
For neuropathic pain For bone pain
Corticosteroids Corticosteroids
Tricyclic antidepressants Bisphosphonates
Mexilitine Calcitonin
Lidocaine Strontium-89
Capsaicin cream
Anticonvulsants
Baclofen
apy but who continue to experience unrelieved pain
is occasionally expressed in behaviors that mimic
those of the addict, such as intense concern about
opioid availability and unsanctioned dose escalation.
Pain relief, usually produced by dose escalation,
eliminates these aberrant behaviors and distinguishes
the patient from the true addict. This syndrome has
been termed pseudo-addiction.
Adjuvant Analgesics
Although it is desirable to achieve pain relief with the
simplest possible analgesic regimen, in some instances
polypharmacy is required to achieve the optimal
balance between pain relief and adverse effects. One
such approach involves the use of adjuvant analgesics
along with opioid therapy (Table 3). These agents,
although not primarily used as analgesics, may have
analgesic effects in specific clinical circumstances.
Adjuvant analgesics are most commonly used in the
management of neuropathic and bone pain. When
using adjuvant analgesics in this manner, it is
important to appreciate the limited likelihood of
benefit from any one agent. If a trial of therapy
incorporating adequate dose titration does not yield
benefit, the medication should be discontinued and
consideration given to another drug or approach.
Selected antidepressants, oral local anesthetics,
and anticonvulsants can be used as adjuvants in the
treatment of neuropathic pain. Bisphosphonates and
radiopharmaceutics, such as strontium-89, are com-
monly used as adjuvants for the management of bone
pain.
NONPHARMACOLOGICAL INTERVENTIONS
IN THE MANAGEMENT OF CANCER PAIN
Invasive Therapies
Validation studies of the WHO analgesic ladder
demonstrated that 10–30% of patients with cancer

do not achieve a satisfactory balance between relief
and side effects using systemic pharmacotherapy
alone. Some of these patients can benefit from the use
of invasive approaches that can be broadly classified
as regional analgesic techniques and neuroablative
techniques.
Regional Analgesic Techniques: These include the
intraspinal or intraventricular delivery of low doses
of opioids usually in conjunction with a local
anesthetic. The development of intraspinal delivery
techniques followed the discovery of opioids recep-
tors in the dorsal horn of the spinal cord. It is
possible to use both the intrathecal and epidural
routes to administer the drug, but the epidural route
is generally preferred because the techniques to
accomplish long-term administration are simpler.
Compared with neuroablative therapies, spinal
opioids have the advantage of preserving sensation,
strength, and sympathetic function. Intraventricular
delivery of opioids via an Ommaya reservoir or an
implantable pump is an infrequently used technique
in the management of otherwise refractory pain
syndromes.
Anesthetic Techniques—Nerve Blocks: Nerve
blocks can be either neurolytic or nonneurolytic.
Neurolytic blocks involve the injection of a neuro-
destructive agent, such as phenol or absolute alcohol,
on or near the target nerve to produce analgesia.
Nonneurolytic blocks involve the application of local
anesthetic that results in a transient neural blockade.
In addition to being a treatment option for sym-
pathetically maintained pain, as a nonneurolytic
blockade it can be used as a diagnostic procedure
to determine the source of pain or as a prognostic
procedure to predict the outcome of a permanent
intervention. Neurolytic nerve blocks are rarely
applicable for extremity pain because the block of
the trunks serving the extremity may induce severe
and debilitating defects. Examples of commonly used
neurolytic blocks include celiac plexus block for
pancreatic and other upper abdominal malignant
diseases and hypogastric plexus block for pelvic
malignant lesions.
Neuroablative Techniques for Somatic and Neuro-
pathic Pain: Techniques include neurosurgical or
chemical procedures that ablate sensory neural
pathways. The technique most commonly used is
chemical rhizotomy, which may be produced by
installation of neurolytic solution into either the
epidural or the intrathecal space. Rhizotomy is an
ANALGESIA, CANCER PAIN AND 149
effective method of pain control for patients with
otherwise refractory localized pain syndromes. This
approach is most commonly used in the management
of chest wall pain due to tumor invasion of somatic
and neural structures. Neurolysis of primary afferent
nerves may provide significant relief of pain for
selected patients with localized pain. Cordotomy, in
which the corticospinal tract of the spinal cord
(which transmits painful sensations) is deliberately
transected, produces contralateral selective loss of
pain and temperature sensibility. The patient with
severe unilateral pain in the torso or lower extremity
is most likely to benefit from this procedure. Pituitary
ablation by chemical or surgical hypophysectomy
has been reported to relieve diffuse and multifocal
pain syndromes in both hormone-dependent and
-independent tumors.
Noninvasive Therapies
Psychological Modalities: The emotional, cogni-
tive, sociocultural, and behavioral factors in the
experience of pain are acknowledged as an important
part of the multimodal approach to pain manage-
ment. Such interventions do not replace but rather
are used in conjunction with appropriate analgesics
for the management of pain. Thoughts, emotions,
and behavior are the observed targets of psycholo-
gical interventions. Psychological interventions based
on cognitive–behavioral methodologies can bring
about changes in how patients think, behave, feel,
and even experience pain. These methods have been
adapted for the treatment of chronic pain and cancer
pain. Several recent studies have shown that relaxa-
tion and imagery training are powerful psychological
strategies for reducing persistent pain.
CONCLUSION
The treatment of cancer pain is an ongoing process.
Whenever pain is present, health care providers
should provide optimal pain relief by routinely
assessing pain and treating it in a systematic manner.
Optimal therapy of cancer pain depends on the
understanding that there is no single approach to
effective pain management and that individualized
pain management should take into account the stage
of disease, concurrent medical condition, character-
istics of pain, and psychological and cultural
characteristics of the patients.
—Rama Sapir and Nathan I. Cherny
150 ANALGESICS, NON-OPIOID AND OTHER
See also–Analgesics, Non-Opioid and Other;
Opioids and Their Receptors; Pain, Cancer and;
Pain, Invasive Procedures for; Pain Management,
Multidisciplinary; Pain, Overview
Further Reading
Cherny, N. I., and Portnoy, R. K. (1994). The management of
cancer pain. CA Cancer J. Clin. 44, 263–303.
Cherny, N. I., Arbit, E., and Jain, S. (1996). Invasive techniques in
the management of cancer pain. Hem. Oncol. Clin. North Am.
10, 121–137.
Emanuel, E. J. (1996). Pain and symptom control: Patients’ rights
and physician responsibilities. Hem. Oncol. Clin. North Am.
10, 41–56.
Fernandez, E., and Turk, D. C. (1989). The utility of cognitive
coping for altering pain perception: A meta analysis. Pain 38,
123–135.
Hippocrates (1977). The art. In Ethics in Medicine (S. J. Reiser and
A. J. Dyck, Eds.), reprint. MIT Press, Cambridge, MA.
Syrjala, K. (1993). Integrating medical and psychological treat-
ments for cancer pain. In Current and Emerging Issues in
Cancer Pain: Research and Practice (C. R. Chapman and K. M.
Foley, Eds.), pp. 393–409. Raven Press, New York.
Syrjala, K., Donaldson, G. W., David, M. W., et al. (1995).
Relaxation and imagery and cognitive–behavioral training
reduce pain during cancer treatment: A controlled clinical trial.
Pain 63, 189–198.
World Health Organization (1982). Cancer Pain Relief. World
Health Organization, Geneva.
World Health Organization (1986). Cancer Pain Relief. World
Health Organization, Geneva.
World Health Organization (1990). Cancer Pain and Palliative
Care. World Health Organization, Geneva.
Analgesics, Non-Opioid
and Other
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALTHOUGH OPIOID ANALGESICS remain the mainstay
of therapy for most acute and chronic pain generated
from pain-specific somatic nerve endings, other types
of medications and pain treatments are useful in
enhancing their effect. These adjuvant therapies also
play an important and primary role in the treatment
of pain that is produced directly from the nerve
(neuropathic pain), which patients usually describe
as ‘‘unfamiliar pain.’’ These therapies consist of a
wide variety of treatments, which can be classified as
medications, alternate delivery systems, procedures,
and intrinsic control mechanisms. As our knowledge
of the nervous system continues to increase, we are
beginning to understand the mechanisms that may
underlie many of these therapies. However, the
complexities of the systems involved and the unique
characteristics of each patient make it difficult to
know which treatment will work in any specific
instance. This same diversity of treatments and
mechanisms also lends hope to finding a therapy
that will work for most of those who suffer from
pain.
TYPES OF PAIN MEDICATIONS
Throughout the years, many medications have been
tried for the treatment of pain. Those with potential
or demonstrated efficacy are classified into a number
of categories. The first comprises the non-opioid
analgesic agents, which include only nonsteroidal
antiinflammatory agents and acetaminophen. By
reducing the inflammatory cause of pain and with a
central activity that is of uncertain importance, they
are often highly effective in somatic pain, acute
(postoperative) or chronic (arthritis). In most cases of
somatic pain, they can substantially enhance the
effects of opioid medications. The second group of
medications comprises agents that have significant
neurological activity, sometimes categorized as neu-
ronal membrane stabilizers, although the mechanism
of activity for many of these agents is not fully
defined. Since there are multiple types of medication,
the group is called adjuvant agents, implying a
nonspecific group that works with the analgesics.
This group includes primarily the anticonvulsants,
antidepressants, and antispasmodics but not the
current antipsychotics. A third group comprises local
anesthetic agents predominantly applied locally but
with possible systemic effects as well. The fourth
group includes agonists or antagonists for receptors
thought to be important in the production or
modulation of pain that are not included in the
previous groups. Two of the primary constituents are
a2-adrenergic agonists and N-methyl-d-aspartate
(NMDA) receptor antagonists.
Nonsteroidal Analgesics
The non-opioid analgesics are the nonsteroidal
antiinflammatory drugs. Unlike opioids, the nonster-
oidal antiinflammatory drugs have a ceiling effect.
Doses higher than the maximum level do not have
additional effect. They are effective in controlling
most somatic pain conditions with fewer cognitive
side effects than opioids, and patients do not develop
tolerance to the effect. They may also be useful in
neuropathic pain syndromes in which inflammation
150 ANALGESICS, NON-OPIOID AND OTHER
See also–Analgesics, Non-Opioid and Other;
Opioids and Their Receptors; Pain, Cancer and;
Pain, Invasive Procedures for; Pain Management,
Multidisciplinary; Pain, Overview
Further Reading
Cherny, N. I., and Portnoy, R. K. (1994). The management of
cancer pain. CA Cancer J. Clin. 44, 263–303.
Cherny, N. I., Arbit, E., and Jain, S. (1996). Invasive techniques in
the management of cancer pain. Hem. Oncol. Clin. North Am.
10, 121–137.
Emanuel, E. J. (1996). Pain and symptom control: Patients’ rights
and physician responsibilities. Hem. Oncol. Clin. North Am.
10, 41–56.
Fernandez, E., and Turk, D. C. (1989). The utility of cognitive
coping for altering pain perception: A meta analysis. Pain 38,
123–135.
Hippocrates (1977). The art. In Ethics in Medicine (S. J. Reiser and
A. J. Dyck, Eds.), reprint. MIT Press, Cambridge, MA.
Syrjala, K. (1993). Integrating medical and psychological treat-
ments for cancer pain. In Current and Emerging Issues in
Cancer Pain: Research and Practice (C. R. Chapman and K. M.
Foley, Eds.), pp. 393–409. Raven Press, New York.
Syrjala, K., Donaldson, G. W., David, M. W., et al. (1995).
Relaxation and imagery and cognitive–behavioral training
reduce pain during cancer treatment: A controlled clinical trial.
Pain 63, 189–198.
World Health Organization (1982). Cancer Pain Relief. World
Health Organization, Geneva.
World Health Organization (1986). Cancer Pain Relief. World
Health Organization, Geneva.
World Health Organization (1990). Cancer Pain and Palliative
Care. World Health Organization, Geneva.
Analgesics, Non-Opioid
and Other
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ALTHOUGH OPIOID ANALGESICS remain the mainstay
of therapy for most acute and chronic pain generated
from pain-specific somatic nerve endings, other types
of medications and pain treatments are useful in
enhancing their effect. These adjuvant therapies also
play an important and primary role in the treatment
of pain that is produced directly from the nerve
(neuropathic pain), which patients usually describe
as ‘‘unfamiliar pain.’’ These therapies consist of a
wide variety of treatments, which can be classified as
medications, alternate delivery systems, procedures,
and intrinsic control mechanisms. As our knowledge
of the nervous system continues to increase, we are
beginning to understand the mechanisms that may
underlie many of these therapies. However, the
complexities of the systems involved and the unique
characteristics of each patient make it difficult to
know which treatment will work in any specific
instance. This same diversity of treatments and
mechanisms also lends hope to finding a therapy
that will work for most of those who suffer from
pain.
TYPES OF PAIN MEDICATIONS
Throughout the years, many medications have been
tried for the treatment of pain. Those with potential
or demonstrated efficacy are classified into a number
of categories. The first comprises the non-opioid
analgesic agents, which include only nonsteroidal
antiinflammatory agents and acetaminophen. By
reducing the inflammatory cause of pain and with a
central activity that is of uncertain importance, they
are often highly effective in somatic pain, acute
(postoperative) or chronic (arthritis). In most cases of
somatic pain, they can substantially enhance the
effects of opioid medications. The second group of
medications comprises agents that have significant
neurological activity, sometimes categorized as neu-
ronal membrane stabilizers, although the mechanism
of activity for many of these agents is not fully
defined. Since there are multiple types of medication,
the group is called adjuvant agents, implying a
nonspecific group that works with the analgesics.
This group includes primarily the anticonvulsants,
antidepressants, and antispasmodics but not the
current antipsychotics. A third group comprises local
anesthetic agents predominantly applied locally but
with possible systemic effects as well. The fourth
group includes agonists or antagonists for receptors
thought to be important in the production or
modulation of pain that are not included in the
previous groups. Two of the primary constituents are
a2-adrenergic agonists and N-methyl-d-aspartate
(NMDA) receptor antagonists.
Nonsteroidal Analgesics
The non-opioid analgesics are the nonsteroidal
antiinflammatory drugs. Unlike opioids, the nonster-
oidal antiinflammatory drugs have a ceiling effect.
Doses higher than the maximum level do not have
additional effect. They are effective in controlling
most somatic pain conditions with fewer cognitive
side effects than opioids, and patients do not develop
tolerance to the effect. They may also be useful in
neuropathic pain syndromes in which inflammation
 ANALGESICS, NON-OPIOID AND OTHER 151

is involved in maintaining the pain (e.g., nerve primary roles, many actually have activity in multiple
entrapment syndromes) or is a consequence of the disorders and can be considered as generally neu-
pain (e.g., muscle spasm secondary to a radiculo- roactive compounds. For example, many of the
pathy). However, with chronic use there is a risk of anticonvulsant drugs demonstrate significant anti-
gastrointestinal bleeding of up to 5% per year. There depressant and antianxiety properties in addition to
is also a risk of hematological abnormalities and their antinociceptive properties.
renal failure with long-term use. The newer selective
cyclooxygenase-2 (Cox-2) blocks inflammation with-
out blocking the prostaglandins involved in main- Anticonvulsants
taining the integrity of the lining of the stomach as
The use of anticonvulsant medications for pain
well as platelet function. As such, the peptic ulcer
management began in the 1960s, but the benefit
rate is much lower and there is less concern about the
was not conclusively shown until well-designed and
potential for bleeding. However, it has the same rate
controlled trials of carbamazepine showed activity in
of gastrointestinal discomfort and risk of renal
controlling trigeminal neuralgia. Valproic acid was
failure.
later shown to prevent migraine headaches. Both
The clinical trials of most Cox-1 NSAIDs have
have significant potential toxicities but were widely
demonstrated a clinical and statistically significant
used because no new agents became available
benefit. Cox-1 NSAIDs can play a major role in the
between the mid-1970s and early 1990s. However,
treatment of pain and inflammation. In analgesic
during the past 10 years there has been an explosion
studies, the currently approved Cox-2 agents demon-
of new compounds with a number of unique
strated that a single low-dose level is as effective as
properties and lower side effect profiles (Table 1).
aspirin for pain relief following dental extraction.
Although all of these drugs were initially approved
Clinical studies have further established higher dose
for epilepsy, with the substantially improved safety
ranges for osteoarthritis and rheumatoid arthritis. In
profile each has or will be tried in various pain
multiple analgesic studies, pain relief has been
syndromes. Based on carefully conducted clinical
demonstrated for postoperative dental pain, post-
trials, some are now as important in pain manage-
orthopedic surgery pain, and primary dysmenorrhea.
ment as they are in epilepsy.
Currently, only a Cox-1 agent is approved for
Their mode of action as analgesics is not well
intravenous use, but a new Cox-2 agent is in final
understood, but it is presumed to relate to their
trials and appears to be effective, safe, and well
action on neurons to suppress abnormal neural
tolerated in treating postoperative oral surgery.
firing, including paroxysmal and aberrant discharges,
Like the NSAIDs, acetaminophen has an analgesic
and decrease neuronal hyperactivity. At the cellular
effect and antipyretic activity, but it does not inhibit
level, possible mechanisms include modulation of ion
platelet function or induce gastrointestinal ulcera-
channel, transmitter production, and/or transmitter
tion. It is 10 times less potent than aspirin as a
reuptake. These mechanisms are hypothesized to be
peripheral Cox inhibitor, but it has almost equivalent
responsible for their activity in pain control.
potency as aspirin in the brain. This has led to the
hypothesis that the analgesic effect of acetaminophen
is due to a central inhibition of the prostaglandin
Table 1 ANTICONVULSANTS
synthesis. However, clinical studies have shown that
local applications of acetaminophen are also effective Anticonvulsant Dose range (mg/day) Timing
in pain relief. Thus, central and peripheral mechan- Gabapentin 300–43600 qhs to qid
isms of action may both exist. Although clearly safe Carbamazepine 100–1600 bid to qid
at standard doses, liver failure can occur at doses as Lamotrigine 150–500 bid
low as twice the maximum recommended dose and is Phenytoin 100–300 qd
the primary concern with this medication. Topiramate 25–400 bid
Adjuvant Analgesic Agents Valproic acid 150–43000 tid
Clonozepan 1–10 bid
Adjuvant analgesics are drugs that were developed Oxcarbazipine 300–2400 bid
for primary indications other than pain but are Zonisamide 100–400 bid (qd)
analgesic in specific circumstances. Although they are Leviteracetam 1000–3000 bid
usually classified into groups according to their
152 ANALGESICS, NON-OPIOID AND OTHER
Just as a seizure is often the final outcome of many
different types of epilepsy and different types of
epilepsy respond to different medication, pain
perception is a final common pathway for many
peripheral and central physiological abnormalities.
Combined with the difference in mode of action of
each anticonvulsant drug and the large degree of
intraindividual variability in the absorption and
metabolism of various drugs, it is not surprising that
the clinically important response rate is often less
than 50% for any one drug. Therefore, the response
to one drug does not necessarily predict the potential
response to others. Although it is sensible to start
with a medication that has been shown to be
effective for a particular pain syndrome, which drug
will ultimately be most effective for a particular
patient generally cannot be predicted with certainty.
This leads to one of the principles of adjuvant
therapy––namely that a chronic pain patient with a
suspected neuropathic pain component should be
started on the drug likely to be most effective for the
syndrome being treated or, baring adequate efficacy
data, the drug that is safest for the patient. However,
if that drug does not provide adequate relief after
trial of the maximum tolerated dose for a long
enough period of time to assess the response, the
patient should be prescribed the next most likely
beneficial drug in the category and so on through all
the possible medications until each possibility has
been tried or an effective dose is found. Examples of
neuroactive drugs are presented next.
Of the older group of drugs, carbamazepine
remains the most widely used antiepileptic for the
treatment of trigeminal neuralgia despite its rare but
well-described serious side effects, including bone
marrow suppression and liver toxicity. The more
common and reversible side effects of dizziness and
reduced cognitive functioning usually attenuate with
time but can be dangerous for older patients who
may be injured in a fall. These centrally acting agents
have also been tried for other neuropathic pain
processes. Due in part to problems in study design
and incomplete understanding of the potential
pathophysiological mechanism, the results were
variable and inconsistent. Only recently have care-
fully performed studies of valproic acid led to Food
and Drug Administration (FDA) approval for pre-
vention of episodic pain, specifically classic migraine
headaches, which are thought to be predominately
mediated through the trigeminal system. Of the
newer agents, gabapentin is the first to have
demonstrated analgesic efficacy in two careful
randomized clinical trials in patients with postherpe-
tic neuralgia and diabetic neuropathy. In both
studies, clinically important efficacy (moderate or
better pain relief) was demonstrated in 30–40% of
cases. Of equal importance is evidence that gaba-
pentin is not appreciably metabolized in the liver and
is predominantly excreted renally unchanged. It also
has almost no drug–drug interactions and is usually
well tolerated by patients. Its primary side effects are
sedation and reduced cognition. Sedation can be
useful in patients who have trouble sleeping, and
patients usually accommodate the cognitive effects
over time. Confirmed by other trials, gabapentin is
the first oral medication to gain FDA approval for
therapy of postherpetic neuralgia.
Many anticonvulsant drugs other than gabapentin
have been tried as treatment for neuropathic pain.
There are ongoing studies for most of the newer
agents, some of which are very promising, but the
available randomized trial data are limited. How-
ever, there is reason to believe that many of these
agents may be useful, as has been suggested by
smaller studies. The newer anticonvulsants being
considered include lamotrigine, topiramate, tiaga-
bine, zonisamide, and leveteracetam. The potential
for life-threatening aplastic anemia with felbamate
has discouraged its use. Lamotrigine is a potent
sodium channel blocker that may reduce the ectopic
discharge of dysfunctional nerves. Lamotrigine has
been shown to have potential benefit in trigeminal
neuralgia, diabetic neuropathy, and HIV neuropathy
in small controlled trials. It may be difficult to use
because it requires very gradual initial dose escala-
tion to reduce the risk of rash, and it should be
stopped if a rash occurs. Topiramate appears to
block voltage-dependent sodium channel and excita-
tory amino acids and potentiate GABA. Clinical
experience with topiramate has been limited but
favorable in some of the clinical trials currently
under way. Oxcarbazepine is currently undergoing
trials for trigeminal neuralgia, and zonisamide will
likely be tested for efficacy in peripheral neuropathic
pain. Since the pathophysiological mechanism for
many of these is different, the clinical impression is
that all these agents should be given a trial until one
is found that is effective for a particular patient with
pain. For all these medications, the initial dose
should be as high as can be safely given or a dose
should be administered that will not produce overly
bothersome side effects. It should then be titrated to
the maximum tolerated dose or effect, whichever
occurs first. The exact spectrum of side effects varies

by drug, but cognitive effects and ataxia are often a
problem.
Based on existing evidence, gabapentin is the first-
line adjuvant analgesic for postherpetic neuralgia
and diabetic neuropathy pain. Because of the
demonstrated safety and ease of use, it may be
appropriate to consider it for the initial trial in other
neuropathic pain syndromes. As with many drugs
used to treat symptoms, it cannot be predicted before
treatment which patients will benefit from gabapen-
tin. If a medication is to be used without knowing
whether it will be effective for any particular patient,
it is vital that the medication be extremely safe. As
the number of antiepileptic agents increases, many
with fewer side effects and proven safety, the number
of medications available for pain therapy will
increase dramatically.
Antidepressants
The role of some antidepressants in the treatment of
neuropathic pain, including tricyclic antidepressants
(TCAs), serotonin reuptake inhibitors (SSRIs), aty-
pical antidepressants, and monoamine oxidase in-
hibitors (MAOIs), is well established. The
improvement of pain symptoms has been demon-
strated for several TCAs and SSRIs, but the existence
of an independent analgesic effect has only been well
studied in the TCAs. In particular, amitriptyline,
nortriptyline, and desipramine can produce signifi-
cant pain relief in postherpetic neuralgia and diabetic
neuropathy. Possible mechanisms of the analgesic
effect include the potentiation of the inhibitory
effects of norepinephrine and possibly serotonin
within the descending pain-modulating system of
the central nervous system or the blocking of sodium
channels mediating ectopic discharges from injured
nerves.
The most common side effects of the TCAs are
sedation, urinary retention, dry mouth, and somno-
lence. These drugs may also cause serious side effects,
such as orthostatic hypotension and cardiac arrhyth-
mias. There is wide variation in side effects among
individual drugs and patients. In general, the tertiary
amines TCAs (e.g., amitriptyline) produce more
somnolence than the secondary amines. If a patient
has trouble sleeping, a tertiary amine is probably
best; excessive somnolence may be improved by
switching to a secondary amine (e.g., desipramine).
These drugs provide relief at lower dosage with
quicker onset for pain than for depression. To allow
for side effects, the initial dose should be low––10 mg
at night for the elderly and those predisposed to side
ANALGESICS, NON-OPIOID AND OTHER 153
effects and 25 mg at night for others. Analgesic
effects usually occur within 4–7 days after achieving
an effective daily dose (50–150 mg for amitriptyline
and desipramine). However, a TCA trial cannot be
considered adequate until satisfactory pain relief or
intolerable side effects occur. If intolerable side
effects do not occur as doses are increased, a trial
of higher doses may be indicated. It is prudent to
obtain blood levels at higher doses and an electro-
cardiogram in patients with known heart disease.
Although there are no data relating a specific plasma
drug concentration to analgesia, measurement of
plasma drug concentration can help guide therapy.
Approximately 10% of the population are rapid
metabolizers and will require higher doses. Dose
escalation is usually not pursued if the concentration
is at or exceeds the upper limit of the antidepressant
range. Side effects include dry mouth, somnolence,
weight gain, constipation, and memory impairment.
The SSRIs are a relatively new class of antidepres-
sants. There are very few controlled trials of the
SSRIs (e.g., fluoxetine, paroxetine, and mirtazapine)
and the atypical antidepressants. However, clinical
studies have shown that citalopram and paroxetine
may relieve some pain in diabetic neuropathy. In the
atypical group are several drugs that have activity at
both serotonin and other monoaminergic receptors
(e.g., venlafaxine and nefazodone). Although results
have been variable, some evidence favors analgesic
effects for venlafaxine. The clinical experience is that
these drugs are effective antidepressants and gener-
ally better tolerated than TCAs. Although the
existence of a large independent analgesic effect is
lacking for SSRIs, the rate of concomitant depression
with pain is high. Effective therapy for depression
may well lead to substantial improvement in a
patient’s condition.
MAOIs have not been used in the management of
patients with pain as a primary problem. The
potential serious interaction between MAOIs and
many other medications commonly used in pain
management make their use dangerous.
Local Anesthetics
Lidocaine is a nonspecific sodium channel blocker
that is primarily administered by injection for
regional anesthesia and intravenously for cardiac
arrhythmia. Controlled clinical trials have reported
that systemic administration of both oral and
parenteral local anesthetic drugs may result in some
degree of analgesia in diverse pain syndromes, but
the results are inconsistent. The proposed mechanism
154 ANALGESICS, NON-OPIOID AND OTHER
of action in neuropathic pain is sodium channel
blockade, which reduces the frequency of abnormal
ectopic impulses generated by dysfunctional nerves.
When given systemically, the onset of pain relief
typically occurs with blood levels lower than the
antiarrhythmic range, and it is usually prompt when
it occurs. A brief intravenous local anesthetic
infusion can sometimes yield analgesic effects that
outlast the duration of the drug by a prolonged
period of time.
Because of the rapid onset of its effect, a trial with
this method could be useful in the management of
patients with severe, rapidly progressive neuropathic
pain that has not responded to intravenous boluses of
opioids. In clinical practice, the response to intrave-
nous lidocaine infusion is used to try to predict the
response to orally administered mexiletine. Lido-
caine is administered in a dose of 2–5 mg/kg for 20–
30 min. If patients obtain significant pain relief, they
are somewhat more likely to respond to a titrating
trial of mexiletine. Alternative drugs, such as
tocainide and flecainide, have also been used for
neuropathic pain. The most common acute side
effect of mexiletine is nausea, and other side effects
include dizziness and anxiety.
Case reports and series have shown efficacy in
neuropathic pain patients, but randomized trials
have had mixed results and few dramatic responses.
Several negative studies have been published; the
largest trial to date tested mexiletine in 126 patients
with diabetic neuropathy and found only minimal
differences between treated and placebo groups in
nighttime pain relief and sleep improvement.
Although relatively safe, patients with a history of
heart disease (either myocardial dysfunction or
arrhythmia) may be at increased risk of serious
adverse effects and should undergo an appropriate
cardiac evaluation before local anesthetic therapy is
initiated. There is even more limited experience in
the use of these drugs as analgesics in the medically
ill. As such, they should be considered as second-line
therapy for those patients who failed anticonvulsants
and antidepressants.
a2-Adrenergic Agonists
The a2-adrenergic agonists have demonstrated an-
algesic efficacy in a few pain syndrome case reports
and a few randomized trials in specific patient
groups. A number of hypotheses have been proposed
for the mechanism of action, including inhibition of
neurotransmission between primary afferent noci-
ceptors and second-order sensory neurons, increased
activation of descending inhibitory pathways, and a
direct inhibitory effect on neuronal firing at receptor
sites in the substantia gelatinosa.
Because of the high density of a2-adrenergic
receptors in the spinal cord, epidural and intrathecal
administration of clonidine are most popular. In a
study of 85 cancer patients who had failed more
conventional therapy, 30 mg/hr epidural clonidine or
placebo was given for 14 days, together with rescue
epidural morphine. Clinically important analgesia
was achieved more often with epidural clonidine
(45%) than with placebo (21%). Patients with
neuropathic pain appeared to have a greater response
(clonidine, 56%; placebo, 5%). In a controlled,
comparative study, intrathecal clonidine was at least
10 times more potent than epidural clonidine in
relieving acute noxious heat stimulation but only up
to 2 times more potent in relieving intradermal
capsaicin-induced hyperalgesia and allodynia. The
mechanism is unknown. Transdermal trials suggest
that approximately one-fourth of patients report
some effect. The most common side effects are
somnolence and xerostomia. The most important
risk is hypotension. Because of its risk and benefit
ratio, a trial of systemic clonidine is usually
considered only after other adjuvant analgesics have
failed.
NMDA Receptor Antagonists
The NMDA receptor is thought to be involved in the
modulation of the transmission of pain. In addition
to primary analgesic effects, NMDA receptor
antagonists may enhance the efficacy of opioid
agents either by reducing the development of
tolerance or by reducing the side effects. The
mechanism of action is that NMDA receptor
antagonist binds to receptor sites in the spinal and
central nervous system, blocking the generation of
the central pain sensation arising from peripheral
nociceptive stimuli and enabling a reduction in the
amount of analgesics required for pain control.
However, only modest benefits have been demon-
strated in human clinical trials. The best studied
agent is dextromethorphan. The beginning dose is
120–240 mg/day in three or four divided doses, and
it should be increased gradually. Sedation is the
primary side effect.
Ketamine, a partial NMDA antagonist, has also
been studied, and there are case reports of marked
improvement in a few patients with refractory
neuropathic pain. However, broader clinical experi-
ence suggests that the drug is only occasionally

effective and has significant central nervous system
side effects, including occasional prolonged halluci-
nations. When administered as an infusion, subanes-
thetic doses typically beginning as low as 0.1–1.5 mg/
kg/hr have been used with limited success in a small
number of patients with refractory neuropathic pain.
Although not well absorbed, occasionally oral doses
are also given with opioid in an attempt to enhance
the effect.
Corticosteroids
Corticosteroids (e.g., prednisone, methylpredniso-
lone, and dexamethasone) are thought to have an
analgesic effect due to their antiinflammatory proper-
ties. In addition, there is also evidence that corticos-
teroids have sodium channel blocking activity and
thereby may reduce ectopic impulse generation in
neuropathic pain. Several small controlled trials have
reported pain relief with brief pulse therapy in
complex regional pain syndrome. In the cancer
population, corticosteroids have been shown to
improve pain, appetite, nausea, malaise, and overall
quality of life over the short term. One of the
accepted pain-related indications is refractory neuro-
pathic pain, although this indication has not been
evaluated in controlled clinical trials. Pain relief for
tumors is presumably related to reduced peritumoral
edema and inflammation, thereby reducing the
pressure and traction on nerves. Current data are
inadequate to evaluate drug-specific differences,
dose–response relationships, predictors of efficacy,
and the durability of favorable effects. However,
clinical experience indicates that a trial of oral
steroids may be beneficial for pain that is due to
the spread of bulky tumor to a nerve plexus or bone.
In a large survey of low-dose corticosteroid
therapy in patients with advanced cancer, the actual
risk of serious adverse effects was acceptably low.
Potential serious adverse effects include increased
risk of infection, myopathy, diabetes, fluid overload,
cushingoid habitus, increased risk of skin break-
down, and neuropsychiatric syndromes (ranging
from mild dysphoria or mental clouding to severe
anxiety, depression, or even psychosis). The risk of
adverse effects associated with corticosteroid therapy
increases with both the dose and the duration of use.
Therefore, the long-term administration of these
drugs for pain is usually considered only for patients
with advanced disease whose limited life expectancy
and overriding need for symptom control justify
the risk.
ANALGESICS, NON-OPIOID AND OTHER 155
ALTERNATE DELIVERY SYSTEMS
Topical Therapies
Topical therapies (local anesthetics) are useful for
patients who have a small area of allodynia or pain.
The FDA recently approved a specially formulated
lidocaine patch for the treatment of postherpetic
neuralgia. Like other local anesthetics, lidocaine
causes sodium channel blockade, reduces peripheral
nociceptor stimulation, and ultimately may decrease
central nervous system hyperexcitability. An initial
trial may use lidocaine patch or a 5% lidocaine
preparation. The patch has been approved with
application 12 hr per day.
There is evidence that topical NSAIDs can be
effective for soft tissue pain and possibly joint pain.
A trial of a compounded formulation containing
diclofenac, ketoprofen, or another NSAID is reason-
able when pain in the medically ill is related to
chronic soft tissue injury. Although likely to be safe,
a trial of these drugs for neuropathic pain has little
support.
Topical capsaicin has been found to be effective in
neuropathic pain caused by peripheral nerve injury
but is difficult to use. Capsaicin impedes afferent
pain impulse by releasing peptides in small primary
afferent neurons and subsequently depleting sub-
stance P. Topical capsaicin has been demonstrated to
have efficacy for painful arthropathy and musculos-
keletal pain. Most patients find the burning and
discomfort associated with capsaicin application
difficult to tolerate, which may be one of the reasons
why clinical experience has been mixed. Starting
with the lower concentration formulation (0.05%) of
capsaicin and simultaneous use of a cutaneous
application of 5% lidocaine ointment or use of an
oral analgesic may help patients tolerate the initial
period of use. A therapeutic trial of the high-
concentration formulation (0.075%) is reasonable
in patients with neuropathic pain presumed to have a
strong peripheral input. An adequate trial is gen-
erally believed to consist of four applications daily
for 1 month. Daily use is required since missing even
a few doses allows the return of substance P and the
discomfort experienced with the initial use.
Intrathecal
In addition to adjuvant therapies, there are alter-
native methods of administering these medications,
including intravenous, subcutaneous, epidural, in-
trathecal, and intraventricular. Of these, the intra-
venous method is best known. The primary form is
156 ANALGESICS, NON-OPIOID AND OTHER
the use of a postoperative intravenous device to
allow titration for adequate pain control. Otherwise
known as opioid patient-controlled analgesia, this
allows the rapid delivery of opioid in the vein at the
push of a button. The dose is dependent on the
patient and the procedure, but it often consists of
1 mg every 10–15 min until the patient achieves
adequate pain control. Although a fair amount of
work for the patient, it is generally safe and unlikely
to result in respiratory depression unless a well-
meaning family member pushes the button for the
patient after the patient has gone to sleep. Patients
who have used an opioid for pain prior to the
procedure almost always require a baseline contin-
uous infusion adequate to meet their daily use of
medication (adjusted for the difference in potency
between oral and intravenous) and a PRN dose of
10–15% of the 24-hr opioid dose for titration.
Opioid use for more than 2 weeks provides
substantial protection against respiratory depres-
sion.
Intrathecal delivery of opioid and other medica-
tions has revolutionized postoperative care for many
types of surgery, especially for bone repair, joint
replacement surgery, or chest surgery. It is clear that
adequate pain therapy after such surgery remarkably
reduces the morbidity and mortality associated with
being bedridden for days. With adequate epidural
care and possibly even epidural patient-controlled
analgesia, many of these patients, especially older
patients, would not have the complications that
result from staying in bed.
Short-term intrathecal use is usually provided by a
catheter with an external pump attachment. Long-
term use for chronic pain is a controversial subject.
Mechanically, it requires an intrathecal catheter to be
placed and tunneled subcutaneously next to an
implantable pump. This pump is programmable
through the skin and refillable by placement of a
needle through the skin and into the reservoir in the
pump. In general, the most appropriate use is for
patients who obtain adequate relief from oral opioids
but have unacceptable side effects. Given the 100:1
intrathecal to oral ratio for many drugs, the dose is
much smaller and closer to the organs involved in the
pain process.
In addition to opioids, other medications that have
been placed intrathecally include baclofen for pa-
tients with severe muscle spasms, clonidine (no
controlled trials), and local anesthetic that can be
combined with the opioid to enhance its effect,
especially in neuropathic pain.
Another route is worth mentioning primarily for
its use in palliative care. A subcutaneous infusion of
narcotic is possible, provided that more than 1.5–2.0
cc is given per hour. Using high concentrations of
morphine or hydromorphone, it is possible to
provide a large dose of narcotic subcutaneously. In
general, this is done with a micropump connected to
a butterfly needle that is placed into the skin. The site
should be changed every 3 days or more frequently if
there is any irritation.
—Dajie Wang and John T. Farrar
See also–Analgesia, Cancer Pain and;
Antidepression Pharmacology; Neuropathic Pain
Syndromes; Opioids and Their Receptors; Pain,
Assessment of; Pain Management, Psychological
Strategies; Pain, Overview
Further Reading
Anonymous (2000). Drug treatment of neuropathic pain. Drug
Ther. Bull. 38, 89–93.
Collins, S. L., Moore, R. A., McQuay, H., et al. (2000).
Antidepressants and anticonvulsants for diabetic neuropathy
and postherpetic neuralgia: A quantitative systematic review. J.
Pain Symptom Manage. 20, 449–458.
Dworkin, R. H., Galer, B. S., and Perkins, F. M. (2000).
Mechanisms and treatment of neuropathic pain. Clin. J. Pain
16, S1–S112.
Fishbain, D. (2000). Evidence-based data on pain relief with
antidepressants. Ann. Med. 32, 305–316.
Harden, R. N., and Cole, P. A. (1998). New developments in
rehabilitation of neuropathic pain syndromes. Neurol. Clin. 16,
937–950.
Padilla, M., Clark, G. T., and Merrill, R. L. (2000). Topical
medications for orofacial neuropathic pain: A review. J. Am.
Dental Assoc. 131, 184–195.
Ross, E. L. (2000). The evolving role of antiepileptic drugs in
treating neuropathic pain. Neurology 55, S41–S46; discussion
S54–S58.
Stojanovic, M. P. (2001). Stimulation methods for neuropathic
pain control. Curr. Pain Headache Rep. 5, 130–137.
Watson, C. P. (2000). The treatment of neuropathic pain:
Antidepressants and opioids. Clin. J. Pain 16, S49–S55.
Wiffen, P., McQuay, H., Carroll, D., et al. (2000). Anticon-
vulsant drugs for acute and chronic pain. Cochrane
Database of Systematic Reviews No. 2, CD001133.
[computer file]
Andersen’s Disease
see Glycogen Storage Diseases

Anencephaly
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANENCEPHALY is a devastating congenital malforma-
tion in which both cerebral hemispheres are absent in
association with an extreme cranioschisis, resulting
in the failure of development of the frontal, parietal,
and occipital bones. The embryonic cranial neural
tube does not fuse, which facilitates exposure of the
differentiating brain to amniotic fluid, resulting in
the subsequent degeneration of the forebrain germ-
inal cells. The malformation probably occurs before
days 24–26 of embryonic life, at which time the
anterior neuropore normally closes. The possible
etiologies for failure of neural tube fusion include
infection, metabolic abnormalities of the mother
such as diabetes mellitus or folic acid deficiency,
chromosomal abnormalities, and exposure to drugs
or other toxic agents or irradiation. However, there is
no known specific cause. Some investigators suggest
that dysraphic states are the result of rupture of the
closed neural tube following its normal closure, but
these hypotheses have not been generally accepted.
The injured neural tissue results in a tangled mass of
disorganized neuro-glial-vascular tissue. The meso-
derm does not differentiate normally into somites
and sclerotomes, which comprise the primordial base
of the skull, the calvarium and vertebrae.
Malformations of the foramen magnum and
cervical vertebrae are commonly associated findings,
and other abnormalities include a small cerebellum,
brainstem, and spinal cord, with an absence of
descending tracts within the spinal cord. The
pituitary is absent with secondary adrenal hypopla-
sia. The optic nerves are missing but the eyes are
normal, suggesting that there is normal optic
vesicular formation from the anterior cephalic end
of the neural tube. The anencephalic patient has a
deformed forehead with large eyes and ears. The
appearance of the face is otherwise generally
considered unremarkable (Fig. 1).
Anencephaly is a lethal condition and most
patients are stillborn; those who survive live only a
matter of days. The primitive reflexes, including the
Moro, sucking, and rooting reflexes, are present and
patients can have spontaneous movements of the
head, face, torso, and limbs and may withdraw from
painful stimuli. Moreover, those who survive several
days or longer may respond to auditory or vestibular
ANENCEPHALY 157
Figure 1
Two-day-old infant with anencephaly. Note the dark neuroglial
vascular tangled mass of tissue occupying what should be cerebral
space (arrows). The ears and eyes are prominent, but facial
appearance is otherwise normal.
stimuli that are facilitated by neural pathways that
are not associated with cerebral neural tracts. Some
anencephalic patients have had seizures, suggesting a
seizure origin in the primitive parts of the central
nervous system.
The prenatal diagnosis of anencephaly and other
neural tube defects can be determined by ultrasono-
graphy as well as by assessing the concentration of a-
fetoprotein in the amniotic fluid and maternal serum.
The diagnostic reliability of ultrasonography has
notably improved during the past several decades,
and when performed by experienced persons it is
approximately 100%. The determination of a-feto-
protein in the amniotic fluid and maternal serum has
enabled the diagnosis of anencephaly and other open
neural tube defects to be made earlier, resulting in the
voluntary termination of pregnancy in some cases.
a-Fetoprotein is the primary component of fetal
serum protein and is initially produced in the yolk
sac and later in the liver and gastrointestinal tract. It
passes from the fetal serum to the fetal urine and
ultimately to the amniotic fluid. In patients with
anencephaly or open neural tube defects, there is a
leak of fetal blood into the amniotic fluid and, hence,
the a-fetoprotein concentrations of the amniotic fluid
158 ANESTHETICS
and maternal serum are increased. The a-fetoprotein
concentration in normal maternal serum and amnio-
tic fluid varies from 15 to 500 ng/ml, but concentra-
tions of 1000 ng/ml or higher at 15–20 weeks of
gestation strongly suggest the presence of an open
neural tube defect. The concentration of a-fetopro-
tein in the amniotic fluid and maternal serum varies
during the gestational period and peaks at 12–15
weeks; thus, it is critical to know the fetal gestational
age in order to determine the optimal time for
determining the a-fetoprotein concentration. Skin-
covered or closed neural tube defects may not be
recognized by assay of the a-fetoprotein.
Anencephaly is one of the most common mal-
formations of the central nervous system, with
variable rates of incidence throughout the world.
For reasons that are unclear, the highest rates occur
in Great Britain and Ireland, and the lowest
incidence rates occur in Asia, Africa, and Latin
America. It occurs more frequently in whites than
blacks, and females are affected much more fre-
quently than males. The recurrence rate of anence-
phaly in families with one similarly affected child is
approximately 35%, and approximately 10% of
siblings of the anencephalic infant have some
manifestation of other neural tube defects. No
known relationship of its occurrence in consangui-
neous mating has been established, nor has any
pattern of inheritance been demonstrated. During the
past several decades, there has been a decline in the
incidence of neural tube defects in the United States
and Great Britain, and from 1971 to 1989 the annual
incidence decreased from 2 to 0.6 per 1000 live
births. It is believed that this decreased incidence is
secondary to the administration of vitamins, parti-
cularly folic acid, to pregnant women.
There is no treatment for this severe malformation,
but British studies have shown that the risk of
recurrence of neural tube defects can be significantly
reduced if mothers are given folic acid supplementa-
tion during pregnancy. The issue of using the
anencephalic infant as a donor for organ transplanta-
tion has been vigorously considered and discussed,
but because of ethical considerations and difficulties
associated with establishing a diagnosis of brain
death in the anencephalic infant, statutory regulations
in the United States have precluded organ donation.
—Bruce Berg
See also–Brain Death; Brain Development,
Normal Postnatal; Moro Reflex; Nervous System,
Neuroembryology of; Neural Tube Defects
Further Reading
Anonymous (1989). Anencephalic infants as organ donors. N.
Engl. J. Med. 321, 388–393.
Brock, D. J. (1976). a-Fetoprotein and the prenatal diagnosis of
central nervous system disorders: A review. Child’s Brain 2, 1–23.
Giroud, A. (1960). Causes and morphogenesis of anencephaly. In
CIBA Foundation Symposium on Congenital Malformation (G.
E. Wolstenholme and C. M. O’Connor, Eds.). Churchill
Livingstone, London.
Johnson, R. T. (1971). Effects of viral infection on the developing
nervous system. N. Engl. J. Med. 287, 598–604.
Lemire, R. J. (1988). Neural tube defects. J. Am. Med. Assoc. 259,
558–562.
Lemire, R. J., Loeser, J. D., and Leach, R. W. (1975). Normal and
Abnormal Development of the Human Nervous System. Harper
& Row, New York.
Medical Task Force on Anencephaly (1990). The infant with
anencephaly. N. Engl. J. Med. 323, 615.
MRC Vitamin Study Research Group (1991). Prevention of neural
tube defects: Result of the Medical Research Council Vitamin
Study. Lancet 338, 131–137.
Nance, W. E. (1971). Anencephaly and spina bifida: An etiologic
hypothesis. Birth Defects 7, 97–102.
Osaka, K., Tanimura, T., Hirayama, A., et al. (1978). Myelome-
ningocoele before birth. J. Neurosurg. 49, 711–724.
Osaka, K., Matsumoto, S., and Tanimura, T. (1978). Myeloschisis
in early human embryos. Child’s Brain 4, 347–359.
Peabody, J., Emery, J., and Ashwal, S. (1989). Experience with
anencephalic infants as prospective organ donors. N. Engl. J.
Med. 321, 344–350.
Stone, D. H. (1987). The declining prevalence of anencephalus and
spina bifida: Its nature, causes and implications. Dev. Med.
Child Neurol. 29, 541–546.
Anesthetics
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANESTHETIC medications are used in three ways: as
inhalation products that induce general anesthesia
with sleepiness or loss of consciousness, as local
anesthetics that block sensation and pain in isolated
areas by topical application or local infusion, and as
spinal or epidural anesthetics that are used especially in
neurological, orthopedic, and gynecological surgeries.
Halothane is the prototype of the inhalational
general anesthetics. Chemically, it is a halogenated
hydrocarbon and is nonflammable, easy to adminis-
ter, and relatively safe. Halothane and related
compounds, enflurane, isoflurane, and sevoflurane,
depress cerebral metabolism. Electrical activity of the
cerebral cortex recorded by electroencephalography
(EEG) shows progressive replacement of fast, low-
voltage activity by slow, high-amplitude waves as
158 ANESTHETICS
and maternal serum are increased. The a-fetoprotein
concentration in normal maternal serum and amnio-
tic fluid varies from 15 to 500 ng/ml, but concentra-
tions of 1000 ng/ml or higher at 15–20 weeks of
gestation strongly suggest the presence of an open
neural tube defect. The concentration of a-fetopro-
tein in the amniotic fluid and maternal serum varies
during the gestational period and peaks at 12–15
weeks; thus, it is critical to know the fetal gestational
age in order to determine the optimal time for
determining the a-fetoprotein concentration. Skin-
covered or closed neural tube defects may not be
recognized by assay of the a-fetoprotein.
Anencephaly is one of the most common mal-
formations of the central nervous system, with
variable rates of incidence throughout the world.
For reasons that are unclear, the highest rates occur
in Great Britain and Ireland, and the lowest
incidence rates occur in Asia, Africa, and Latin
America. It occurs more frequently in whites than
blacks, and females are affected much more fre-
quently than males. The recurrence rate of anence-
phaly in families with one similarly affected child is
approximately 35%, and approximately 10% of
siblings of the anencephalic infant have some
manifestation of other neural tube defects. No
known relationship of its occurrence in consangui-
neous mating has been established, nor has any
pattern of inheritance been demonstrated. During the
past several decades, there has been a decline in the
incidence of neural tube defects in the United States
and Great Britain, and from 1971 to 1989 the annual
incidence decreased from 2 to 0.6 per 1000 live
births. It is believed that this decreased incidence is
secondary to the administration of vitamins, parti-
cularly folic acid, to pregnant women.
There is no treatment for this severe malformation,
but British studies have shown that the risk of
recurrence of neural tube defects can be significantly
reduced if mothers are given folic acid supplementa-
tion during pregnancy. The issue of using the
anencephalic infant as a donor for organ transplanta-
tion has been vigorously considered and discussed,
but because of ethical considerations and difficulties
associated with establishing a diagnosis of brain
death in the anencephalic infant, statutory regulations
in the United States have precluded organ donation.
—Bruce Berg
See also–Brain Death; Brain Development,
Normal Postnatal; Moro Reflex; Nervous System,
Neuroembryology of; Neural Tube Defects
Further Reading
Anonymous (1989). Anencephalic infants as organ donors. N.
Engl. J. Med. 321, 388–393.
Brock, D. J. (1976). a-Fetoprotein and the prenatal diagnosis of
central nervous system disorders: A review. Child’s Brain 2, 1–23.
Giroud, A. (1960). Causes and morphogenesis of anencephaly. In
CIBA Foundation Symposium on Congenital Malformation (G.
E. Wolstenholme and C. M. O’Connor, Eds.). Churchill
Livingstone, London.
Johnson, R. T. (1971). Effects of viral infection on the developing
nervous system. N. Engl. J. Med. 287, 598–604.
Lemire, R. J. (1988). Neural tube defects. J. Am. Med. Assoc. 259,
558–562.
Lemire, R. J., Loeser, J. D., and Leach, R. W. (1975). Normal and
Abnormal Development of the Human Nervous System. Harper
& Row, New York.
Medical Task Force on Anencephaly (1990). The infant with
anencephaly. N. Engl. J. Med. 323, 615.
MRC Vitamin Study Research Group (1991). Prevention of neural
tube defects: Result of the Medical Research Council Vitamin
Study. Lancet 338, 131–137.
Nance, W. E. (1971). Anencephaly and spina bifida: An etiologic
hypothesis. Birth Defects 7, 97–102.
Osaka, K., Tanimura, T., Hirayama, A., et al. (1978). Myelome-
ningocoele before birth. J. Neurosurg. 49, 711–724.
Osaka, K., Matsumoto, S., and Tanimura, T. (1978). Myeloschisis
in early human embryos. Child’s Brain 4, 347–359.
Peabody, J., Emery, J., and Ashwal, S. (1989). Experience with
anencephalic infants as prospective organ donors. N. Engl. J.
Med. 321, 344–350.
Stone, D. H. (1987). The declining prevalence of anencephalus and
spina bifida: Its nature, causes and implications. Dev. Med.
Child Neurol. 29, 541–546.
Anesthetics
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANESTHETIC medications are used in three ways: as
inhalation products that induce general anesthesia
with sleepiness or loss of consciousness, as local
anesthetics that block sensation and pain in isolated
areas by topical application or local infusion, and as
spinal or epidural anesthetics that are used especially in
neurological, orthopedic, and gynecological surgeries.
Halothane is the prototype of the inhalational
general anesthetics. Chemically, it is a halogenated
hydrocarbon and is nonflammable, easy to adminis-
ter, and relatively safe. Halothane and related
compounds, enflurane, isoflurane, and sevoflurane,
depress cerebral metabolism. Electrical activity of the
cerebral cortex recorded by electroencephalography
(EEG) shows progressive replacement of fast, low-
voltage activity by slow, high-amplitude waves as

anesthesia gets deeper. Since cerebral blood flow
generally increases during halothane anesthesia,
cerebrospinal fluid pressure increases. Several hours
after anesthesia with halothane the changes in
cerebral blood flow and metabolism return toward
normal. Recovery of mental function after anesthesia
with halothane is not complete for several hours.
In contrast to the general depressive effects of most
anesthetics on cerebral function, tonic–clonic muscle
activity and spike and wave EEG complexes have been
reported with enflurane anesthesia. Deepening an-
esthesia and hyperventilation may exacerbate these
phenomena. This excitatory action of enflurane does
not appear to be associated with aggravation of
seizures in epileptic patients, but enflurane is generally
avoided in subjects with a known history of epilepsy.
Rarely, the induction of anesthesia with halothane
or any of the other halogenated inhalation anes-
thetics triggers a condition termed malignant hy-
perthermia that provokes high fever and marked
muscle rigidity. In these patients, there is a defect in
the uptake of calcium into the portion of skeletal
muscle known as the sarcoplasmic reticulum, and as
a result of this defect intracellular free calcium levels
rise. Malignant hyperthermia has an incidence of 1 in
12,000 and a mortality rate of 24%. It is more
common in men and children than adult women and
occurs especially in subjects with underlying muscle
diseases or myopathies. In descending order, ha-
lothane, enflurane, and isoflurane are associated with
the precipitation of malignant hyperthermia in
predisposed subjects. The concomitant use of other
drugs such as suxamethonium and gallamine, tran-
quilizers called neuroleptics, infection, stress, heat,
and alcohol tend to increase the risk of malignant
hyperthermia.
Clinically, malignant hyperthermia is characterized
by a rapid increase in body temperature, generalized
muscular rigidity, rapid and irregular heart rhythms,
metabolic acidosis, and high levels of blood potas-
sium (hyperkalemia). The most reliable method of
diagnosis prior to exposure to anesthesia is by muscle
biopsy and a special laboratory test called the in vitro
contracture test using halothane and caffeine. If
malignant hyperthermia develops during anesthesia
with halothane or another agent, treatment consists
of cessation of the anesthetic, rapid body cooling,
supportive measures, and the drug dantrolene.
Nitrous oxide (N2O) or laughing gas was first
utilized as a dental anesthetic. When used by itself, it
produces only a light level of anesthesia, but when
used to supplement more potent anesthetics it
ANESTHETICS 159
reduces the dose requirements for those other agents.
Its euphorogenic properties, ready availability, and
low cost have contributed to its popularity as a
recreational and abuse drug. Nitrous oxide toxicity is
due to inactivation of methionine synthase, a vitamin
B12-dependent enzyme, resulting in defective synth-
esis of DNA and myelin, the chemical substance that
surrounds nervous cell projections. In animal studies,
toxic exposure with nitrous oxide causes spinal cord
damage in areas important to sensation, motor
strength, and coordination. Nitrous oxide is more
likely to produce spinal cord damage in individuals
already deficient of vitamin B12. From epidemiologi-
cal studies, without B12 deficiency or chronic and
regular exposure to high levels of nitrous oxide,
medical and dental personnel exposed to nitrous
oxide are not likely to develop adverse neurological
signs. A survey of more than 30,000 dental personnel
occupationally exposed to nitrous oxide found an
incidence of neurological complaints of less than 2%
in the population at risk. In the elderly, in whom
subclinical B12 deficiency reportedly ranges from 7.3
to 21%, the frequency of neuropathic symptoms
after anesthesia due to nitrous oxide may be under-
recognized.
Clinically, nitrous oxide neuropathy/myelopathy
presents with numbness, paresthesias, unsteady gait
(ataxia), and clumsiness in the extremities. Many but
not all the symptoms resolve with time if exposure is
discontinued. With further exposure, weakness,
impotence, and loss of bladder and bowel control
can occur. Administration of folinic acid or methio-
nine has been shown to protect against neurotoxicity.
Tension pneumoencephalus or air within the
cranium is a second problem that can occur with
nitrous oxide, specifically when it is used as part of
anesthesia for any intracranial neurosurgical proce-
dure. Following closure of the external lining of the
brain, called the dura, the increased pressure changes
can lead to seizures, brainstem herniation, and death.
Discontinuing nitrous oxide at the time of dural
closure can prevent tension pneumoencephalus.
Similarly, nitrous oxide use is also associated with
air emboli in the bloodstream—tiny air bubbles that
can act like blood clots. In patients placed in the
sitting position and undergoing surgical procedures
that involve exploration of the region called the
posterior fossa, nitrous oxide strongly increases the
risk of air emboli, and this gas should be avoided.
Local anesthetics are applied to one body region
and reversibly block nerve conduction. The most
commonly used local anesthetics are cocaine,
160 ANESTHETICS
lidocaine, bupivacaine, chloroprocaine, etidocaine,
mepivacaine, prilocaine, ropivacaine, procaine, and
tetracaine. Usually, when administered locally they
cannot reach sufficient systemic concentrations to
interfere with the function of organs where conduc-
tion or transmission of impulses occurs. However,
when local anesthetics enter the systemic circulation,
they produce adverse effects primarily on the central
nervous system. In certain instances, systemic
absorption can occur after topical use of local
anesthetics. In these cases, central nervous system
toxicity has been described.
The first sign of systemic toxicity following
administration of local anesthetics is drowsiness,
followed by tremor, restlessness, convulsions, and
ultimately central nervous system depression with
respiratory failure. Lidocaine and cocaine can
produce changes in mood and behavior. Finally,
local anesthetics can affect neuromuscular transmis-
sion, and conditions such as myasthenia gravis are
severely aggravated by use of these drugs.
Epidural anesthesia is administered by injecting
local anesthetic into the area called the epidural
space outside the dural lining of the spinal cord and
can be performed in the sacral hiatus or in the
lumbar, thoracic, or cervical regions of the spine. In
spinal anesthesia, anesthetic medication is delivered
closer to the spinal cord since the injection involves
instillation of local anesthetic into the cerebrospinal
fluid in the lumbar space. A significant difference
between epidural and spinal anesthesia is that the
dose of local anesthetic used in epidural anesthesia
can produce high concentrations in blood following
absorption from the epidural space.
Neurological complications following epidural and
spinal anesthesia are caused by trauma from the
injection, the nature of the injected material, infec-
tion, vascular lesions, or preexisting disorders that are
exacerbated by the anesthesia procedure. The in-
cidence of transient paralysis following epidural
anesthesia is 0.1% and that of permanent paralysis
is 0.02%. Neurological sequelae after spinal anesthe-
sia are rare as well. Neurological complications of
spinal or epidural anesthesia tend to be more severe in
the presence of the medical condition spinal stenosis.
During epidural anesthesia, damage to a single
nerve can occur and this trauma-induced irritation is
the most frequent complication. Strange tingling or
paresthesia with or without weakness is the present-
ing symptom and the majority of patients recover
completely. Paraplegia, resulting from spinal cord or
nerve root damage (cauda equina syndrome), can
occur secondary to epidural hematoma or abscess
formation, adhesive arachnoiditis, or anterior spinal
artery occlusion. Blood accumulation (epidural
hematoma) or infection (abscesses) should be sus-
pected if severe backache appears in combination
with weakness and decreased sensation capacity in
the lower extremities. Signs and symptoms of
extradural abscess may be delayed for several days
until the abscess has developed. Adhesive arachnoi-
ditis is an inflammation of the arachnoid, a thin
membranous cover of the spinal cord, and this occurs
especially when medications that should not be given
by this route are accidentally administered. Addi-
tionally, chemical contaminants such as detergents or
antiseptics that may be in anesthetics act as irritants
and induce a meningeal reaction that may progress to
constrictive adhesive arachnoiditis. Clinically, gra-
dual progressive weakness and sensory loss of the
lower extremities occur beginning several weeks to
months after the procedure. Pre- and postcontrast
magnetic resonance imaging of the spinal cord is
usually sufficient to diagnose arachnoiditis. Spinal
cord infarction or stroke is usually associated with
prolonged arterial hypotension that can occur in
some patients receiving anesthesia. Finally, dural
puncture may cause severe and prolonged headache
because of leakage of cerebrospinal fluid into the
extradural space. The incidence of dural puncture is
approximately 1% with these anesthetic procedures.
However, most subjects who receive these forms of
anesthesia never develop a spinal headache or, if they
do, their headache resolves spontaneously in a few
days. The use of an extradural injection of auto-
logous blood (a blood patch) is usually effective in
treating spinal headaches.
The neurological syndromes that appear after
spinal anesthesia are similar to the ones described
following epidural anesthesia. The most benign is
aseptic meningitis, characterized by high fever,
headache, nuchal rigidity, and photophobia. Symp-
toms usually appear within 24 hr of spinal anesthesia
and recovery occurs spontaneously within several
days to a week. Cauda equina syndrome is char-
acterized by urinary and fecal incontinence, localized
sensory loss in the perineal area, and varying degrees
of leg weakness. These symptoms are evident after
the effect of anesthesia has worn off and may be
permanent or show gradual regression over weeks or
months. Single nerve injury, lumbosacral polyradicu-
lopathy, adhesive arachnoiditis, spinal cord ischemia,
and postural headache can occur in circumstances
similar to the ones described for epidural anesthesia.

Spinal anesthesia is sometimes regarded as contra-
indicated in patients with preexisting disease of the
spinal cord. Although there is no experimental
evidence to support this hypothesis, it is prudent to
avoid spinal anesthesia in patients with progressive
diseases of the spinal cord.
—Katie Kompoliti and Christopher G. Goetz
See also–Consciousness; Pain, Basic
Neurobiology of; Pain, Overview (see also
various Neurosurgery articles)
Further Reading
Berthoud, M. C., and Reilly, C. S. (1992). Adverse effects of
general anaesthetics. Drug Safety 7, 434–459.
Ferdinand, R. T. (1994). Myelotoxic, neurotoxic and reproductive
adverse effects of nitrous oxide. Adverse Drug React. Toxicol.
Rev. 13, 193–206.
Kompoliti, K. (1998). Drug-induced and iatrogenic neurological
disorders. In Textbook of Clinical Neurology (C. G. Goetz and
E. J. Pappert, Eds.), pp. 1123–1152. Saunders, Philadelphia.
Marshall, B. E., and Longnecker, D. E. (1996). General
anesthetics. In Goodman and Gilman’s The Pharmacological
Basis of Therapeutics (J. G. Hardman and L. E. Limbird, Eds.),
9th ed., pp. 307–330. McGraw-Hill, New York.
Reynolds, F. (1987). Adverse effects of local anaesthetics. Br. J.
Anaesth. 59, 78–95.
Scott, D. B., and Hibbard, B. M. (1990). Serious non-fatal
complications associated with extradural block in obstetric
practice. Br. J. Anaesth. 64, 537–541.
Yuen, E. C., Layzer, R. B., Weitz, S. R., et al. (1995). Neurologic
complications of lumbar epidural anesthesia and analgesia.
Neurology 45, 1795–1801.
Aneurysms
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
INTRACRANIAL ANEURYSMS are rare vascular lesions;
however, because their rupture typically results in
significant morbidity and mortality, a great deal of
effort has been devoted to their early detection and
treatment. It is well recognized that almost all
intracranial aneurysms are acquired, and although
some occur after trauma and infection, most arise
spontaneously. The annual risk of aneurysmal sub-
arachnoid hemorrhage (SAH) in previously unrup-
tured aneurysms is approximately 1%, although
many factors may increase this risk. The natural
history of aneurysmal SAH without treatment is
almost uniformly fatal. Despite advances in detection
and treatment, morbidity and mortality remain high.
ANEURYSMS 161
EPIDEMIOLOGY
The prevalence of unruptured aneurysms is the
subject of controversy; however, most reports esti-
mate their occurrence in approximately 1–6% of the
general population. The incidence of aneurysmal
SAH is approximately 10–15 per 100,000 people per
year, of which 80–90% are from ruptured saccular
aneurysms. Despite recent advances in the early
diagnosis and treatment, SAH from aneurysms is an
important cause of premature death, occurring most
frequently between the ages of 35 and 65, with the
highest incidence between 55 and 60 years of age.
The age distribution of patients with ruptured
aneurysms is bell shaped, and the occurrence of
aneurysmal SAH in children or adults older than 80
years of age is rare. Approximately 60% of ruptured
aneurysms occur in women, who are particularly
prone to aneurysms of the intracranial carotid artery
(3:2 ratio). Men are more susceptible to anterior
communicating artery aneurysms (3:2 ratio), and the
incidence of aneurysms at the middle cerebral artery
bifurcation has an equal sex distribution.
Saccular aneurysms are usually acquired lesions
that are believed to result from prolonged hemody-
namic stress and resultant local arterial degeneration
that occurs at branch points and bifurcations of
major cerebral arteries. Hypertension, cigarette
smoking, oral contraceptives, alcohol consumption,
pregnancy, and cocaine use are all known risk factors
for SAH in general and probably also increase the risk
of aneurysm rupture. Despite the general perception
that physical exertion and emotional stress are logical
precursors to aneurysm rupture, no causal relation-
ship has been proven and, indeed, some reports
suggest that as many as 30% rupture during sleep.
The incidence of aneurysms is increased in patients
with aortic coarctation and polycystic kidney disease.
Aneurysms have also been associated with arteriove-
nous malformations, moyamoya disease, fibromus-
cular dysplasia, and other hereditary connective tissue
disorders. The occurrence of intracranial aneurysms
in more than one family member is uncommon;
however, a small percentage of patients have such a
striking family history that inherited factors seem
likely to play some part in their development. Reports
of aneurysms in familial series indicate that rupture
occurs at a smaller size and younger age.
NATURAL HISTORY
Despite advances in the recognition, diagnosis, and
treatment, the natural history of ruptured saccular

Spinal anesthesia is sometimes regarded as contra-
indicated in patients with preexisting disease of the
spinal cord. Although there is no experimental
evidence to support this hypothesis, it is prudent to
avoid spinal anesthesia in patients with progressive
diseases of the spinal cord.
—Katie Kompoliti and Christopher G. Goetz
See also–Consciousness; Pain, Basic
Neurobiology of; Pain, Overview (see also
various Neurosurgery articles)
Further Reading
Berthoud, M. C., and Reilly, C. S. (1992). Adverse effects of
general anaesthetics. Drug Safety 7, 434–459.
Ferdinand, R. T. (1994). Myelotoxic, neurotoxic and reproductive
adverse effects of nitrous oxide. Adverse Drug React. Toxicol.
Rev. 13, 193–206.
Kompoliti, K. (1998). Drug-induced and iatrogenic neurological
disorders. In Textbook of Clinical Neurology (C. G. Goetz and
E. J. Pappert, Eds.), pp. 1123–1152. Saunders, Philadelphia.
Marshall, B. E., and Longnecker, D. E. (1996). General
anesthetics. In Goodman and Gilman’s The Pharmacological
Basis of Therapeutics (J. G. Hardman and L. E. Limbird, Eds.),
9th ed., pp. 307–330. McGraw-Hill, New York.
Reynolds, F. (1987). Adverse effects of local anaesthetics. Br. J.
Anaesth. 59, 78–95.
Scott, D. B., and Hibbard, B. M. (1990). Serious non-fatal
complications associated with extradural block in obstetric
practice. Br. J. Anaesth. 64, 537–541.
Yuen, E. C., Layzer, R. B., Weitz, S. R., et al. (1995). Neurologic
complications of lumbar epidural anesthesia and analgesia.
Neurology 45, 1795–1801.
Aneurysms
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
INTRACRANIAL ANEURYSMS are rare vascular lesions;
however, because their rupture typically results in
significant morbidity and mortality, a great deal of
effort has been devoted to their early detection and
treatment. It is well recognized that almost all
intracranial aneurysms are acquired, and although
some occur after trauma and infection, most arise
spontaneously. The annual risk of aneurysmal sub-
arachnoid hemorrhage (SAH) in previously unrup-
tured aneurysms is approximately 1%, although
many factors may increase this risk. The natural
history of aneurysmal SAH without treatment is
almost uniformly fatal. Despite advances in detection
and treatment, morbidity and mortality remain high.
ANEURYSMS 161
EPIDEMIOLOGY
The prevalence of unruptured aneurysms is the
subject of controversy; however, most reports esti-
mate their occurrence in approximately 1–6% of the
general population. The incidence of aneurysmal
SAH is approximately 10–15 per 100,000 people per
year, of which 80–90% are from ruptured saccular
aneurysms. Despite recent advances in the early
diagnosis and treatment, SAH from aneurysms is an
important cause of premature death, occurring most
frequently between the ages of 35 and 65, with the
highest incidence between 55 and 60 years of age.
The age distribution of patients with ruptured
aneurysms is bell shaped, and the occurrence of
aneurysmal SAH in children or adults older than 80
years of age is rare. Approximately 60% of ruptured
aneurysms occur in women, who are particularly
prone to aneurysms of the intracranial carotid artery
(3:2 ratio). Men are more susceptible to anterior
communicating artery aneurysms (3:2 ratio), and the
incidence of aneurysms at the middle cerebral artery
bifurcation has an equal sex distribution.
Saccular aneurysms are usually acquired lesions
that are believed to result from prolonged hemody-
namic stress and resultant local arterial degeneration
that occurs at branch points and bifurcations of
major cerebral arteries. Hypertension, cigarette
smoking, oral contraceptives, alcohol consumption,
pregnancy, and cocaine use are all known risk factors
for SAH in general and probably also increase the risk
of aneurysm rupture. Despite the general perception
that physical exertion and emotional stress are logical
precursors to aneurysm rupture, no causal relation-
ship has been proven and, indeed, some reports
suggest that as many as 30% rupture during sleep.
The incidence of aneurysms is increased in patients
with aortic coarctation and polycystic kidney disease.
Aneurysms have also been associated with arteriove-
nous malformations, moyamoya disease, fibromus-
cular dysplasia, and other hereditary connective tissue
disorders. The occurrence of intracranial aneurysms
in more than one family member is uncommon;
however, a small percentage of patients have such a
striking family history that inherited factors seem
likely to play some part in their development. Reports
of aneurysms in familial series indicate that rupture
occurs at a smaller size and younger age.
NATURAL HISTORY
Despite advances in the recognition, diagnosis, and
treatment, the natural history of ruptured saccular
162 ANEURYSMS
aneurysms remains poor. Of the approximately
28,000 patients per year in North America who
have ruptured aneurysms, only 10,000 are functional
survivors. Approximately 10,000 die or are severely
disabled from the initial hemorrhage, 3000 without
warning and 7000 following unrecognized warning
symptoms. Of the 18,000 patients available for
treatment, half die or are disabled, largely because
of rebleeding or cerebral vasospasm. Results from a
cooperative study reveal the peak incidence of
rebleeding from a ruptured aneurysm occurs during
the first 24 hr (4%). The cumulative rebleed rate is
approximately 19% after the first 2 weeks, 50%
during the first 6 months, and 3% per year thereafter.
The mortality rate with rerupture is reported to be as
high as 78%. Therefore, only 1 in 3 patients with a
ruptured aneurysm returns to the premorbid state,
and some reports suggest that 66% never return to
the same quality of life before the SAH because of
mild cognitive or other neurological deficits.
Survival and successful treatment from a ruptured
aneurysm do not provide cure of the disease. Patients
who have had a previous SAH from an aneurysm are
at increased risk for the development of new
aneurysms. There is a 2% annual rate of new
aneurysm development in this patient population,
and in this subset of patients, the incidence of
aneurysmal rupture is five times higher than in the
general aneurysmal population.
Asymptomatic unruptured aneurysms are most
often encountered in patients who have had an SAH
and have two or more aneurysms, only one of which
has ruptured. Incidental aneurysms are also discov-
ered in the course of neuroimaging to investigate
unrelated neurological conditions. The risk of
aneurysmal rupture in previously unruptured aneur-
ysms in patients without a prior history of SAH
(from another ruptured aneurysm) has been esti-
mated at 1% per year, and younger age, larger
aneurysm size, and cigarette smoking increase the
risk of rupture. However, unruptured aneurysms
o7–10 mm in diameter in patients with no previous
SAH (from another ruptured aneurysm) may bleed at
a rate of 0.05% annually—a rate that is lower than
that found for unruptured aneurysms Z7–10 mm in
diameter (approximately 1% annually) or for un-
ruptured aneurysms in patients with prior SAH from
another aneurysm (approximately 1% annually).
Nonhemorrhagic symptoms and signs from unrup-
tured aneurysms occur secondary to mass effect,
thrombosis, emboli, seizures, and meningeal irrita-
tion. Aneurysms causing symptoms via mass effect
have a higher rate of rupture compared with that of
the overall aneurysm patient population, with a
frequency of 6% per year.
ANATOMY
Saccular aneurysms are focal protrusions arising
from vessel wall weaknesses at major bifurcations
on the arteries along the base of the brain. These
protrusions are generally spherical in shape, although
asymmetric expansion of the wall is not unusual,
often resulting in a multilocular appearance. Unlike
normal cerebral arteries, saccular aneurysms have no
elastic or muscular tissue in their walls. The media
and the internal elastic lamina disappear at the neck
of the aneurysm, although small fragments of elastica
may extend for short distances in the dome.
Infundibula are pyramidal-shaped dilatations at the
origins of arteries less than 3 mm in maximal
diameter that usually have a normal media and
internal elastic lamina. The infundibula must be
differentiated from saccular aneurysms because their
risk of rupture causing SAH is remote but has been
reported.
Approximately 85–90% of saccular aneurysms
occur in the anterior circulation, with the most
common locations being the anterior communicating
artery, the internal carotid artery at the origin of the
posterior communicating artery, and the middle
cerebral artery at its first major division. Posterior
circulation aneurysms comprise 10–15% of saccular
aneurysms, with the most common locations being
the basilar apex, the vertebrobasilar junction, and
the origin of the posterior inferior cerebellar artery.
However, aneurysms can occur in either circulation
and anywhere on a major cerebral artery (Fig. 1).
Aneurysms are arbitrarily classified as small (r12
mm), large (12–25 mm), and giant (425 mm).
Aneurysms of any size can rupture, but most are
found to be 6–10 mm when they do so. The size at
which aneurysms usually begin to rupture is 3 mm in
diameter, and they may cause symptoms other than
rupture when they attain a size of approximately 7
mm. Mathematical models based on blood pressure,
wall strength, and total volume of wall substance
predict aneurysmal rupture at 8 mm.
Approximately one in five patients with an
aneurysm will have more than one, and multiple
aneurysms are relatively more common in women. In
patients with multiple aneurysms, approximately
50% have aneurysms that occur on opposite sides,
20% have aneurysms that occur on the same side,
 ANEURYSMS 163

Figure 1
Sites and distribution of cerebral saccular aneurysms. The percentages are based on data reported by Fox and Drake for adults with single
aneurysms. PcoA, posterior communicating artery; AcoA, anterior communicating artery; SCA, superior cerebellar artery; PICA, posterior
inferior cerebellar artery. [From Netter, F. H. (1986). The Ciba Collection of Medical Illustrations Vol. I: The Nervous System, Part II:
Neurologic and Neuromuscular Disorders, p. 80. Ciba-Geigy, West Caldwell, NJ. Modified with permission from ICON Learning Systems.]

and 30% have one aneurysm in the midline, high-
lighting the importance of four-vessel angiography
following diagnosis of SAH. When patients with
SAH are found to have multiple aneurysms, several
factors aid in determining which lesion bled, includ-
ing the area of greatest concentration of blood on
computed tomography (CT), the area of vasospasm
on angiogram, irregularity of aneurysm contour, and
largest aneurysm size. Whenever possible, multiple
aneurysms should be treated by a single surgery,
minimizing the risk of future hemorrhage.
PATHOPHYSIOLOGY
Origins, Growth, and Rupture
Although the exact etiology of saccular aneurysms is
unclear, considerable evidence indicates that aneur-
ysms are acquired lesions resulting from a compli-
cated interplay of anatomical, hemodynamic, and
degenerative factors. Wall stress at arterial bifurca-
tions caused by pulsatile blood flow is believed to
initiate local destruction of internal elastic lamina.
Turbulent blood flow within small saccular out-
pouchings is then believed to contribute to aneurysm
growth. Aneurysm growth reduces aneurysm wall
thickness and increases wall tension and rupture risk.
Rupture results in the acute discharge of blood into
the subarachnoid spaces, causing meningeal irrita-
tion, increased intracranial pressure (ICP), and mass
effect on local structures (e.g., cranial nerves and
brain). The factors that slow the flow rate of SAH are
uncertain but likely include the size of the aneur-
ysmal tear, the presence of intact cisternal barriers,
elevation of ICP, and local reduction in cerebral
perfusion. The slowed flow allows for activation of
164 ANEURYSMS
the coagulation cascade and the formation of fibrin
clot.
Clinical Presentation of Aneurysmal SAH
Major SAH is usually characterized by the acute
onset of severe headache that may initially be
localized but often generalizes quickly. Headache is
the most common symptom in more than 90% of
cases and is classically described as ‘‘the worst
headache of my life.’’ Nausea and vomiting fre-
quently accompany the headache, and loss of
consciousness may occur. Signs of meningeal irrita-
tion, including nuchal rigidity (especially to flexion)
and photophobia, are often present within 4–8 hr
after the onset of SAH and are found in most
patients. Focal neurological signs and symptoms may
also be present, depending on the size and location of
the aneurysm and the severity and location of the
hemorrhage. Ocular hemorrhages may cause blurred
vision and are frequently found on funduscopic
examination; the most common ocular hemorrhages
are subhyaloid (preretinal) hemorrhages, seen in
approximately 25% of patients.
As many as 10% of patients with intracranial
aneurysms receive medical attention for reasons
other than a major rupture. Retrospective studies
suggest that minor hemorrhages or sentinel leaks
occur in as many as 30–60% of patients who present
with a major rupture. These leaks may also cause
acute-onset headaches, nausea, and vomiting; how-
ever, the intensity is usually less severe and the
symptoms clear within 1 day. Warning headaches
may also occur without SAH and may be due to
hemorrhage confined within the aneurysmal wall or
from mass effect. Aneurysmal compression of the
brainstem or cranial nerves may present as focal
neurological deficits. Hemiparesis from pontine
compression by giant aneurysms, non-pupil-sparing
third nerve palsy from expanding posterior commu-
nicating artery aneurysms, visual loss from ophthal-
mic artery aneurysms, and facial pain from
intracavernous or supracliniod artery aneurysms are
all common. Small infarcts or transient ischemic
attacks due to distal embolization of intraaneurysmal
thrombus may also herald an intracranial aneurysm,
as do seizures.
Hunt and Hess described a common clinical
grading system used for patients with aneurysmal
SAH (Table 1). The prognosis associated with SAH
largely depends on the presenting clinical status,
which indicates the extent of the injury from the
initial hemorrhage. The Hunt and Hess grade, which
Table 1 HUNT AND HESS CLASSIFICATION SYSTEM FOR
SUBARACHNOID HEMORRHAGE
Grade Description
0 Unruptured
1 Asymptomatic or a minimal headache, slight nuchal
rigidity
2 Moderate to severe headache, nuchal rigidity, no
neurological deficit other than cranial nerve palsy
3 Drowsiness, confusion, or mild focal neurological deficit
4 Stupor, moderate to severe hemiparesis, possible early
decerebrate rigidity, and vegetative disturbances
5 Deep coma, decerebrate rigidity, and moribund
appearance
can be determined by a quick examination of the
patient, correlates well with patient outcome. Other
grading systems, including the Botterell and the
World Federation of Neurological Surgeons scales,
may also be used to predict patient outcome.
Diagnostic Approach to Aneurysmal SAH
The sequence of evaluation for suspected aneurysmal
SAH begins with a high-resolution, noncontrast CT
scan (Fig. 2). A good quality head CT will detect
SAH in more than 95% of patients who undergo the
study within 24 hr of the hemorrhage. The scan will
also demonstrate the extent and location of the
hemorrhage, which has prognostic significance in
predicting the severity of future vasospasm (Table 2).
Approximately 5% of SAHs are not detected on CT
scan. Therefore, patients with high clinical suspicion
of hemorrhage but with negative head CT should
undergo a lumbar puncture (LP). This is the most
sensitive test for SAH. Typical cerebrospinal fluid
(CSF) findings in SAH are an elevated opening
pressure, nonclotting bloody fluid that fails to clear
with sequential tubes, xanthrochromia of the super-
natant, a red blood cell (RBC) count of usually
4100,000 cells/ml, elevated protein, and normal
glucose. Since RBCs in sentinel hemorrhages can be
resorbed in 1 or 2 weeks, xanthrochromia of the
supernatant after centrifugation is diagnostic of SAH
and can occur as early as 4–6 hr after a bleed and last
for weeks. Cerebral angiography is the ‘‘gold
standard’’ for diagnostic evaluation of aneurysms
(Figs. 3–7) and should be performed in CT- or LP-
confirmed nontraumatic SAH and in patients in
whom the clinical suspicion remains high despite
negative CT scan and/or inconclusive LP. The

Figure 2
Computed tomography of a Fisher grade 3 subarachnoid
hemorrhage (SAH) from a 15-mm superior cerebellar artery
aneurysm. High signal attenuation indicating SAH is centered in
the basilar cisterns, with diffuse spread bilaterally into the Sylvian
fissures and anteriorly into the interhemispheric fissure.
importance of a four-vessel angiogram demonstrat-
ing both the carotid and the vertebral arteries is
evident by the 20% chance of multiple aneurysms in
patients with aneurysmal disease. The risks of
cerebral angiography are low, with most large series
reporting mortality less than 0.1% and a rate of
permanent neurological injury of 0.5%.
Table 2 FISHER CT SCAN CLASSIFICATION SYSTEM FOR
SUBARACHNOID HEMORRHAGE
Grade Description
1 No blood detected
2 Diffuse deposition or thin layer of blood, with all
vertical layers of blood (interhemispheric fissure,
insular cistern, and ambient cistern) o1 mm thick
3 Localized clots or vertical layers of blood Z1 mm in
thickness (or both)
4 Diffuse or no subarachnoid blood but with intracerebral
or intraventricular clots
ANEURYSMS 165
Although magnetic resonance imaging is not
sensitive in detecting acute SAH because acute blood
carries a similar magnetic signal to the normal brain,
it is useful in detecting aneurysmal disease. Experi-
ence with magnetic resonance angiography (MRA)
(Fig. 3a) is evolving as investigators determine
optimal acquisition protocols and with improve-
ments in scanner hardware and software. Factors
influencing the ability of MRA to detect intracranial
aneurysms include aneurysm size, rate and direction
of blood flow in the aneurysm relative to the
magnetic field, intraluminal thrombosis, and vessel
calcification. Recent studies suggest that MRA can
now detect most aneurysms Z3 mm with a
sensitivity of approximately 86% compared to
intraarterial digital subtraction angiography,
although rates as high as 95% have been quoted.
The false-positive rate has been estimated to be
approximately 16%. MRA therefore provides a
useful noninvasive modality to screen high-risk
patients. Rapid spiral CT angiography has also
emerged as a useful tool to detect intracranial
aneurysms (Fig. 3b). It has demonstrated sensitivity
comparable to that of MRA with the added benefits
of a three-dimensional image and better illustration
of relationships with bony structures.
Pathology of Aneurysmal SAH
In addition to hemorrhage in the subarachnoid space,
aneurysm rupture may cause hemorrhage within the
brain parenchyma, the ventricles, and the subdural
space. All worsen the prognosis of SAH. Intracerebral
hemorrhage is believed to occur when aneurysms are
partly embedded in the brain surface. It has also been
speculated that recurrent hemorrhages allow adhe-
sions to seal off the aneurysm from the subarachnoid
space deflecting bleeding into the brain parenchyma
during a major rupture. Intracerebral hematomas are
seen in approximately 30–40% of aneurysmal rup-
tures, most of which are frontal clots associated with
anterior communicating artery aneurysms. Temporal
lobe clots are second most common and are usually
related to middle cerebral artery aneurysms. Rupture
of an aneurysm is second only to hypertension as the
cause of intraventricular bleeding and occurs in
approximately 13–28% of patients with aneurysmal
hemorrhage. The resulting obstructive hydrocephalus
significantly worsens prognosis and requires place-
ment of an external ventricular drain. Hemorrhage
into the third ventricle is especially prone to occur
with anterior communicating artery aneurysms
through the lamina terminalis or from basilar tip
166 ANEURYSMS

Figure 3
Comparison of imaging modalities. A 7-mm anterior communicating artery aneurysm (arrow) is demonstrated in oblique view on MRA (a)
and in AP views on CT angiography (b) and with digital subtraction angiography (c). The aneurysm points superiorly and to the right, and it
has a base-to-neck ratio of 2:1.

aneurysms through the third ventricular floor. Poster-
ior inferior cerebellar artery aneurysms often bleed
directly into the fourth ventricle via access through
the foramen of Luschka. Subdural hematoma sec-
ondary to aneurysm rupture is rare, occurring in less
than 2% of patients. Given its infrequent occurrence,
no particular aneurysm location has been associated
with this pathology. However, as with the other
hemorrhage patterns, the prognosis is poor, with an
associated mortality of 50%.

Figure 4
Clip occlusion of a large left middle cerebral artery (MCA) aneurysm. (a) Digital subtraction angiography of a 15-mm left MCA bifurcation
aneurysm (arrow) seen in the AP view. (b) Postoperative angiogram also seen in AP view shows occlusion of the MCA aneurysm by clip
(straight arrow). A 6-mm anterior communicating artery aneurysm was also concomitantly treated with clip occlusion (curved arrow).
Neurological Complications of
Aneurysmal SAH
The four main neurological complications following
rupture of an intracranial aneurysm are cerebral
vasospasm, aneurysmal rehemorrhage, hydrocepha-
lus, and seizures. Cerebral vasospasm is the leading
cause of morbidity and mortality in patients who
survive the initial SAH. It is the sustained narrowing
of cerebral arteries, which typically occurs several
days to several weeks after SAH. It rarely presents
before the third day, and the peak incidence is
between days 6 and 8 after the SAH. The exact
mechanism for the prolonged contractile response is
not known but is believed to be secondary to the
irritating effects of oxyhemoglobin released from
lysed erythrocytes in the subarachnoid space. The
incidence and distribution have been correlated with
the thickness and location of the subarachnoid clot.
Angiographic vasospasm refers to the radiographi-
cally visualized narrowing of the cerebral blood
vessel caliber depicted on angiography, and it has
been estimated to occur in 40–70% of patients
following SAH. Most, however, remain asympto-
matic during the 2 or 3 weeks that it takes to resolve.
ANEURYSMS 167
Clinical vasospasm is the syndrome of ischemic
consequences produced by the progressive narrowing
of these vessels. It is characterized by insidious onset
of confusion and decreased level of consciousness,
followed by waxing and waning of focal neurological
deficits. Severe spasm may result in focal infarction,
ultimately leading to coma and death. Although 40–
70% of patients with SAH develop angiographic
evidence of vasospasm, only 20–30% manifest the
clinical syndrome.
Treatment of cerebral vasospasm remains proble-
matic. Nevertheless, the combination of calcium
channel blockers, hypervolemic–hypertensive ther-
apy, and endovascular treatments has reduced the
risk of permanent deficits and death to 5–10%. The
influx of intracellular calcium is an important step in
the initiation and maintenance of vascular smooth
muscle contraction, and therapies aimed at blocking
this influx are intended to the prevent vasospasm by
promoting smooth muscle relaxation. The calcium
channel blocker nimodipine has been demonstrated
in prospective, randomized, placebo-controlled clin-
ical trials to improve the outcome after aneurysmal
SAH and should be routinely administered during
the first 21 days following SAH. Interestingly,
168 ANEURYSMS

Figure 5
Coil embolization of a large left superior cerebellar artery (SCA) aneurysm. A digital subtraction angiogram demonstrating the 15-mm left
SCA aneurysm that ruptured, resulting in the hemorrhage shown in Fig. 2. AP views show aneurysm (arrow) prior to treatment (a) and
complete obliteration of aneurysm following placement of GDC coils (b, arrow).

nimodipine has not been shown to decrease angio-
graphic vasospasm, and its beneficial effects may
actually be secondary to direct neuronal protection.
Blood flow through vessels is characterized by
Poiseuille’s law and is normally controlled by
autoregulation of arterial diameter. When this
regulation is abolished, as in cerebral vasospasm,
therapies to increase blood flow must decrease blood
viscosity and/or increase perfusion pressure. Volume
expansion with crystalloids and colloids is therefore
used to reduce blood viscosity and increase blood
volume. Selective peripheral vasopressors are em-
ployed to increase perfusion pressure. This is the
so-called ‘‘triple-H’’ therapy: hypertension, hyper-
volemia, and hemodilution. In cases of severe
spasm refractory to medical treatment, intraarterial
administration of papaverine (a smooth muscle
relaxant) or direct angioplasty may be performed
endovascularly.
The goal of early treatment of ruptured aneurysms
is to prevent rehemorrhage, which is the third most
common cause of death in aneurysm patients after
vasospasm and brain damage caused by the initial
bleed. The rate of rebleeding from aneurysms is
maximal in the first 24 hr after SAH and declines
precipitously after the first 48 hr to 1.5% per day for
the next 2 weeks. The signs and symptoms of
rehemorrhage are the same as those for the primary
SAH, heralded by sudden, severe worsening of
headache and/or acute deterioration in neurological
status. Patients in poor neurological condition, who
have had a severe initial hemorrhage, are at the
greatest risk for rebleeding. Recurrent SAH is usually
more devastating than the initial SAH, and the
mortality rate associated with a second hemorrhage
doubles to approximately 80%.
Hydrocephalus after aneurysmal SAH is the
ventricular dilatation that results secondary to
blockage of CSF circulation pathways by subarach-
noid blood. This common complication has a
reported incidence of 6–67% and depends on the
extent of the hemorrhage. Patients suffering from
aneurysmal SAH with intraventricular bleeding al-
most uniformly develop this condition. The clinical
manifestations may be a depressed level of con-
sciousness that ranges from stupor to deep coma due
to increased ICP. The treatment of acute hydroce-
phalus requires placement of an external ventricular

Figure 6
Giant left paraclinoid internal carotid artery (ICA) aneurysm. (a) Digital subtraction angiography demonstrates a 2.5-cm aneurysm (arrow)
originating from the left paraclinoid ICA. (b) Postoperative angiogram shows occlusion of the aneurysm using multiple clips (arrow).
drain (EVD), which results in significant clinical
improvement in approximately two-thirds of pa-
tients. The risks of an EVD causing aneurysm
rebleeding and ventriculitis may be reduced by
careful drainage and administration of prophylactic
intravenous antibiotics. Chronic hydrocephalus may
be treated with ventriculoperitoneal shunting.
Figure 7
Fusiform distal MCA aneurysm.
ANEURYSMS 169
Seizures following aneurysmal SAH are not
unusual; they occurred in 4.5% of patients in the
Cooperative Study. Aneurysm patients who experi-
ence seizures typically do so within 2 weeks
following the hemorrhage (early seizures), and most
occur within the first 24 hr. The pathogenesis is
believed to be due to cortical irritation by blood, and
early seizures do not predict long-term recurrence in
survivors. Therefore, patients who experience a
seizure after SAH should be treated with an
appropriate anticonvulsant and, if no further events
occur, weaned after 6 months to 1 year. No role has
been found for the routine administration of
prophylactic anticonvulsants following SAH. Pa-
tients who have seizures weeks after their hemor-
rhage and progress to epilepsy usually have sustained
cortical injury by infarction, operative trauma, or
gliosis from the initial brain injury. These patients
will require maintenance antiepileptics.
TREATMENT
Most cerebral aneurysms are treated with clip
ligation (Figs. 4 and 6); if the aneurysmal neck is
occluded without residual, long-term data suggest
that this treatment is curative. Most anterior
170 ANEURYSMS
circulation aneurysms are approached through a
frontotemporal (pterional) craniotomy. Posterior
circulation aneurysms are exposed through fronto-
temporal, subtemporal, or suboccipital approaches
depending on aneurysm location. Brain retraction is
minimized through the use of extensive skull-base
removal, hyperventilation, lumbar or ventricular
drainage, intravenous diuretic agents, and head
positioning. Proximal control of the arterial feeders
may be obtained by temporary occlusion of parent
vessels either intracranially or by occlusion of the
cervical internal carotid artery. Temporary parent
arterial occlusion is useful for performing the final
neck dissection and preventing intraoperative rup-
ture. Electrophysiological monitoring of bilateral
somatosensory evoked potentials and brainstem
auditory evoked potentials may be employed and is
useful for detecting early ischemia during temporary
occlusion. Neuroprotective techniques utilized dur-
ing temporary occlusion include induced hyperten-
sion (mean arterial pressure, 100–110 mmHg) and
mild hypothermia (temperature, 32–331C). Finally,
clip application is facilitated by titanium clips and
clip appliers that come in a variety of shapes and
sizes, allowing optimal placement with minimal
distortion of the normal anatomy.
Aneurysm occlusion through the use of intraarter-
ial microcatheters has also emerged as a viable means
of surgical intervention. The advent of detachable,
thrombogenic platinum coils by Guglielmi (GDC
coils) in 1991 extended the role that endovascular
therapy affords in the treatment of intracranial
aneurysms. Many large centers are capable of
treating some aneurysms with coil embolization.
Affected vessels are selectively catheterized, GDC
coils are then deposited and repositioned to fit the
contour of the aneurysm, and the coils are then
permanently detached, promoting thrombosis
(Fig. 5). This technique was approved in the United
States by the Food and Drug Administration in 1995,
and since that time data have accumulated regarding
its safety, efficacy, and morbidity. Results suggest that
intraaneurysmal GDC coiling is safe and effective in
preventing short-term rebleeding for some aneur-
ysms, but long-term recanalization rates and efficacy
are not known.
The indications for treatment of intracranial
aneurysms include SAH, the development of neuro-
logical signs and symptoms referable to mass effect,
ischemic events from distal embolization, and, in
some cases, the incidental finding of an asympto-
matic aneurysm. Which aneurysms should be treated
with microsurgical clip ligation versus endovascular
coil embolization is a subject of debate regarding
many simple aneurysms, whereas neither treatment
alone may be suitable for complex or giant aneur-
ysms. The risk of open microsurgery is generally
related to aneurysm size, location, and the complex-
ity of adjacent parent and perforating vessels. In
addition, advanced patient age, medical comorbid-
ities, and poor neurological condition are all negative
prognostic factors for a good surgical result. The
initially approved indications for GDC coiling were
aneurysms with difficult surgical access, aneurysms
that had been unsuccessfully explored, aneurysms in
patients with advanced age or significant medical
comorbidities, and as palliative treatment of aneur-
ysms in patients with poor neurological grade.
Successful treatment in these instances has led to
more widespread usage. The lowest rates of morbid-
ity and the highest rates of aneurysm obliteration
with GDC embolization have been reported in
smaller lesions, with narrow necks, without intra-
mural thrombus, in good grade patients. These are
the same cases in which open microsurgery provides
the best outcome. Although clip ligation has been
demonstrated in most cases to be curative, more time
is required to assess the long-term efficacy of GDC
coiling. Delayed recanalization after GDC coiling
occurs in 6% of small aneurysms with small necks,
32% of aneurysms with wide necks, and 47% of
giant aneurysms at some of the most experienced
centers.
SPECIAL SACCULAR ANEURYSMS
Giant saccular aneurysms deserve special mention
because their clinical presentation, natural history,
and treatment differ from those of aneurysms of
smaller size. These aneurysms are by definition 425
mm, comprise approximately 2–5% of all saccular
aneurysms, and are believed to have matured from
their smaller counterparts. Sixty percent of these
lesions occur in the anterior circulation, with most
on the internal carotid artery (Fig. 6). The remaining
40% found in the posterior circulation have a
predilection for the vertebrobasilar vessels. They
generally present like tumors, with headaches, visual
loss, and other cranial nerve dysfunction as the most
common features. Nevertheless, 35% present with
SAH, which significantly worsens the prognosis,
and 10% show evidence of remote bleeding.
Although the exact natural history is unknown,
most untreated giant aneurysms are uniformly fatal.

Specifically, some epidemiological results suggest
that 80% of patients with anterior circulation and
85–100% of those with posterior circulation giant
aneurysms left untreated are severely disabled or
dead after 5 years. Treatment of giant aneurysms is
extremely difficult. Their wide necks and multi-
layered intraluminal clot often require arterial
reconstruction and thrombectomy. A variety of
surgical approaches (direct clipping, proximal
arterial occlusion, bypass grafting, and vessel re-
construction) have recently been combined with
endovascular techniques (GDC coiling and balloon
occlusion) to improve the outcome. Despite their
poor natural history and the technical challenges of
treatment, several centers have demonstrated ex-
pertise in treating these aneurysms with good out-
comes. Drake et al. reported a series of Hunterian
ligations of giant anterior circulation aneurysms in
160 patients: 144 patients (90%) had satisfactory
outcome, and aneurysm obliteration was achieved in
all but 4 patients (2%). Steinberg et al. reported a
series of Hunterian ligation of basilar or vertebral
arteries for treating posterior circulation aneurysms
in 201 patients, of which 87% were classified as
giant. The overall results were excellent in 68% of
patients, good in 5%, and poor in 3%; 24% of
patients died. Successful aneurysm thrombosis was
achieved in 78% of patients.
Aneurysms in childhood are rare, occurring in
approximately 2% of patients, providing credence to
the argument that aneurysms are acquired lesions.
Their treatment is similar to that in adults, except the
childhood brain appears to often have better
collateral flow and greater potential for recovery
after injury compared to the adult brain.
NONSACCULAR ANEURYSMS
Fusiform aneurysms are segments of artery in which
there is circumferential dilatation and tortuous
elongation (Fig. 7). They are typically the result of
severe cerebral atherosclerosis in older patients and
vessel wall abnormalities in children that predispose
these vessels to vascular enlargement with hemody-
namic stress. The vertebral, basilar, and intracranial
internal carotid arteries are the most commonly
affected. These aneurysms usually present with
cranial nerve or brainstem compression but may
occasionally cause ischemia or SAH. Treatment of
these aneurysms is difficult and often controversial.
Mass effect and ischemia from intraluminal throm-
bus can often be treated with anticoagulation.
ANEURYSMS 171
Aneurysms that hemorrhage or are associated with
symptoms that persist despite anticoagulation may
be treated with microsurgical or endovascular
Hunterian ligation or trapping.
Traumatic intracranial aneurysms are rare, con-
stituting less than 1% of all intracranial aneurysms.
In contrast to saccular aneurysms that occur at
arterial bifurcations, traumatic aneurysms occur
along the longitudinal aspect of vessel walls. The
most common etiologies are closed head injuries,
gunshot wounds, stab wounds, and iatrogenic
causes, which result in direct arterial trauma from
skull fractures, contusion against the falcine edge, or
stretch injury. The majority of traumatic aneurysms
are supratentorial, most frequently affecting the
middle cerebral and anterior cerebral arteries and
their branches. Histologically, although in some
aneurysms there is disruption of the intima, internal
elastic lamina, and media layers of the vessel wall
leaving the adventitia intact, most traumatic aneur-
ysms are false aneurysms in which there is disruption
of the entire arterial wall and the resultant hematoma
is contained by surrounding structures. The natural
history of these aneurysms is unpredictable. Some
enlarge, rupture, calcify, or disappear spontaneously.
However, when symptomatic, they most often
present with acute intracranial hemorrhage 2–8
weeks following the trauma. Other symptoms
include recurrent epistaxis, progressive cranial nerve
palsy, enlarging skull fracture, and severe headache.
Treatments include proximal arterial ligation, trap-
ping and bypass, surgical obliteration (often requir-
ing encircling clips), and wrapping.
—Robert L. Dodd and Gary K. Steinberg
See also–Aneurysms, Intracranial; Aneurysms,
Surgery; Cerebral Vasospasm, Treatment of;
Endovascular Therapy; Subarachnoid
Hemorrhage (SAH)
Further Reading
Barker, F. G., 2nd, and Ogilvy, C. S. (1996). Efficacy of
prophylactic nimodipine for delayed ischemic deficit after
subarachnoid hemorrhage: A metaanalysis. J. Neurosurg. 84,
405–414.
Drake, C. G. (1979). Giant intracranial aneurysms: Experience
with surgical treatment in 174 patients. Clin. Neurosurg. 26,
12–95.
Fisher, C. M., Kistler, J. P., and Davis, J. M. (1980). Relation of
cerebral vasospasm to subarachnoid hemorrhage visualized by
computerized tomographic scanning. Neurosurgery 6, 1–9.
Fox, J. (1983). Intracranial Aneurysms, Vol. 1. Springer-Verlag,
New York.
172 ANEURYSMS, INTRACRANIAL
Hop, J. W., Rinkel, G. J., Algra, A., et al. (1997). Case-fatality
rates and functional outcome after subarachnoid hemorrhage:
A systematic review. Stroke 28, 660–664.
Hunt, W. E., and Hess, R. M. (1968). Surgical risk as related to
time of intervention in the repair of intracranial aneurysms. J.
Neurosurg. 28, 14–20.
Kassell, N. F., and Torner, J. C. (1983). Aneurysmal rebleeding: A
preliminary report from the Cooperative Aneurysm Study.
Neurosurgery 13, 479–481.
Linn, F. H., Wijdicks, E. F., van der Graaf, Y., et al. (1994).
Prospective study of sentinel headache in aneurysmal subar-
achnoid haemorrhage. Lancet 344, 590–593.
Nishioka, H., Torner, J. C., Graf, C. J., et al. (1984). Cooperative
study of intracranial aneurysms and subarachnoid hemorrhage:
A long-term prognostic study. II. Ruptured intracranial
aneurysms managed conservatively. Arch. Neurol. 41, 1142–
1146.
Schievink, W. I., Schaid, D. J., Michels, V. V., et al. (1995).
Familial aneurysmal subarachnoid hemorrhage: A community-
based study. J. Neurosurg. 83, 426–429.
Steinberg, G. K., Drake, C. G., and Peerless, S. J. (1993).
Deliberate basilar or vertebral artery occlusion in the treatment
of intracranial aneurysms. Immediate results and long-term
outcome in 201 patients. J. Neurosurg. 79, 161–173.
Vinuela, F., Murayama, Y., Duckwiler, G., et al. (1999). Present
and future technical developments in aneurysm embolization.
Impact on indications and anatomic results. In Clinical
Neurosurgery (M. A. Howard, Ed.), Vol. 47, pp. 221–241.
Lippincott Williams and Wilkins, Boston, MA.
Weir, B., and Findlay, J. M. (1995). Subarachnoid hemorrhage. In
Neurovascular Surgery (L. P. Carter and R. F. Spetzler, Eds.),
pp. 557–581. McGraw-Hill, New York.
Aneurysms, Intracranial
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AN ANEURYSM is a saccular dilatation of an artery
that typically occurs at a branch point or curve in an
artery’s course and tends to point in the direction of
blood flow. Usual aneurysm morphology consists of
a neck (where the aneurysm originates from the
parent artery), the body or fundus, and the dome.
Small perforating branches that supply adjacent
brain arise from the neck at some aneurysm sites
[anterior communicating artery (ACoA), internal
carotid artery (ICA) bifurcation, and basilar apex].
Aneurysms enlarge and rupture at the dome, where
walls are thinnest and there is frequently a daughter
sac or lobe. Saccular aneurysms are thought to be
acquired, degenerative defects that develop in re-
sponse to relentless hemodynamic stress. However,
defects in the media or internal elastic lamina may be
genetically or congenitally influenced.
Aneurysms are named by their associated branch
artery or, when not associated with a discrete branch,
by their anatomical location. Aneurysms in the
anterior circulation, in order proximally to distally,
include petrous ICA, cavernous ICA, clinoidal ICA,
ophthalmic artery (OphA), superior hypophyseal
artery (SHA), posterior communicating artery
(PCoA), anterior choroidal artery (AChA), ICA
bifurcation, ACoA, pericallosal artery, and middle
cerebral artery (MCA) aneurysms. Aneurysms in the
posterior circulation, in anatomical order proximally
to distally, include vertebral artery (VA), posterior
inferior cerebellar artery (PICA), vertebrobasilar
junction (VBJ), anterior inferior cerebellar artery
(AICA), superior cerebellar artery (SCA), basilar tip,
and posterior cerebral artery (PCA) aneurysms. The
most common aneurysms are ACoA, PCoA, MCA,
and basilar tip aneurysms.
The prevalence rate of intracranial saccular
aneurysms is between 0.1 and 9%, with rates
approximately 0.5–1% in angiographic series and
approximately 1–6% in autopsy studies. Approxi-
mately 25% of patients have multiple aneurysms.
Intracranial arteries lie in the subarachnoid space
between the pia and arachnoid layers, a space filled
with cerebrospinal fluid (CSF) and compartmenta-
lized into interconnecting cisterns. Consequently,
aneurysms also lie in the subarachnoid space (except
for petrous, cavernous, and clinoidal ICA aneurysms)
and ruptured aneurysms produce subarachnoid
hemorrhage (SAH). In the United States, the annual
incidence of SAH is 11 per 100,000, with an
estimated 30,000 new cases each year. It accounts
for 5–10% of all strokes, and it afflicts women more
than men and African Americans more than Cauca-
sians. SAH most commonly occurs in patients
between the ages of 40 and 60 years. Aneurysmal
rupture is a potentially devastating event. The 30-day
mortality rate for SAH is approximately 45%. Half
of these patients die from the effects of the initial
hemorrhage before arriving at a hospital, and the
other half die later from rebleeding or the effects of
vasospasm. Approximately 30% of survivors experi-
ence neurological deficits.
Although saccular aneurysms are the most com-
mon type, other nonsaccular aneurysms include
fusiform (atherosclerotic), dissecting, traumatic, in-
fectious, and neoplastic aneurysms. Fusiform aneur-
ysms are tortuous, elongated, dilated arteries with
separate inflow and outflow and most commonly
occur in elderly patients with generalized athero-
sclerosis. Traumatic aneurysms are the result of
172 ANEURYSMS, INTRACRANIAL
Hop, J. W., Rinkel, G. J., Algra, A., et al. (1997). Case-fatality
rates and functional outcome after subarachnoid hemorrhage:
A systematic review. Stroke 28, 660–664.
Hunt, W. E., and Hess, R. M. (1968). Surgical risk as related to
time of intervention in the repair of intracranial aneurysms. J.
Neurosurg. 28, 14–20.
Kassell, N. F., and Torner, J. C. (1983). Aneurysmal rebleeding: A
preliminary report from the Cooperative Aneurysm Study.
Neurosurgery 13, 479–481.
Linn, F. H., Wijdicks, E. F., van der Graaf, Y., et al. (1994).
Prospective study of sentinel headache in aneurysmal subar-
achnoid haemorrhage. Lancet 344, 590–593.
Nishioka, H., Torner, J. C., Graf, C. J., et al. (1984). Cooperative
study of intracranial aneurysms and subarachnoid hemorrhage:
A long-term prognostic study. II. Ruptured intracranial
aneurysms managed conservatively. Arch. Neurol. 41, 1142–
1146.
Schievink, W. I., Schaid, D. J., Michels, V. V., et al. (1995).
Familial aneurysmal subarachnoid hemorrhage: A community-
based study. J. Neurosurg. 83, 426–429.
Steinberg, G. K., Drake, C. G., and Peerless, S. J. (1993).
Deliberate basilar or vertebral artery occlusion in the treatment
of intracranial aneurysms. Immediate results and long-term
outcome in 201 patients. J. Neurosurg. 79, 161–173.
Vinuela, F., Murayama, Y., Duckwiler, G., et al. (1999). Present
and future technical developments in aneurysm embolization.
Impact on indications and anatomic results. In Clinical
Neurosurgery (M. A. Howard, Ed.), Vol. 47, pp. 221–241.
Lippincott Williams and Wilkins, Boston, MA.
Weir, B., and Findlay, J. M. (1995). Subarachnoid hemorrhage. In
Neurovascular Surgery (L. P. Carter and R. F. Spetzler, Eds.),
pp. 557–581. McGraw-Hill, New York.
Aneurysms, Intracranial
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AN ANEURYSM is a saccular dilatation of an artery
that typically occurs at a branch point or curve in an
artery’s course and tends to point in the direction of
blood flow. Usual aneurysm morphology consists of
a neck (where the aneurysm originates from the
parent artery), the body or fundus, and the dome.
Small perforating branches that supply adjacent
brain arise from the neck at some aneurysm sites
[anterior communicating artery (ACoA), internal
carotid artery (ICA) bifurcation, and basilar apex].
Aneurysms enlarge and rupture at the dome, where
walls are thinnest and there is frequently a daughter
sac or lobe. Saccular aneurysms are thought to be
acquired, degenerative defects that develop in re-
sponse to relentless hemodynamic stress. However,
defects in the media or internal elastic lamina may be
genetically or congenitally influenced.
Aneurysms are named by their associated branch
artery or, when not associated with a discrete branch,
by their anatomical location. Aneurysms in the
anterior circulation, in order proximally to distally,
include petrous ICA, cavernous ICA, clinoidal ICA,
ophthalmic artery (OphA), superior hypophyseal
artery (SHA), posterior communicating artery
(PCoA), anterior choroidal artery (AChA), ICA
bifurcation, ACoA, pericallosal artery, and middle
cerebral artery (MCA) aneurysms. Aneurysms in the
posterior circulation, in anatomical order proximally
to distally, include vertebral artery (VA), posterior
inferior cerebellar artery (PICA), vertebrobasilar
junction (VBJ), anterior inferior cerebellar artery
(AICA), superior cerebellar artery (SCA), basilar tip,
and posterior cerebral artery (PCA) aneurysms. The
most common aneurysms are ACoA, PCoA, MCA,
and basilar tip aneurysms.
The prevalence rate of intracranial saccular
aneurysms is between 0.1 and 9%, with rates
approximately 0.5–1% in angiographic series and
approximately 1–6% in autopsy studies. Approxi-
mately 25% of patients have multiple aneurysms.
Intracranial arteries lie in the subarachnoid space
between the pia and arachnoid layers, a space filled
with cerebrospinal fluid (CSF) and compartmenta-
lized into interconnecting cisterns. Consequently,
aneurysms also lie in the subarachnoid space (except
for petrous, cavernous, and clinoidal ICA aneurysms)
and ruptured aneurysms produce subarachnoid
hemorrhage (SAH). In the United States, the annual
incidence of SAH is 11 per 100,000, with an
estimated 30,000 new cases each year. It accounts
for 5–10% of all strokes, and it afflicts women more
than men and African Americans more than Cauca-
sians. SAH most commonly occurs in patients
between the ages of 40 and 60 years. Aneurysmal
rupture is a potentially devastating event. The 30-day
mortality rate for SAH is approximately 45%. Half
of these patients die from the effects of the initial
hemorrhage before arriving at a hospital, and the
other half die later from rebleeding or the effects of
vasospasm. Approximately 30% of survivors experi-
ence neurological deficits.
Although saccular aneurysms are the most com-
mon type, other nonsaccular aneurysms include
fusiform (atherosclerotic), dissecting, traumatic, in-
fectious, and neoplastic aneurysms. Fusiform aneur-
ysms are tortuous, elongated, dilated arteries with
separate inflow and outflow and most commonly
occur in elderly patients with generalized athero-
sclerosis. Traumatic aneurysms are the result of

direct arterial injury, with rupture of all three arterial
layers (intima, media, and adventitia) and fibrous
organization of the surrounding hematoma. In
contrast, dissecting aneurysms result from tears
through, but no deeper than, the intima and internal
elastic lamina. Infectious and neoplastic aneurysms
develop from the circulation of infectious material or
tumor cells, often from a focus within the heart (e.g.,
bacterial endocarditis or atrial myxoma). Infectious
emboli lodge in small distal cerebral arteries and
occlude blood flow, after which intense inflammation
in the adventitia and media destroys the integrity of
the wall and weakens it. Neoplastic aneurysms have
a similar pathogenesis, except that arterial invasion is
directly from tumor cells. The resulting aneurysms
are typically fusiform, eccentric, and at distal sites.
CLINICAL MANIFESTATIONS
Most aneurysms become symptomatic with rupture.
The classic presentation is a sudden, unusually severe
headache that may be associated with nausea,
vomiting, painful nuchal rigidity, and photophobia.
The critical features that distinguish this headache
from other headaches are its instantaneous onset and
its severity. When asked to evaluate severity on a
scale from 1 to 10, patients typically respond with a
number off the scale. They describe their headaches
as ‘‘the worst headache of my life’’ and can remember
vivid details of events surrounding its onset. These
symptoms are characteristic of a ‘‘sentinel hemor-
rhage,’’ or a small, contained leak from the aneurysm
without frank rupture. Misdiagnosis of a sentinel
hemorrhage can be catastrophic because patients
have the highest risk of rehemorrhage in the
following 24 hr. An estimated 60% of SAH patients
who seek medical attention are misdiagnosed, and
they experience worse outcomes than those who are
diagnosed properly.
More severe hemorrhages produce seizures, neu-
rological deficits, impaired consciousness, and death.
These more devastating presentations are often due
to intraparenchymal or intraventricular extension of
the hemorrhage or sustained elevation of intracranial
pressure (ICP). Several grading scales (Table 1) are
used to evaluate the severity of hemorrhage, provid-
ing a ‘‘short-hand’’ description of a patient’s clinical
condition and also some guidance in treatment
decisions and prognosis. The Hunt and Hess Scale
is the most common, but others include the Glasgow
Coma Scale (GCS) and the World Federation of
Neurological Surgeons (WFNS) Scale.
ANEURYSMS, INTRACRANIAL 173
Typically, unruptured aneurysms are diagnosed
incidentally during the evaluation of unrelated pro-
blems such as headaches or other neurological
symptoms. Still, unruptured aneurysms can manifest
with symptoms related to mass effect or cerebral
ischemia. The cranial nerve most often involved is the
ocular motor nerve, which runs parallel to the poster-
ior communicating artery and can be compressed by
PCoA and basilar apex aneurysms (BTA and SCA). A
patient with a new oculomotor palsy (unilateral dilated
pupil with deviation of the eye downward and
laterally) should be considered to harbor an aneurysm
until proven otherwise. With PCoA aneurysms, the
dilated pupil usually precedes the diplopia because of
the greater sensitivity and peripheral location of the
parasympathetic fibers within the nerve. Cavernous
ICA aneurysms can manifest with oculomotor palsy
but also may involve the trochlear, abducens, and
trigeminal nerves. These patients have an immobile
eye, retro-orbital pain, and facial numbness or
dysesthesias. AChA aneurysms rarely cause oculomo-
tor deficits, but they can impinge on the mesial
temporal lobe to produce epilepsy or compress the
optic tract. ICA bifurcation aneurysms can also
compress the optic tract and, when giant, the internal
capsule to produce a contralateral hemiparesis.
Ophthalmic artery aneurysms lie under the optic
nerve, and their growth to giant sizes (Z25 mm)
causes a progressive visual field loss, initially a
unilateral inferior nasal field defect that can enlarge
to involve the entire ipsilateral nasal field, and a
superior temporal loss in the contralateral eye
(junctional scotoma). SHA aneurysms project medi-
ally toward the sella and produce bitemporal
hemianopsias similar to pituitary tumors.
Large or giant basilar aneurysms can cause pressure
on the midbrain, causing a contralateral hemiparesis
from compression of the cerebral peduncle or hydro-
cephalus from occlusion of the Sylvian aqueduct. The
oculomotor deficits from basilar aneurysms tend to
spare the pupil and cause ipsilateral ptosis and
weakness of upgaze. Large basilar trunk, VBJ, and
VA aneurysms can compress lower cranial nerves or
nuclei with corresponding dysphagia, dysarthria,
hoarseness, gait instability, and incoordination.
Giant aneurysms with intraluminal thrombus can
present with ischemic symptoms if clot from the
aneurysm embolizes downstream. This is particularly
true of ICA and MCA aneurysms, which manifest
with symptoms of aphasia and contralateral motor
and sensory deficits. Ischemic symptoms account for
5–25% of symptoms from unruptured aneurysms.
174 ANEURYSMS, INTRACRANIAL

Table 1 CLASSIFICATION SCALES FOR SUBARACHNOID HEMORRHAGE

Hunt–Hess Scale
Grade Criteria

I Asymptomatic, or minimal headache, nuchal rigidity

II Moderate to severe headache, no neurological deficit except for cranial nerve palsy
III Drowsiness, confusion, mild focal deficit
IV Stupor, moderate to severe hemiparesis, early decerebrate posturing
V Deep coma, decerebrate posturing, moribund
Glasgow Coma Scale
Points Eye opening Verbal Motor

6 Obeys commands
5 Oriented Localizes pain
4 Spontaneous Confused Withdraws to pain
3 To voice Inappropriate Flexes (decorticate)
2 To pain Incomprehensible Extends (decerebrate)
1 None None None

World Federation of Neurological Surgeons Scale

Grade Glasgow Coma Scale Motor deficit

I 15 None
II 13–14 None
III 13–14 Present
IV 7–12 Any
V 3–6 Any

Fisher Grading Scale

Grade Subarachnoid blood

I No blood detected
II Diffuse, o1 mm thick
III Localized clot or thick layer, 41 mm thick
IV Diffuse or none, with intracerebral or intraventricular blood

IMAGING STUDIES Ultimately, the diagnosis of an intracranial aneur-

The diagnosis of SAH requires the confirmation of
blood in the subarachnoid space, which can be
accomplished best with computed tomography (CT).
Blood is easily seen on noncontrast CT, which has a
sensitivity higher than 95%. In addition, the location
of blood provides clues to the aneurysm’s location
and identifies associated intracerebral and intraven-
tricular hemorrhage. Hydrocephalus is a common
finding in these patients because subarachnoid blood
interferes with the normal circulation and reabsorp-
tion of CSF. Often, this associated hydrocephalus is
more responsible for a patient’s depressed level of
consciousness than the hemorrhage and can be
reversed with ventriculostomy.
ysm depends on its identification by catheter
angiography. A complete angiogram includes injec-
tions of all four major intracranial arteries (both
ICAs and both VAs), filmed in two orthogonal views
(anteroposterior and lateral). Additional views of the
aneurysm are often needed to fully visualize its
anatomy. Pre- and postinjection images are digitally
subtracted to visualize the vascular structures alone;
shadows cast by the skull and skull base and
overlying opacities are removed. These digital sub-
traction angiograms provide detailed information
about the aneurysm’s location, anatomy, and hemo-
dynamics; other aneurysms; and collateral circula-
tion. It should be remembered that angiographic
images show the internal anatomy of an aneurysm,

which may be much smaller than its external
diameter if it is filled with thrombus or coil material
or thickened with calcium or atherosclerotic changes.
Catheter angiography has disadvantages; namely,
it is invasive, time-consuming, costly, and associa-
ted with increased risks (dissection, embolization,
aneurysmal rupture, and groin hematomas). How-
ever, it remains the gold standard for the diagnosis of
aneurysms. Angiography generated with magnetic
resonance or CT data (MRA and CTA, respectively)
is a newer imaging modality and currently does not
provide all the information that catheter angiogra-
phy provides. Both CTA and MRA are noninvasive
and easier to obtain. CTA is acquired quickly and
may play a role in unstable patients with ruptured
aneurysms that need urgent surgery. MRA is slower
and lacks the resolution of CTA or conventional
angiography, not detecting small aneurysms less than
3 mm in diameter. However, MR imaging/MRA is
becoming a common method of detecting unruptured
aneurysms in patients with other neurological issues.
LABORATORY FINDINGS
Lumbar puncture is the only laboratory study that
needs to be considered in the evaluation of an
aneurysm patient. It is used when a patient’s history
strongly suggests SAH but CT is normal. There are
two explanations for this inconsistency. The first
explanation is that a sentinel hemorrhage has leaked
so little blood that it is not radiographically
apparent. In this case, CSF may be blood tinged
and will not clear in successive tubes. The second
explanation is related to delayed CT performed days
after the SAH. A delay in seeking medical attention
or in ordering the CT scan allows subarachnoid
blood to disperse, making it difficult to detect in the
imaging study. In this case, CSF will be xanthochro-
mic, indicating that blood has been present for days
and is being metabolized. If the CSF from a lumbar
puncture is positive for new or old blood, further
angiographic evaluation is indicated. So-called ‘‘trau-
matic taps’’ yield CSF that initially is bloody but
clears in successive tubes. This finding should not be
mistaken for true SAH.
TREATMENT RATIONALE
Once an aneurysm has been diagnosed, a treatment
must be chosen. The primary cause of death and
disability from aneurysms is the brain injury pro-
ANEURYSMS, INTRACRANIAL 175
duced by the initial hemorrhage, and no treatment
can reverse it. Instead, existing treatments are aimed
at preventing the initial rupture or rerupture and at
reversing the effects of SAH such as vasospasm.
There is little controversy about the need to treat
ruptured aneurysms because of their high risk of
rerupture (4% in the first 24 hr and 20% in the first 2
weeks after the initial hemorrhage). Furthermore, the
mortality rate associated with rebleeding is 40%.
Therefore, treatment is undertaken quickly after
diagnosis, usually within 72 hr of the initial bleed.
The only treatment controversy arises in poor-grade
patients (Hunt and Hess grades IV and V) because
these patients have a poor prognosis to begin with
and aggressive management will yield good out-
comes in only 25–40% of patients. Patients with
uncontrollable ICP or who are moribund are
managed expectantly. In all other poor-grade patients
an aggressive treatment policy is generally more
prudent. In addition to protecting against rerupture,
early treatment of ruptured aneurysms enables
aggressive postoperative management of delayed
vasospasm with induced hypertension.
The treatment of unruptured aneurysms is more
controversial because of the difficulty of accurately
determining the risks of rupture and the risks of
treatment. The annual risk of aneurysm rupture is
between 0.05 and 2%. Factors that contribute to
rupture risk are size, location, the presence of another
ruptured aneurysm, and possibly hypertension and
smoking. There is no critical size or cutoff value, but
prospective data show an increased risk of rupture in
aneurysms Z10 mm in diameter. The cumulative
natural history risk of an aneurysm is determined by
estimating the life expectancy in years and extrapolat-
ing the annual rupture risk over this interval. There-
fore, a patient’s age and general health impact the
treatment decision. In making a choice between
treating an aneurysm or observing it, one must
compare this natural history risk with the treatment
risk. Morbidity and mortality rates associated with
surgery for unruptured aneurysms vary from 4 to 15%
and 0 to 4%, respectively. Many factors influence
surgical outcome, including aneurysm size, location,
and morphology; patient age, symptoms, and medical
condition; and the experience of the surgical team and
hospital staff. Weighing these factors, treatment is
generally recommended for patients with large or
symptomatic aneurysms or those with another pre-
viously ruptured aneurysm. Treatment is favored in
young patients with a long life expectancy, family
history of aneurysmal rupture, multiple aneurysms, or
176 ANEURYSMS, INTRACRANIAL
documented growth. Conservative management is
favored in older patients with small aneurysms, a
short life expectancy, or severe comorbid medical
conditions. Ultimately, patient preferences will deter-
mine the final decision for unruptured aneurysms.
INITIAL MANAGEMENT OF SAH
After a ruptured aneurysm is diagnosed, the aneur-
ysm is secured as quickly as possible. In the mean-
time, efforts are made to stabilize the patient and
minimize the risk of rerupture. Most important is
control of blood pressure. Rebleeding is caused by
absolute elevations in blood pressure and also rapid
variations. Blood pressure should be monitored
carefully with invasive arterial lines in an intensive
care unit (ICU) setting in which intravenous agents
or drips can be administered. Hydrocephalus is
present in approximately 25% of SAH patients and
resolves with the insertion of a ventriculostomy.
External ventricular drainage can improve the
clinical status of patients dramatically and is
recommended in all obtunded or comatose patients.
Ventriculostomy also allows ICP to be transduced
and can guide preoperative management of increased
pressures. In poor-grade patients, intubation and
mechanical ventilation are usually needed to protect
the airway and sometimes to hyperventilate the
patient for ICP management. Other comfort mea-
sures, such as bed rest, sedation, and analgesics, help
minimize agitation that might precipitate rerupture.
Seizures can precipitate rerupture, and anticonvul-
sants are given in the immediate period after SAH.
SURGICAL MANAGEMENT
Clipping the neck of an aneurysm effectively closes
the aneurysm and keeps blood from flowing into it.
The clip is applied under direct visualization under an
operating microscope while preserving blood flow in
the parent and perforating arteries around its base.
Once clipped, an aneurysm can be deflated or opened
to removed blood and thrombus that might be
compressing neural structures. Blood in the subar-
achnoid spaces can also be removed directly or
diluted with irrigation, which may have some
beneficial effects on subsequent vasospasm. Micro-
surgical clipping provides an immediate, durable cure
for aneurysms. The recurrence rate after clipping is
less than 1%, and after an immediate postoperative
angiogram no follow-up imaging is required.
Surgical clipping requires exposure of the aneur-
ysm. There are many surgical approaches for
aneurysms, but the most common is the pterional or
frontotemporal craniotomy. It provides direct expo-
sure of the ICA from its entry into the subarachnoid
space to its terminus, working in the space between
the frontal and temporal lobes. Removing bone
extensively from the skull base (pterion, sphenoid
ridge, and orbital roof) and opening the Sylvian
fissure to further separate the frontal and temporal
lobes create ample room to access all ICA, ACoA,
MCA, and basilar apex aneurysms. Additional
exposure can be gained by removing the orbital rim
with the orbitozygomatic approach, which is com-
monly used for giant anterior circulation aneurysms
and basilar apex aneurysms. Posterior circulation
aneurysms are accessed through the far-lateral
approach (PICA aneurysms), one of the transpetrosal
approaches (VBJ, AICA, and midbasilar artery
aneurysms), or a combined transpetrosal–subtempor-
al approach that communicates the regions above and
below the tentorium in front of the sigmoid sinus.
More than 95% of aneurysms can be treated with
direct surgical clipping. However, giant fusiform
aneurysms or those lacking a defined neck may require
alternative techniques, such as trapping or proximal
occlusion. These techniques can be performed safely if
the patient tolerates trial arterial occlusion with a
balloon-tipped catheter without ischemic deficits.
Hypotensive challenge or cerebral blood flow studies
increase the accuracy of balloon test occlusion (BTO).
Bypass procedures are indicated in patients who do
not tolerate BTO, and various bypasses are available
to meet the demands of blood flow in the involved
vascular territory. The superficial temporal artery
(STA) is a commonly used donor artery that can
revascularize the MCA territory. Saphenous vein grafts
can also be used to bypass aneurysms along the ICA as
it travels through the skull base and cavernous sinus,
providing rates of blood flow equal to those of the
native ICA. Intracranial arteries, such as the distal
MCA, ACA, or PICA, can be used as donor arteries to
revascularize adjacent arteries with proximal aneur-
ysms. Wrapping an aneurysm with cotton is another
surgical alternative used as a last resort. The walls are
reinforced externally with a material that elicits an
inflammatory reaction to promote scarring and
thickening of the aneurysm.
ENDOVASCULAR MANAGEMENT
Endosaccular occlusion of intracranial aneurysms has
become a viable alternative to microsurgical clipping
during the past decade. This technique is performed

using electrolytically detachable Guglielmi detachable
coils (GDCs) deployed through transfemoral intra-
aneurysmal catheters and angiographic visualization.
In general, aneurysm coiling appears to be associated
with lower morbidity and mortality rates than those
for surgery, but rates of incomplete obliteration and
recurrence are higher than those for surgery, making
its long-term efficacy unproven. Complications from
endovascular coiling are different from those asso-
ciated with surgery and include arterial dissection,
intraoperative aneurysmal rupture, parent artery
occlusion, distal embolization, and groin hematomas.
Although overall complications rates are approxi-
mately 8%, permanent neurological morbidity is
observed in approximately 4% of cases. Mortality
rates range between 0 and 2%. The rates of complete
aneurysm occlusion vary according to aneurysm size
and morphology and range between 35 and 80%.
Consequently, incompletely coiled aneurysms may not
be protected from the risk of rehemorrhage, and the
rate of new hemorrhages in patients treated with coils
has been reported to be approximately 3 or 4%.
Furthermore, endosaccular coils remain exposed to
hemodynamic forces that can shift or compact the
coils or promote growth of the aneurysm around the
coils. Aneurysm recurrence after coiling has been
reported in 5–45% of cases. Therefore, surveillance
angiography is required and recurrences can pose
complicated treatment issues.
Currently in North America, endovascular coils
are used as a primary treatment for elderly patients,
those considered to have a high surgical risk, and
those who are medically unsuitable for surgery. The
minimally invasive appeal of this treatment is
increasing patients’ interest and demand. In addition,
new deployment techniques that use balloons to
protect the parent artery from coil herniation and
new devices such as three-dimensional coils and
stents make aneurysms with unfavorable anatomy
treatable with endovascular methods. For example,
for stent-supported coil embolization a stent is laid
across a wide aneurysm neck and coils are deployed
through the interstices of the stent. Endovascular
techniques have become an integral part of multi-
modality therapy for aneurysms and will be used
increasingly in the future.
VASOSPASM
Vasospasm is the narrowing of cerebral arteries from
the contraction of smooth muscle cells in the vessel
ANEURYSMS, INTRACRANIAL 177
walls and, perhaps, from inflammatory infiltration of
the vessel walls, leading to diminished cerebral
perfusion, ischemia, and infarction. Vasospasm typi-
cally occurs 4–14 days after SAH and resolves
spontaneously thereafter. The pathogenesis is unclear
but related to the amount and distribution of blood in
the subarachnoid space. The Fisher Grading Scale is a
useful predictor of a patient’s likelihood of developing
vasospasm (Table 1). Approximately 70% of patients
experience some degree of vasospasm, with 20–30%
developing ischemic symptoms. The mortality rate
from vasospasm alone has been estimated to be
between 5 and 15%, and the rate of neurological
morbidity has been estimated to be approximately 6%.
Patients at risk of developing vasospasm are
monitored closely in an ICU. All patients are given
nimodipine, which is a calcium-channel blocker that
inhibits the contraction of vascular smooth muscle
cells and platelet aggregation. It is started within 4
days of SAH and continued for 21 days, regardless of
admission grade, at a dose of 60 mg every 4 hr.
Vasospasm is detected with angiography, transcranial
Doppler ultrasonography (TCD), or changes in
neurological examination. Angiography is the opti-
mal diagnostic study, but it is limited by its
invasiveness. TCD measures velocity of blood flow
in cerebral arteries, which increases as arteries
narrow with vasospasm. Therefore, by measuring
TCD velocities, vasospasm is monitored indirectly.
TCD is noninvasive and can be done repeatedly to
detect trends. Rising TCD velocities guide the timing
of more aggressive measures, such as hypertensive
therapy and angioplasty.
The mainstay of medical management is hypervo-
lemia, hypertension, and hemodilution. Volume
expansion is achieved with packed red blood cells,
albumin solution, or hypertonic saline solution.
Invasive monitoring with either a central venous
pressure line or a pulmonary artery catheter is
required to guide fluid management. Volume expan-
sion to central venous pressures 48 mmHg or
diastolic pulmonary artery pressures 414 mmHg is
usually enough to dilute the hematocrit to less than
35%. In addition, volume expansion may increase
systolic blood pressure to desired endpoints. As the
patient’s clinical condition demands, the blood
pressure is elevated with pressor agents to systolic
values between 180 and 220 mmHg.
Endovascular therapies for vasospasm are becom-
ing increasingly used when aggressive medical man-
agement fails, when TCD velocities rise, or when
there are multiple risk factors for severe vasospasm.
178 ANEURYSMS, SURGERY
Transluminal balloon angioplasty (TBA) mechani-
cally dilates segments of large cerebral arteries that
are in spasm, usually restoring the normal caliber of
the lumen. This intervention immediately improves
blood flow to ischemic brain and typically results in
clinical improvement. Furthermore, the effects of
angioplasty appear to last up to 1 week, which
corresponds to the duration of vasospasm. The
success of this intervention has largely to do with
timing. Early angioplasty before or immediately after
neurological deterioration enhances its efficacy.
TBA is limited to large cerebral arteries, such as
the ICA, MCA, and ACA. Smaller distal arteries are
not amenable to angioplasty; instead, they can be
treated with an intra-arterial papaverine infusion.
Superselective infusion of papaverine, a potent
vasodilator, can improve the caliber of vasospastic
arteries, but the effects are short-lived (o12 hr).
Repeated treatments may be needed for severe distal
vasospasm, which limits its utility.
PROGNOSIS
Outcome depends on the extent of damage done by
the initial aneurysm hemorrhage or subsequent
rehemorrhage, complications resulting from treat-
ment, and complications resulting from vasospasm.
Of these factors, the initial injury is most important.
The patient’s preoperative status as assessed by the
Hunt–Hess Scale is perhaps the best predictor of
outcome. Good recovery, as defined by Glasgow
outcome scores, can be expected in 97% of grade I
patients, 88% of grade II patients, and 81% of grade
III patients. In these low-grade patients, 55%
resumed in their normal living conditions, 67%
returned to full-time work, and 23% reported
physical disabilities. In contrast, poor-grade patients
(Hunt–Hess grades IV and V) have less favorable
outcomes. Left untreated, more than 90% of grade V
patients will die or be severely disabled. When treated
aggressively, between one-fourth and one-third of
poor-grade patients will have a favorable outcome.
—Philip V. Theodosopolous and Michael T. Lawton
See also–Aneurysms; Aneurysms, Surgery;
Cerebral Vasospasm, Treatment of; Endovascular
Therapy; Subarachnoid Hemorrhage (SAH)
Further Reading
Findlay, J. M. (1997). Current management of aneurysmal
subarachnoid hemorrhage guidelines from the Canadian
Neurosurgical Society. Can. J. Neurol. Sci. 24, 161–170.
Guglielmi, G., Viñuela, F., Sepetka, I., et al. (1991). Electro-
thrombosis of saccular aneurysms via endovascular approach.
Part 1: Electrochemical basis, technique, and experimental
results. J. Neurosurg. 75, 1–7.
Haley, E. C., Jr., Kassell, N. F., and Torner, J. C. (1992). The
International Cooperative Study on the Timing of Aneur-
ysm Surgery. The North American experience. Stroke 23,
205–214.
Hayakawa, M., Murayama, Y., Duckwiler, G. R., et al. (2000).
Natural history of the neck remnant of a cerebral aneurysm
treated with the Guglielmi detachable coil system. J. Neurosurg.
93, 561–568.
Higashida, R. T., Halbach, V. V., Cahan, L. D., et al. (1989).
Transluminal angioplasty for treatment of intracranial arterial
vasospasm. J. Neurosurg. 71, 648–653.
International Study of Unruptured Intracranial Aneurysms In-
vestigators (1998). Unruptured intracranial aneurysms—risk of
rupture and risks of surgical intervention. N. Engl. J. Med. 339,
1725–1733. [Published erratum appears in N. Engl. J. Med.
340(9), 744, 1999].
Juvela, S., Porras, M., and Poussa, K. (2000). Natural history of
unruptured intracranial aneurysms: Probability of and risk
factors for aneurysm rupture. J. Neurosurg. 93, 379–387.
Kassell, N. F., Torner, J. C., Jane, J. A., et al. (1990).
The International Cooperative Study on the Timing of
Aneurysm Surgery. Part 2: Surgical Results. J. Neurosurg. 73,
37–47.
Lawton, M. T., and Spetzler, R. F. (1995). Surgical management of
giant intracranial aneurysms: Experience with 171 patients
(honored guest lecture). Clin. Neurosurg. 42, 245–266.
Lawton, M. T., Hamilton, M. G., Morcos, J. J., et al. (1996).
Revascularization and aneurysm surgery: Current
techniques, indications, and outcome. Neurosurgery 38,
83–94.
Report of the World Federation of Neurological Surgeons
Committee on a Universal Subarachnoid Hemorrhage Grading
Scale (1988). J. Neurosurg. 68, 985–986.
Aneurysms, Surgery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
INTRACRANIAL ANEURYSMS are acquired lesions
usually found where the major arteries at the base
of the brain branch in the subarachnoid space. Each
year, approximately 30,000 people in the United
States suffer rupture of an intracranial aneurysm or
nontraumatic subarachnoid hemorrhage (SAH):
60% die or are disabled. In addition, persistent
neuropsychological and cognitive deficits remain in
approximately half of the patients who appear to
experience an otherwise favorable outcome. This
entry reviews the epidemiology, pathogenesis,
pathology, clinical characteristics, diagnosis, and
treatment of intracranial aneurysms.
178 ANEURYSMS, SURGERY
Transluminal balloon angioplasty (TBA) mechani-
cally dilates segments of large cerebral arteries that
are in spasm, usually restoring the normal caliber of
the lumen. This intervention immediately improves
blood flow to ischemic brain and typically results in
clinical improvement. Furthermore, the effects of
angioplasty appear to last up to 1 week, which
corresponds to the duration of vasospasm. The
success of this intervention has largely to do with
timing. Early angioplasty before or immediately after
neurological deterioration enhances its efficacy.
TBA is limited to large cerebral arteries, such as
the ICA, MCA, and ACA. Smaller distal arteries are
not amenable to angioplasty; instead, they can be
treated with an intra-arterial papaverine infusion.
Superselective infusion of papaverine, a potent
vasodilator, can improve the caliber of vasospastic
arteries, but the effects are short-lived (o12 hr).
Repeated treatments may be needed for severe distal
vasospasm, which limits its utility.
PROGNOSIS
Outcome depends on the extent of damage done by
the initial aneurysm hemorrhage or subsequent
rehemorrhage, complications resulting from treat-
ment, and complications resulting from vasospasm.
Of these factors, the initial injury is most important.
The patient’s preoperative status as assessed by the
Hunt–Hess Scale is perhaps the best predictor of
outcome. Good recovery, as defined by Glasgow
outcome scores, can be expected in 97% of grade I
patients, 88% of grade II patients, and 81% of grade
III patients. In these low-grade patients, 55%
resumed in their normal living conditions, 67%
returned to full-time work, and 23% reported
physical disabilities. In contrast, poor-grade patients
(Hunt–Hess grades IV and V) have less favorable
outcomes. Left untreated, more than 90% of grade V
patients will die or be severely disabled. When treated
aggressively, between one-fourth and one-third of
poor-grade patients will have a favorable outcome.
—Philip V. Theodosopolous and Michael T. Lawton
See also–Aneurysms; Aneurysms, Surgery;
Cerebral Vasospasm, Treatment of; Endovascular
Therapy; Subarachnoid Hemorrhage (SAH)
Further Reading
Findlay, J. M. (1997). Current management of aneurysmal
subarachnoid hemorrhage guidelines from the Canadian
Neurosurgical Society. Can. J. Neurol. Sci. 24, 161–170.
Guglielmi, G., Viñuela, F., Sepetka, I., et al. (1991). Electro-
thrombosis of saccular aneurysms via endovascular approach.
Part 1: Electrochemical basis, technique, and experimental
results. J. Neurosurg. 75, 1–7.
Haley, E. C., Jr., Kassell, N. F., and Torner, J. C. (1992). The
International Cooperative Study on the Timing of Aneur-
ysm Surgery. The North American experience. Stroke 23,
205–214.
Hayakawa, M., Murayama, Y., Duckwiler, G. R., et al. (2000).
Natural history of the neck remnant of a cerebral aneurysm
treated with the Guglielmi detachable coil system. J. Neurosurg.
93, 561–568.
Higashida, R. T., Halbach, V. V., Cahan, L. D., et al. (1989).
Transluminal angioplasty for treatment of intracranial arterial
vasospasm. J. Neurosurg. 71, 648–653.
International Study of Unruptured Intracranial Aneurysms In-
vestigators (1998). Unruptured intracranial aneurysms—risk of
rupture and risks of surgical intervention. N. Engl. J. Med. 339,
1725–1733. [Published erratum appears in N. Engl. J. Med.
340(9), 744, 1999].
Juvela, S., Porras, M., and Poussa, K. (2000). Natural history of
unruptured intracranial aneurysms: Probability of and risk
factors for aneurysm rupture. J. Neurosurg. 93, 379–387.
Kassell, N. F., Torner, J. C., Jane, J. A., et al. (1990).
The International Cooperative Study on the Timing of
Aneurysm Surgery. Part 2: Surgical Results. J. Neurosurg. 73,
37–47.
Lawton, M. T., and Spetzler, R. F. (1995). Surgical management of
giant intracranial aneurysms: Experience with 171 patients
(honored guest lecture). Clin. Neurosurg. 42, 245–266.
Lawton, M. T., Hamilton, M. G., Morcos, J. J., et al. (1996).
Revascularization and aneurysm surgery: Current
techniques, indications, and outcome. Neurosurgery 38,
83–94.
Report of the World Federation of Neurological Surgeons
Committee on a Universal Subarachnoid Hemorrhage Grading
Scale (1988). J. Neurosurg. 68, 985–986.
Aneurysms, Surgery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
INTRACRANIAL ANEURYSMS are acquired lesions
usually found where the major arteries at the base
of the brain branch in the subarachnoid space. Each
year, approximately 30,000 people in the United
States suffer rupture of an intracranial aneurysm or
nontraumatic subarachnoid hemorrhage (SAH):
60% die or are disabled. In addition, persistent
neuropsychological and cognitive deficits remain in
approximately half of the patients who appear to
experience an otherwise favorable outcome. This
entry reviews the epidemiology, pathogenesis,
pathology, clinical characteristics, diagnosis, and
treatment of intracranial aneurysms.

EPIDEMIOLOGY
Autopsy studies suggest that 1–6% of adults harbor
an intracranial aneurysm. Aneurysms are rare in
children. Many of these lesions are small; the
frequency of intracranial aneurysms among adults
undergoing cerebral angiography is between 0.5 and
1%. Most intracranial aneurysms (80%) are found in
the anterior cerebral circulation, particularly at the
junction of the posterior communicating artery and
the internal carotid artery, the anterior communicat-
ing artery complex, or the middle cerebral artery
bifurcation. Posterior circulation aneurysms are most
frequently located at the basilar artery bifurcation or
the junction of a vertebral artery and posterior
inferior cerebellar artery. Between 20 and 30% of
patients have multiple aneurysms.
Between 5 and 15% of all stroke cases result from
ruptured aneurysms. The annual incidence of SAH in
the United States is estimated to be approximately 1
per 10,000 people. Although the incidence of stroke
Figure 1
Aneurysm pathology. Angiograms illustrating (A) saccular aneurysm arising from the junction of the internal carotid and posterior
communicating arteries (arrow), (B) saccular aneurysm at the junction of the vertebral and posterior inferior cerebellar arteries (arrow),
(C) fusiform aneurysm of the right middle cerebral artery, and (D) infective aneurysm of the distal right middle cerebral artery (arrow).
ANEURYSMS, SURGERY 179
from other causes, such as cerebral infarction, has
decreased in the past several decades, a similar
decline has not been observed for SAH. Aneurysmal
rupture is more frequently observed in females than
in males. The mean age of patients with aneurysmal
SAH is approximately 55 years.
PATHOLOGY OF ANEURYSMS
There are a variety of intracranial aneurysms,
including saccular or berry, infective or mycotic,
fusiform, dissecting, and traumatic (Fig. 1). The most
common intracranial aneurysm is the saccular
aneurysm. Compared with extracranial arteries of
similar size, intracranial arteries have an attenuated
tunica media and lack an external elastic lamina.
These features may partially explain why saccular
aneurysms are more frequent on intracranial than
extracranial vessels of similar size. Macroscopically,
many intracranial aneurysms, particularly ruptured
180 ANEURYSMS, SURGERY
aneurysms, have an irregular appearance and vari-
able wall thickness. The point of rupture is usually
the aneurysm dome. Histological analysis has shown
that the earliest change in the formation of saccular
aneurysms is intimal outpouching through the media
with internal elastic membrane fragmentation. Next,
the media is replaced by fibrous tissue, resulting in an
aneurysm wall consisting of intima separated from
the adventitia by fibrous tissue.
Mycotic or infective aneurysms comprise 2–6% of
intracranial aneurysms. Most of these lesions result
from bacterial infections, particularly staphylococcus
and streptococcus infections, and are associated with
septic emboli from bacterial endocarditis. These
lesions are typically found on distal branches of the
middle cerebral artery. Infective aneurysms may also
result from direct vessel invasion; these aneurysms
tend to be located on proximal vessels and result
from fungal infections, particularly aspergillosis or
candida. Histopathology of mycotic aneurysms
reveals destruction of the intima, internal elastic
membrane, and varying amounts of the media. An
inflammatory cell infiltrate initially consists of
polymorphonuclear cells and then lymphocytes and
macrophages. In some patients, antimicrobial ther-
apy may be sufficient to treat the infective aneurysm.
Fusiform intracranial aneurysms are characterized
by circumferential dilatation, elongation, and tortu-
osity of cerebral arteries and are associated with
atherosclerosis and dolichoectasia. These lesions
most often involve the vertebrobasilar system or
proximal internal carotid artery. Most patients with
fusiform aneurysms present with ischemic symptoms,
hydrocephalus, or mass effect rather than aneurys-
mal rupture. In some instances, these patients can be
treated with antiplatelet agents rather than aneurysm
occlusion. Other patients require sophisticated pro-
cedures such as bypass and parent vessel occlusion or
aneurysm excision to treat the lesion.
Dissecting aneurysms are formed through the
creation of a false lumen by a break in the intima
of the blood vessel. Blood then accumulates within
the vessel wall and subsequently may rupture into the
true lumen or break through the vessel wall and
cause hemorrhage. Dissecting aneurysms are asso-
ciated with trauma and vasculopathies such as
Marfan’s syndrome or fibromuscular dysplasia.
Traumatic aneurysms comprise approximately 1%
of intracranial aneurysms and most manifest within
2 or 3 weeks of original injury. Traumatic aneurysms
are usually associated with a penetrating head injury
or contiguous skull fracture and are most common in
the middle cerebral artery region after low-velocity
shrapnel injuries or stab wounds. These lesions may
also be associated with blunt trauma, or they may
originate iatrogenically. The traumatic event disrupts
the vessel wall, leading to the formation of an
aneurysmal bulge. In true traumatic aneurysms, the
remnant of the vessel wall contains intima. In
contrast, a false traumatic aneurysm is essentially a
hematoma constrained by the surrounding tissue.
Traumatic aneurysms often cannot be occluded
directly and may require other surgical approaches,
such as parent vessel occlusion and bypass or
aneurysm excision.
PATHOGENESIS OF SACCULAR ANEURYSMS
The specific biological mechanisms leading to the
development or rupture of intracranial saccular
aneurysms are not clearly defined. Genetic, acquired,
hormonal, and even climatic factors may be im-
portant. The association of intracranial aneurysms
with heritable connective tissue disorders, such as
autosomal dominant polycystic kidney disease, Eh-
lers–Danlos syndrome type IV, neurofibromatosis
type 1, and Marfan’s syndrome, and their familial
occurrence suggest a role for genetic factors. Several
epidemiological studies suggest that 7–20% of
patients suffering rupture of an intracranial aneur-
ysm have a first- or second-degree relative with a
confirmed intracranial aneurysm. The inheritance
pattern is unclear but may be highest among siblings.
Affected siblings are often in the same decade of life
at the time of aneurysm rupture. The risk of
aneurysmal SAH is approximately four times higher
among first-degree relatives of patients with ruptured
aneurysms than in the general population. In
addition, familial aneurysms may differ from spora-
dic aneurysms; they rupture at an earlier age, are
often smaller when they rupture, are associated with
worse outcomes, and are more often followed by the
formation of a new aneurysm.
Acquired factors have an important role in
intracranial aneurysm pathogenesis. For example,
intracranial aneurysms are very rare in children,
whereas the mean age of patients with aneurysmal
rupture is 55 years. Recent longitudinal and case
control studies have also shown that modifiable
acquired factors, such as atherosclerosis, hyperten-
sion, elevated cholesterol, and particularly cigarette
smoking, may play a role in aneurysm formation. In
addition, long-term heavy cigarette smoking and
cigarette smoking within 3 hr or heavy alcohol

consumption within 24 hr of aneurysmal rupture are
significant independent risk factors for SAH. The
estimated risk of an aneurysmal SAH is 3–10 times
higher among smokers than among nonsmokers.
Cigarette smoking may increase the rate of aneurysm
formation through a decrease in the effectiveness of
a1 antitrypsin, the main inhibitor of proteolytic
enzymes such as elastase.
Several lines of evidence suggest that hemody-
namic stress also plays a role in the formation of
aneurysms. For example, aneurysms are frequently
associated with high flow states such as on the
feeding vessels of an arteriovenous malformations,
following carotid ligation, or when circle of Willis
abnormalities are present. Most aneurysms are also
found where the greatest amount of hemodynamic
stress occurs—the apex at the bifurcation of blood
vessels. Similarly, hypertension is associated with an
increased risk of aneurysmal SAH and unruptured
intracranial aneurysms.
PATHOLOGY OF ANEURYSM RUPTURE
Aneurysmal rupture is a complex pathophysiological
event associated with a variety of intracranial and
systemic pathophysiological events and biochemical
and metabolic changes. Intracranial pathology in-
cludes subarachnoid hemorrhage, intracerebral he-
morrhage, intraventricular hemorrhage, subdural
hemorrhage in rare patients, brain edema, hydro-
cephalus, and vasospasm or narrowing of the
intracranial arteries. Brain edema may be vasogenic,
cytotoxic, interstitial, or oncotic; after an SAH,
vasogenic edema is the most frequent type. Systemic
abnormalities, such as decreased total systemic blood
volume; electrolytic disturbances, including cerebral
salt wasting, diabetes insipidus, and inappropriate
antidiuretic hormone secretion; activation of the
coagulation and fibrinolytic system; and cardiopul-
monary dysfunction occur. There are many biochem-
ical abnormalities after SAH, such as increased levels
of excitatory amino acids or cytokines, altered levels
of nitric oxide, or endothelin metabolism. In addi-
tion, aneurysmal rupture also disturbs cerebral
physiology and leads to increased intracranial
pressure, reduced cerebral blood flow (CBF), de-
creased tissue oxygen supply, and impaired auto-
regulation or CO2 reactivity. The frequency and
severity of these various pathophysiological abnorm-
alities are greater among patients in a poor clinical
condition, and some may progress in severity from
the day of SAH for the next several days to weeks.
ANEURYSMS, SURGERY 181
CLINICAL PRESENTATION
Subarachnoid Hemorrhage
Most intracranial aneurysms are asymptomatic until
they rupture. Aneurysm rupture may occur at any
time but appears to be more common during times of
exertion or stress. The typical manifestation of
aneurysmal rupture is a severe headache of sudden
onset. This headache is often described as the worst
headache the patient has ever experienced. There
may be associated nausea or vomiting, and the
patient may or may not lose consciousness. Approxi-
mately 30% of patients with SAH have a history of a
prodromal headache that precedes the hemorrhage
by several days or weeks. This headache is thought to
represent minor leaking and so is often called a
warning leak. These warning leaks are difficult to
recognize but are important because clinical studies
suggest that these patients have a poor outcome after
aneurysmal rupture.
Neck stiffness and intraocular hemorrhages are
common findings among patients with SAH. Neck
stiffness may take several hours to develop and
results from meningeal irritation caused by the
breakdown of blood products in the subarachnoid
space and the associated inflammatory response.
Subhyaloid hemorrhages may occur in approxi-
mately 25% of patients with aneurysmal SAH on
ophthalmological examination. These hemorrhages
are venous in origin and are located between the
retina and vitreous membrane. Altered consciousness
or focal neurological abnormalities are also found on
physical examination and depend on the location
and severity of the SAH. Aneurysmal SAH is often
misdiagnosed as migraine headache, sinusitis, influ-
enza, or a hypertensive crises.
The most important predictor of outcome after
aneurysmal rupture is a patient’s clinical condition at
admission to hospital. A number of clinical grading
systems are used to guide management. The most
frequently used grading systems include the Hunt
and Hess system and the World Federation of
Neurological Surgeons Scale (WFNS), which is based
on the Glasgow Coma Scale (Table 1). In addition,
the Fischer grading system, based on the severity of
subarachnoid hemorrhage seen on head computed
tomography (CT) scan, is frequently used to predict
whether vasospasm will develop. Compared to
patients in a poor clinical grade (Hunt and Hess or
WFNS grade IV or V), patients in good clinical grade
(Hunt and Hess or WFNS grade I–III) are less likely
to have severe SAH on CT or other consequences of
182 ANEURYSMS, SURGERY

Table 1 COMMON CLINICAL GRADING SCALES USED AFTER INTRACRANIAL ANEURYSM RUPTUREa

Hunt and Hess Scaleb

Grade Clinical findings

0 Unruptured, no SAH
I Mild headache, mild neck stiffness
II Moderate to severe headache, neck stiffness
III Drowsy, confusion, mild focal deficit
IV Stupor, mild to moderate hemiparesis, possible early decerebrate rigidity
V Deep coma, moribund, decerebrate posturing

World Federation of Neurosurgical Societies Scalec

Grade GCS score Motor deficit

0 15 Absent, no SAH
I 15 Absent
II 13–14 Absent
III 13–14 Present
IV 7–12 Present or absent
V 3–6 Present or absent
a
Grade 0 in both scales represents an unruptured aneurysm. GCS, Glasgow Coma Scale; SAH, subarachnoid hemorrhage.
b
Hunt, W. E., and Hess, R. M. (1968). Surgical risk related to time of intervention in the repair of intracranial aneurysms. J. Neurosurg.
24, 14–19.
c
Drake, C. G. (1988). Report of World Federation of Neurological Surgeons Committee on universal subarachnoid hemorrhage grading
scale. J. Neurosurg. 38, 575–580.

aneurysm rupture, such as intracerebral hemorrhage,
intraventricular hemorrhage, hydrocephalus, sys-
temic complications, or vasospasm. Similarly, out-
come is significantly better in good grade patients
than in those with a poor clinical grade.
Unruptured Intracranial Aneurysms
The discrepancy between the prevalence of intracra-
nial aneurysms and the frequency of aneurysmal
rupture suggests that most aneurysms may never
rupture. With the widespread use of CT and
magnetic resonance imaging (MRI), many unrup-
tured asymptomatic intracranial aneurysms can now
be detected (Fig. 2). The natural history of unrup-
tured aneurysms is incompletely understood. Several
long-term follow-up studies show that the overall
risk of SAH from an unruptured aneurysm is 1 or 2%
per year. The annual risk of rupture, however, may
vary between 0.05 and 6% per year and largely
depends on aneurysm characteristics rather than the
patient. Increased aneurysm size, posterior circula-
tion aneurysms, symptomatic aneurysms, aneurysms
associated with arteriovenous malformations, un-
ruptured aneurysms that increase in size on follow-
up imaging, and previous SAH from another
aneurysm are thought to be associated with an
increased risk of rupture. There is considerable
controversy about the size below which the risk of
aneurysm rupture is low. Some authors suggest that
asymptomatic aneurysms less than 10 mm are
unlikely to rupture. However, analysis of ruptured
aneurysms shows that more than half of the lesions
are less than 10 mm in diameter.
Mass Effect or Cerebral Ischemia
Intracranial aneurysms may become symptomatic
because of mass effect, or they can be associated with
cerebral ischemia. These aneurysms often but not
invariably are large or giant aneurysms (425 mm in
diameter). Common manifestations of mass effect
include headache, third nerve palsy typically caused
by a posterior communicating artery aneurysm,
brainstem dysfunction associated with vertebrobasi-
lar aneurysms, or monocular visual loss from
carotid–ophthalmic aneurysms. Cerebral ischemia
may result from embolization of an intra-aneurysmal
thrombus. The symptoms are usually referable to the
vascular territory distal to the aneurysm.
 ANEURYSMS, SURGERY 183

Figure 2
Aneurysm clinical presentation and diagnosis: (A) head CT scan demonstrating SAH, (B) head CT scan demonstrating intracerebral
hemorrhage (open arrow) and after contrast administration (CT angiography) a middle cerebral artery aneurysm (arrow), (C) MRI and MRI
with contrast illustrating a superior cerebellar artery aneurysm compressing the brainstem (arrows), and (D) MRA study demonstrating right
middle cerebral artery aneurysm (arrow).

DIAGNOSTIC STUDIES seen on CT. When a CT study is normal but clinical

SAH
CT is the investigation of choice to diagnose a
ruptured aneurysm (Fig. 2) largely because it is very
sensitive in detecting acute hemorrhage. SAH is
observed in approximately 95% of patients who
undergo CT within 24 hr of an aneurysmal rupture.
Blood, however, is cleared rapidly from the subar-
achnoid space. One week after SAH, blood is
observed on CT in only 50% of patients. Intracer-
ebral or intraventricular hemorrhage or hydrocepha-
lus are also easily detected by CT. The distribution of
subarachnoid blood may suggest the location of the
ruptured aneurysm; however, aneurysms are rarely
suspicion of a SAH is strong, a lumbar puncture
should be performed. Xanthochromia, a yellow
discoloration of the supernatant after cerebrospinal
fluid is centrifuged, is diagnostic of SAH. Xantho-
chromia results from the breakdown of blood, so a
lumbar puncture performed soon after an aneurysm
ruptures may not be xanthochromic. When using
spectrophotometry, xanthochromia is found in all
patients 12 hr to 2 weeks after an aneurysm ruptures
and can still be detected in approximately 40% 4
weeks later. MRI is not sensitive in detecting acute
hemorrhage, and its role in evaluating SAH is
limited. However, MRI may help show subacute or
chronic SAH.
184 ANEURYSMS, SURGERY

Intracranial Aneurysms
Intracranial aneurysms can be imaged using con-
ventional catheter angiography, MR angiography
(MRA), or CT angiography (CTA; Fig. 2). Conven-
tional angiography remains the method of choice for
detecting an intracranial aneurysm and determining
its anatomical characteristics necessary for treat-
ment planning. The procedure is invasive and
associated with a small risk of stroke, renal failure,
allergic reactions, or hematoma formation at the
puncture site. These complications, however, are
more typical in elderly patients with severe athero-
sclerotic disease. MRA is noninvasive because no
intravascular contrast agents are required. This
technique is the most commonly used diagnostic
study for screening or detecting unruptured intra-
cranial aneurysms. However, its value is limited in
planning surgical or endovascular procedures to
occlude the aneurysm. Intracranial aneurysms as
small as 2 or 3 mm in diameter can be detected using
MRA. Sensitivities for detecting aneurysms between
3 and 5 mm vary between 69 and 93%, suggesting
that the critical size for detection is approximately
5 mm. Recently, CTA, which requires intravenous
contrast administration, has been used to detect and
evaluate intracranial aneurysms. This technique has
several advantages over MRA, including greater Figure 3
sensitivity, illustration of the three-dimensional Techniques of aneurysm occlusion. (A) Preoperative and (B)
anatomy, the ability to show the relationship postoperative angiograms illustrating an aneurysm at the
between the aneurysm and the bony structures of bifurcation of the basilar artery occluded through craniotomy by
the skull base, and the ability to image calcifications an aneurysm clip (arrow). (C) Angiogram showing microcatheter
positioned within a posterior communicating artery aneurysm.
within the aneurysm wall. CTA can also be used in (D) Radiograph illustrating GDC coils in the aneurysm (arrow)
surgical planning. CTA alone may be sufficient and (E) angiogram demonstrating endovascular aneurysm
preoperatively in some patients with large associated occlusion with GDC coils (arrow). (F) Angiogram demonstrating a
intracerebral hemorrhages that require emergent saphenous vein bypass between the extracranial and intracranial
evacuation (Fig. 2). circulation (arrowheads) and a large proximal aneurysm of the
internal carotid artery that is not amenable to direct occlusion
(arrow). (G) The aneurysm was occluded (arrow) through parent
vessel occlusion.
TREATMENT
The primary goal of intracranial treatment is
complete and permanent occlusion of an aneurysm. cians, primary care physicians, neurologists, neuro-
Aneurysms can be occluded using surgical or surgeons, radiologists, neuroanesthesiologists,
endovascular techniques or a combination of both. interventional neuroradiologists, intensivists, and
Some aneurysms, however, may be unamenable to rehabilitation therapists. SAH should be managed
direct occlusion and may be better treated by parent in specialized cerebrovascular centers directed by a
vessel occlusion, with or without a bypass, or neurosurgeon. Aneurysm obliteration to prevent
revascularization to alter the direction of blood flow rebleeding and to prepare for the management of
and thus induce aneurysm thrombosis (Fig. 3). The the pathophysiological consequences of SAH is
successful management of aneurysmal rupture re- central to successful treatment. In addition, specific
quires a dedicated multidisciplinary team that management is often required for intracerebral
includes paramedical staff, emergency room physi- hemorrhage, hydrocephalus, and vasospasm.

Surgery for Aneurysms
For most aneurysms, clip ligation of the aneurysm’s
neck through a craniotomy is the preferred therapy
because of its proven long-term efficacy. The first
planned surgical repair of an aneurysm was per-
formed in 1936. Surgical techniques for repairing
intracranial aneurysms have improved significantly
since then, particularly during the past 20 years, with
the introduction of the operating microscope, micro-
surgical techniques, and various self-closing aneur-
ysm clips. Some aneurysms are not amenable to safe
direct clipping because of their size, location, or
configuration. In these patients, sophisticated tech-
niques, such as vascular bypass grafting, parent
vessel occlusion, intraoperative angiography, or
hypothermic cardiac arrest, may be necessary.
Surgery to occlude aneurysms is effective. Overall,
more than 90% of aneurysms can be occluded
successfully using surgical techniques.
Endovascular Aneurysm Occlusion
During the past 10 years, endovascular treatment has
emerged as a useful alternative to surgical clipping for
select intracranial aneurysms. Current endovascular
therapy involves the insertion of soft metallic coils
known as Gugliemi detachable coils (GDCs) within
the aneurysm lumen. Once the coils have been
satisfactorily placed in the aneurysm, they are
detached from a microcatheter that has been threaded
through the intracranial blood vessels. The coils then
promote thrombosis in the aneurysm. Initial clinical
series suggest that overall 50% of aneurysms are
totally occluded using endovascular techniques.
However, some aneurysms occluded using GDCs
can recanalize and recur. The success of GDCs is
associated with aneurysm morphology. In general,
large aneurysms and aneurysms with wide inflow
necks are inadequately treated with GDCs, whereas
small aneurysms with small inflow necks invariably
can be occluded completely. Recent advances in other
endovascular techniques, including balloon remodel-
ing and endovascular stents, have improved the
efficacy of aneurysm occlusion using GDCs.
Unruptured Aneurysms
The identification and repair of unruptured aneur-
ysms may provide an effective means to reduce the
overall mortality and morbidity rates associated with
SAH. A clear understanding of the natural history
and risks of treatment and knowledge of the patients’
overall medical condition and life expectancy are
ANEURYSMS, SURGERY 185
necessary before an unruptured aneurysm is treated.
Surgical outcomes tend to be good. In most clinical
series, the overall morbidity and mortality rate
associated with the treatment of unruptured aneur-
ysms is 5%. Several aneurysm-related factors, such
as size, location, morphology of the aneurysm or its
neck, and atherosclerosis or calcification in the
aneurysm, are often associated with outcome. In
particular, size is the most important factor asso-
ciated with poor outcome. Overall, aneurysms
425 mm in diameter or giant aneurysms have a
fourfold increased risk of poor outcome compared
with aneurysms o10 mm in diameter. This relation-
ship is particularly true of giant aneurysms involving
the posterior circulation. Endovascular techniques
using GDCs may be an attractive alternative to
surgery for some patients. Early experience with coil
embolization for the treatment of intracranial
aneurysms suggests that the procedural risks are
fairly low; permanent complications are observed in
4–7% of patients. However, the long-term effective-
ness of coil embolization has not been proved.
Based on the available literature, patients with
unruptured aneurysms should be treated if they have
the following, provided that their life expectancy is
reasonable and they have no significant medical risk
factors: SAH from another aneurysm, symptomatic
aneurysms, aneurysms 410 mm, and aneurysms
between 6 and 9 mm if the patient is young or
middle-aged. Patients with unruptured asymptomatic
aneurysms o6 mm should undergo follow-up angio-
graphy or CTA and be treated if the lesion enlarges.
The decision to occlude the aneurysm using surgical
or endovascular techniques should be based on the
aneurysm’s morphology and the patient’s age and
medical condition. Surgical occlusion is preferred
because the risk of recanalization with current
interventional techniques is unknown. This decision
requires close collaboration between the neurosur-
geon and the interventional neuroradiologist after all
imaging studies have been reviewed.
Ruptured Aneurysms
Aneurysmal rupture is a devastating condition; the
primary causes of poor outcomes are the effects of
the initial hemorrhage, subsequent rebleeding, and
vasospasm. Following SAH, patients require rapid
evaluation and resuscitation in an emergency room
and then admission to the neurosurgical intensive
care unit at specialized cerebrovascular centers.
Intensive care therapy is important and should
include invasive hemodynamic monitoring, careful
186 ANEURYSMS, SURGERY
management of fluid status and blood pressure,
evaluation of intracranial physiology, and frequent
assessment of cerebral blood flow using techniques
such as transcranial Doppler ultrasonography or
radioisotope studies. In many instances, such care
improves outcomes by preventing secondary cerebral
insults, such as hypotension, hypoxia, or hypergly-
cemia. Emergency surgery, such as a craniotomy to
evacuate an intracerebral hemorrhage or a ventricu-
lostomy to manage hydrocephalus or intraventricular
hemorrhage, may be necessary in patients in poor
clinical condition. In all patients, however, it is
necessary to occlude the ruptured aneurysm using
surgical or endovascular techniques to prevent
rebleeding and to allow aggressive treatment of
vasospasm. After an aneurysm has been occluded,
patients require approximately 10 days of intensive
care therapy followed by rehabilitation to optimize
their chance of neurological recovery.
Aneurysm Rebleeding
Left untreated, 20–30% of ruptured aneurysms
rerupture or rebleed within the first 30 days of
SAH and then rerupture at a rate of approximately
3% per year. The frequency of rebleeding is greatest
the day after SAH (4%) and then occurs at a constant
rate between 1 and 2% per day during the
subsequent 4 weeks. There are no uniformly de-
scribed predictors of rebleeding, but poor clinical
condition, abnormal hemostatic parameters, and
posterior circulation aneurysms appear to be asso-
ciated with an increased risk of rebleeding. Between
70 and 90% of patients who rebleed after SAH die.
Rehemorrhage can only be prevented by occluding
the aneurysm using direct surgical obliteration
through a craniotomy or by using endovascular
techniques in select patients. Consequently, most
neurosurgeons favor surgery within 3 days of SAH to
prevent rebleeding. Soon after aneurysm rupture,
however, the brain may be swollen. If so, surgery
may be delayed 10–14 days to improve operating
conditions in some patients with complex aneurysms
that pose potential technical difficulties to occlude or
when sophisticated techniques such as bypass are
required. Alternatively, endovascular techniques can
be used in these patients soon after the aneurysm
ruptures if difficult surgical conditions are expected.
VASOSPASM
Vasospasm, which is narrowing of cerebral arteries,
occurs in 70% of all patients after aneurysmal SAH.
Half of these patients may develop cerebral infarction
or delayed ischemic neurological deficits. This arterial
narrowing typically develops 4–12 days after SAH
and is maximal approximately 7 days after an
aneurysm ruptures. It is attributed to the breakdown
products of blood in the subarachnoid space. Despite
extensive experimental and clinical research, effective
treatment for vasospasm and the delayed ischemic
neurological deficits associated with vasospasm re-
mains elusive. In several randomized trials, calcium
channel blockers such as nimodipine reduced the
frequency of cerebral infarction after SAH, and these
are now used routinely after SAH. However, these
studies found no effect on the frequency of vasospasm
on follow-up angiography. In animal studies, volume
expansion improved cerebral blood flow in regions of
ischemia and prevented stroke. Consequently, hyper-
volemic fluid therapy, often augmented with hyper-
tension and hemodilution, is now routinely
performed in most neurosurgical centers to treat
patients with SAH. It is assumed that this treatment
will improve CBF and thus prevent delayed cerebral
ischemia associated with vasospasm. Patients who are
symptomatic after vasospasm despite volume expan-
sion can also be treated with endovascular techniques
by using either a balloon or papaverine to dilate the
constricted blood vessels.
—Peter D. Le Roux, Gavin W. Britz, and
H. Richard Winn
See also–Aneurysms; Aneurysms, Intracranial;
Cerebral Vasospasm, Treatment of; Endovascular
Therapy; Subarachnoid Hemorrhage (SAH)
Further Reading
Adams, H. P., Jr., Kassell, N. F., Boarini, D. J., et al. (1991).
Clinical spectrum of aneurysmal subarachnoid hemorrhage. J.
Stroke Cerebrovasc. Dis. 1, 3–8.
Bederson, J., Awad, I. A., Wiebers, D. O., et al. (2000).
Recommendations for the management of patients with un-
ruptured intracranial aneurysms. Circulation 102, 2300–2308.
Brilstra, E., Rinkel, G., van der Graaf, Y., et al. (1999). Treatment
of intracranial aneurysms by embolization with coils: A
systematic review. Stroke 30, 470–476.
ISUIA (1998). Unruptured intracranial aneurysms—Risk of
rupture and risks of surgical intervention. N. Engl. J. Med.
339, 1725–1733.
Kassell, N. F., Torner, J. C., Haley, C., et al. (1990). The
International Cooperative Study on the Timing of Aneurysm
Surgery: Part 1: Overall management results. J. Neurosurg. 73,
18–36.
King, J., Berlin, J., and Flamm, E. (1994). Morbidity and mortality
from elective surgery for asymptomatic, unruptured, intracra-
nial aneurysms: A meta-analysis. J. Neurosurg. 81, 837–842.

Le Roux, P., and Winn, H. R. (1998). Management of cerebral
aneurysms: How can current management be improved?
Neurosurg. Clin. North Am. 9, 421–433.
Le Roux, P., and Winn, H. R. (1998). Management of the ruptured
aneurysm. Neurosurg. Clin. North Am. 9, 525–540.
Le Roux, P., and Winn, H. R. (2002). Surgical decision making for
treatment of cerebral aneurysms. In Youmans Neurological
Surgery (H. R. Winn, Ed.), 5th ed. Elsevier, Philadelphia.
Mayberg, M. (1998). Cerebral vasospasm. Neurosurg. Clin. North
Am. 9, 615–627.
Raaymakers, T. W., Rinkel, G., Limburg, M., et al. (1998).
Mortality and morbidity of surgery for unruptured intracranial
aneurysms. A meta-analysis. Stroke 29, 1531–1538.
Rinkel, G. J. E., Djibuti, M., Algra, A., et al. (1998). Prevalence
and risk of rupture of intracranial aneurysms. A systematic
review. Stroke 29, 251–256.
Schievink, W. (1998). Genetics and aneurysm formation. Neuro-
surg. Clin. North Am. 9, 485–495.
Stebhens, W. E. (1995). Aneurysms. In Vascular Pathology (W. E.
Stebhens and J. T. Lie, Eds.). Chapman & Hall, New York.
Teunissen, L. L., Rinkel, G. J. E., Algra, A., et al. (1996). Risk
factors for subarachnoid hemorrhage—A systematic review.
Stroke 27, 544–549.
Weir, B. (1987). Aneurysms Affecting the Nervous System.
Williams & Wilkins, Baltimore.
Angiitis
see Vasculitis, Cerebral
Angiography
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CONVENTIONAL (x-ray) angiography provides high-
resolution, two-dimensional images of the arteries
and veins of the head and neck. It is used to identify
abnormalities of these vessels, such as aneurysms,
arteriovenous malformations, and atherosclerotic
disease. Angiography involves two major compo-
nents: the introduction of contrast media into the
vessel of interest and the acquisition of x-ray images
before and after contrast injection. Conventional
angiography provides the highest resolution and detail
of normal and abnormal vascular anatomy of any of
the currently available imaging tools (Fig. 1). The
limitations of this technique are primarily due to risks
of placing catheters directly into the vessels of interest.
HISTORY
The technique of conventional angiography has
evolved considerably since Egaz Moniz performed
ANGIOGRAPHY 187
the first intra-arterial injection of contrast media for
a cerebral angiogram in 1927. As a consequence of
these advancements, both the safety of the procedure
and the quality of the acquired images have
improved. Transfemoral catheterization has replaced
direct puncture of the carotid or vertebral arteries.
The catheters and guidewires used for selective
injection of the cervical and cerebral arteries are less
traumatic and less thrombogenic. A variety of safe
and well-tolerated contrast media have been devel-
oped. Angiographic images are now acquired and
manipulated using computer-based digital systems
rather than plain x-ray films. This advancement has
eliminated problems with the timing of contrast
injection and image acquisition as well as reduced
the amount of contrast media necessary for opacifi-
cation of the vessels. The single limitation of digital
imaging compared to plain x-ray films (known as
‘‘cut-film’’ angiography) is a loss of image resolution.
The role of angiography in the diagnosis of
diseases affecting the nervous system became more
focused with the advent of computed tomography
(CT) in the 1970s. Prior to this, patients with
neurological deficits frequently underwent angiogra-
phy as a primary diagnostic tool. Mass lesions were
detected by their displacement of cerebral arteries
and veins. The degree of vascularity of the mass
could often differentiate tumor from hemorrhage (an
avascular mass). CT and, recently, magnetic reso-
nance imaging (MRI) have supplanted angiography
for these purposes. Currently, the most common
indication for angiography is for the evaluation of
patients with known or suspected cerebrovascular
disease. Doppler ultrasound, MRI angiography, and
CT angiography are playing an increasingly impor-
tant role in the diagnosis of extracranial vascular
stenosis. The accuracy of these tools for the
identification of arterial stenoses or intracranial
aneurysms has improved and has led to their
increased use as screening tools prior to angiography.
Angiography remains the definitive technique for the
reliable measurement of arterial stenosis and the
accurate detection or exclusion of intracranial
aneurysms.
PHYSICAL PRINCIPLES
An angiographic suite contains an x-ray tube and
image intensifier, often in a dual fashion to allow
simultaneous image acquisition in two orthogonal
planes (biplane). This enables the acquisition of twice
the anatomical information from each injection of
188 ANGIOGRAPHY

Figure 1
(A) Lateral angiogram after injection of the left vertebral artery (LVA)—arterial phase. Both vertebral arteries are filled (the right retrograde)
as well as the basilar artery (arrowhead at the confluence of the vertebral arteries). Note the small visibility of small branches and the high
resolution of the image. (B) Lateral projection from same injection—venous phase. These images, taken after the contrast circulated through
the arteries and capillaries, show the contrast in the superficial veins and dural sinuses (white asterisk shows the sigmoid sinus).

contrast compared to single-plane units. The image
intensifier absorbs a fraction of the photons that have
passed through the patient from the x-ray tube and
converts the energy of the photon to light. The
amount of light is proportional to the number of
photons. The number of photons reaching a parti-
cular spot on the image intensifier is affected by the
electron density of the tissues encountered on their
way through the body (contrast media is relatively
electron dense compared to other soft tissues of the
body). A television system converts the light from the
image intensifier to an electronic video signal. The
image matrix of modern digital equipment has
1024  1024 pixels. This resolution allows the
definition of vessels as small as 300 mm.
The term digital subtraction angiography (DSA)
refers to the subtraction of images acquired after
contrast injection from images acquired before
contrast. The shadows of soft tissue and bony
structures present on pre- and postcontrast images
are subtracted, leaving only the contrast introduced
into the vessel. Computer manipulation of the digital
images allows for correction of mild motion artifact
(causing misregistration of the bones and soft tissues
in the image). Selected images of arterial, capillary,
and venous structures can be generated by subtract-
ing images acquired progressively later after injec-
tion. The resolution of these images is much greater
than that of those acquired with any other imaging
modality.
TECHNIQUE
A baseline neurological and medical examination
and history are necessary before beginning the
procedure for the following reasons: First, the
examination should be tailored to answer the clinical
question. For example, selective injections of the
vertebral arteries may not be necessary for some
patients with symptomatic carotid artery stenosis.
Second, knowledge of baseline status is necessary to
accurately determine if an embolic complication may
have occurred during the procedure or afterwards.
Third, it is important to find out if the patient has
had a prior allergic reaction to contrast media.
Finally, some medical conditions, such as renal
failure, may change the amount and type of contrast
media used for the examination. An intravenous

catheter is placed for administration of short-acting
sedatives and other drugs or fluids, if necessary. After
obtaining informed consent, the patient is placed on
the angiographic table.
The site of arterial puncture (usually the common
femoral artery at the hip) is prepped and draped in a
sterile fashion. The skin is infiltrated with a local
anesthetic. The catheter is placed into the artery
using the technique developed by Seldinger. A hollow
needle is directed through the skin toward the pulse
until pulsatile flow through the needle is encoun-
tered. A flexible wire is sent up through the needle
into the artery. The needle is removed over the wire,
and a catheter with an inner lumen tapered to the
diameter of the wire is advanced over the wire into
the artery. Using fluoroscopy (real-time x-ray), the
catheter and wire are guided into the aortic arch and
subsequently into the origins of the carotid and
vertebral arteries. Angiograms of the desired cervical
and cerebral arteries and veins are obtained after
injection of the catheter with contrast media. The
catheter is removed after the procedure. The site of
puncture is then sealed by either manual compression
or using a percutaneous device.
RISKS
The list of potential complications from a cerebral
angiogram is long. The initial arterial puncture
carries risks of vessel damage, hemorrhage, and
infection. Contrast injections may lead to severe
allergic reactions or renal damage. Catheterization
may damage the vessel. Fortunately, the risk of these
untoward events is very low (o1 in 1000). The
primary concern with selective arterial catheteriza-
tion is embolic stroke. This may be due to local vessel
wall injury or thrombus formation on the catheter.
The risk of embolic stroke in patients without
atherosclerotic disease is very low (o1 in 1000 for
a permanent stroke). However, the embolic risks
with angiography are higher for patients presenting
with ischemic symptoms.
APPLICATIONS
Atherosclerotic Disease
The angiographic evaluation of patients with known
or suspected atherosclerotic disease is tailored to
answer the clinically relevant questions. For exam-
ple, the purpose of angiography in patients with
evidence of stenosis of the extracranial carotid
ANGIOGRAPHY 189
bifurcation by screening Doppler ultrasound or
MRI examinations is to provide an accurate mea-
surement of the actual degree of stenosis. Surgical
trials of endarterectomy for the prevention of future
stroke are based on the angiographic measurement of
the degree of stenosis (Fig. 2). The purpose of a
cerebral angiogram in patients with subarachnoid
hemorrhage is to identify a possible etiology. This
requires a more detailed and extensive examination.
An injection of the aortic arch may reduce the risks
and the duration of the procedure. Severe stenoses of
the origins or proximal portions of the vessels from
the arch or of the vertebral arteries from the
subclavian arteries can be identified before blindly
attempting to cross them with a guidewire and
catheter. In addition, there is anatomical variability
in the configuration of the arch. Knowledge of the
location of the target vessel origin often saves time
and effort in catheterization. For instance, the left
vertebral artery may arise from the aortic arch rather
than from the left subclavian artery. Finally, with
severe atherosclerotic disease, collateral flow through
alternative channels may be important. For example,
an arch injection in a patient with occlusion of the
proximal vertebral artery may show its reconstitu-
Figure 2
Right common carotid artery injection showing diffuse
atherosclerotic irregularity and focal high-grade stenosis of the
internal carotid artery (arrowhead).
190 ANGIOGRAPHY
tion by muscular branches of the ascending cervical
artery.
The primary role of angiographic investigation of
carotid bifurcation disease is to provide measure-
ments of linear diameter narrowing. The landmark
North American Symptomatic Carotid Endarterect-
omy Trial determined that surgical endarterectomy
for patients with 450% narrowing of the internal
carotid artery (relative to the diameter of the distal
normal vessel), as measured on angiographic images,
was much more effective in reducing stroke risk than
aspirin alone. Currently, linear diameter narrowing
measured by angiography is the only validated
predictor of stroke risk and surgical benefit for
carotid atherosclerotic disease. Other findings on the
angiogram, such as the location, length, and irregu-
larity of the stenosis, are important for surgical
planning. The presence of distal disease (tandem
stenosis) should be investigated, although its impact
on stroke risk is unclear. Selective injections of the
vessel in question, with images in several planes, are
necessary for adequate measurement of stenosis. An
arch injection will not provide enough contrast
opacification for diagnostic images of the carotid
bifurcation or the intracranial vessels, for example.
Complete occlusion of the carotid artery is
commonly found in patients presenting with is-
chemic symptoms. The angiographic assessment of
these patients should include detailed views of the
affected carotid bifurcation to confirm complete
occlusion and to exclude a subtle extremely high-
grade stenosis occlusion. It is important to document
the sources of collateral flow, which may be the
origin of emboli affecting the hemisphere distal to the
occluded carotid artery.
Dissection
Spontaneous dissection of the cervical carotid artery
is a common cause of stroke in young patients. The
appearance of a dissection on angiography is a
smooth, tapered narrowing of the vessel (due to
blood burrowing beneath the intima). Typically, this
begins beyond the carotid bifurcation, as opposed to
atherosclerotic narrowing. Pseudoaneurysms com-
monly develop at the site of dissection.
Arteritis
The arteries of the neck and brain may be affected by
inflammatory conditions secondary to a number of
causes, including autoimmune disorders and infec-
tion. Angiography is often employed to identify
possible sites of involvement and to guide biopsy.
Aneurysms
Saccular aneurysms commonly arise at branchings of
the vessels of the circle of Willis, the anastomotic
connection between the intracranial internal carotid
arteries and the basilar artery (Fig. 3). There are
three situations in which angiography is performed
on patients with aneurysms. Patients with ruptured
aneurysms usually present with subarachnoid he-
morrhage (SAH). Approximately 70% of patients
with spontaneous, nontraumatic SAH are found to
have an aneurysm. Another way that patients present
is with signs and symptoms of mass effect due to the
size and location of the aneurysm. Finally, many
aneurysms are found or suspected incidentally on CT
or MRI performed for other reasons. Angiography is
the most accurate and definitive tool for the detection
of cerebral aneurysms. Although CT and MRI
angiographic techniques are capable of identifying
many aneurysms, they remain screening tools at best.
Arteriovenous Malformations
Arteriovenous malformations (AVMs) are congenital
lesions consisting of abnormal vascular channels
connecting arteries and veins. No intervening capil-
laries are present. Patients with AVMs often present
with seizures, headaches, or hemorrhage, although
some AVMs are found incidentally. The appearance
of most AVMs on angiography is distinctive, with
enlarged feeding arteries, a tangled, densely opacify-
ing nidus, and enlarged draining veins that fill with
contrast much earlier than the veins draining normal
brain (Fig. 4).
Figure 3
Anteroposterior injection after left vertebral artery injection
showing an aneurysm of the basilar apex (arrowhead). Normal
posterior cerebral arteries (arrows) arise at the base of the
aneurysm.

Figure 4
Arteriovenous malformation of the left cerebellar hemisphere. An
enlarged anterior inferior cerebellar artery (small arrowhead)
supplies the nidus (white asterisk). Note the size of the normal
anterior inferior cerebellar artery on the right (large arrowhead).
Early draining veins course superiorly (arrows).
Other Vascular Lesions
The lesions previously described represent the most
common applications of conventional angiography.
Other abnormalities that deserve mention include
fistulous connections between the carotid artery and
the cavernous sinus, dural arteriovenous fistulas, and
venous occlusive disease such as thrombosis of the
dural sinuses. Angiography is also used to demon-
strate the vascularity of intra- and extra-axial
tumors.
—Colin P. Derdeyn
See also–Aneurysms; Arteriovenous
Malformations (AVM), Surgical Treatment of;
Cerebral Angiography; Cerebrovascular
Malformations (Angiomas); Magnetic
Resonance Angiography (MRA); Neuroimaging,
Overview; Therapeutic Neuroradiology, Intra-
Arterial Thrombolysis
Further Reading
Morris, P. (1997). Practical Neuroangiography. Williams &
Wilkins, Philadelphia.
Newton, T. H., and Potts, D. G. (1974). Radiology of the Skull and
Brain. Volume 2: Angiography. MediBooks, Great Neck, NY.
ANGULAR GYRUS SYNDROME 191
Angiomas
see Cerebrovascular Malformations
Angular Gyrus Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE ANGULAR GYRUS SYNDROME is a constellation
of neuropsychological deficits found in patients with
damage to the dominant angular gyrus and sur-
rounding brain regions. It has been defined as
consisting of the following neuropsychological defi-
cits: extrasylvian sensory aphasia (transcortical
sensory aphasia), alexia with agraphia, plus compo-
nents of Gerstmann’s syndrome. Gerstmann’s syn-
drome includes acalculia, agraphia, difficulty in
distinguishing left from right, and finger agnosia.
The angular gyrus syndrome is often associated with
constructional disturbances such as constructional
apraxia.
Damage to the inferior parietal lobe of the
dominant hemisphere, which includes the angular
gyrus, the supramarginal gyrus, and/or the white
matter underlying these structures, produces the
angular gyrus syndrome. In most patients the left
hemisphere is dominant for language; thus, damage
to the left angular gyrus region produces the
syndrome (Fig. 1). Because the angular gyrus is
functionally connected to both cerebral hemispheres,
the deficits that comprise the angular gyrus syndrome
are observed on both sides of the body. For example,
finger agnosia is observed in both hands. Although
Figure 1
The approximate location of the left angular gyrus traced on the
surface of the brain from a neurologically normal human cadaver
(left) and an axial T1-weighted magnetic resonance imaging scan
from a neurologically normal adult human male (right).

Figure 4
Arteriovenous malformation of the left cerebellar hemisphere. An
enlarged anterior inferior cerebellar artery (small arrowhead)
supplies the nidus (white asterisk). Note the size of the normal
anterior inferior cerebellar artery on the right (large arrowhead).
Early draining veins course superiorly (arrows).
Other Vascular Lesions
The lesions previously described represent the most
common applications of conventional angiography.
Other abnormalities that deserve mention include
fistulous connections between the carotid artery and
the cavernous sinus, dural arteriovenous fistulas, and
venous occlusive disease such as thrombosis of the
dural sinuses. Angiography is also used to demon-
strate the vascularity of intra- and extra-axial
tumors.
—Colin P. Derdeyn
See also–Aneurysms; Arteriovenous
Malformations (AVM), Surgical Treatment of;
Cerebral Angiography; Cerebrovascular
Malformations (Angiomas); Magnetic
Resonance Angiography (MRA); Neuroimaging,
Overview; Therapeutic Neuroradiology, Intra-
Arterial Thrombolysis
Further Reading
Morris, P. (1997). Practical Neuroangiography. Williams &
Wilkins, Philadelphia.
Newton, T. H., and Potts, D. G. (1974). Radiology of the Skull and
Brain. Volume 2: Angiography. MediBooks, Great Neck, NY.
ANGULAR GYRUS SYNDROME 191
Angiomas
see Cerebrovascular Malformations
Angular Gyrus Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE ANGULAR GYRUS SYNDROME is a constellation
of neuropsychological deficits found in patients with
damage to the dominant angular gyrus and sur-
rounding brain regions. It has been defined as
consisting of the following neuropsychological defi-
cits: extrasylvian sensory aphasia (transcortical
sensory aphasia), alexia with agraphia, plus compo-
nents of Gerstmann’s syndrome. Gerstmann’s syn-
drome includes acalculia, agraphia, difficulty in
distinguishing left from right, and finger agnosia.
The angular gyrus syndrome is often associated with
constructional disturbances such as constructional
apraxia.
Damage to the inferior parietal lobe of the
dominant hemisphere, which includes the angular
gyrus, the supramarginal gyrus, and/or the white
matter underlying these structures, produces the
angular gyrus syndrome. In most patients the left
hemisphere is dominant for language; thus, damage
to the left angular gyrus region produces the
syndrome (Fig. 1). Because the angular gyrus is
functionally connected to both cerebral hemispheres,
the deficits that comprise the angular gyrus syndrome
are observed on both sides of the body. For example,
finger agnosia is observed in both hands. Although
Figure 1
The approximate location of the left angular gyrus traced on the
surface of the brain from a neurologically normal human cadaver
(left) and an axial T1-weighted magnetic resonance imaging scan
from a neurologically normal adult human male (right).
192 ANGULAR GYRUS SYNDROME
each of the neuropsychological impairments that
comprise this syndrome may exist independently,
when they are found together they reliably indicate
damage to the previously mentioned structures.
The most common cause of the angular gyrus
syndrome is cerebrovascular disease, especially oc-
clusion of the angular branch of the middle cerebral
artery. Although the areas of pathology that produce
the angular gyrus syndrome fall into a vascular
watershed (between two cerebral artery distribu-
tions) area, such infarcts typically do not produce the
syndrome because aphasia masks many of the
deficits. Other lesions that have been reported to
cause angular gyrus syndrome include neurodegen-
erative diseases such as Alzheimer’s and frontotem-
poral dementia, developmental anomalies in
children, arteriovenous malformations, brain tu-
mors, trauma, abscesses, and gunshot wounds.
COMPONENTS OF THE ANGULAR
GYRUS SYNDROME
Extrasylvian (Transcortical)
Sensory Aphasia
This language impairment is thought to be caused by
a disconnection between sensory language processes
and semantic knowledge of objects. Conversational
speech is fluent; however, patients have severe
problems with naming objects. The naming deficit
may be category specific. There is often alienation of
word meaning; that is, even after accurately repeat-
ing a word and demonstrating its use in a sentence,
patients report that they do not understand it.
Abundant use of one word, nonspecific filler words
such as ‘‘one,’’ ‘‘it,’’ and ‘‘things,’’ and paraphrasic
errors result in an emptiness of spoken content.
Speech may be verbose and uninhibited. By defini-
tion, repetition is always normal. Extrasylvian
sensory aphasia is classically associated with echola-
lia; that is, patients will often incorporate words and
phrases uttered by the examiner into their speech
while apparently failing to understand the meaning
of the words. Comprehension of spoken language is
impaired, sometimes leading to misidentification of
the language disorder as a psychogenic problem.
Alexia with Agraphia
(Parietal–Temporal Alexia)
Alexia is the inability to read. In alexia with
agraphia, the impairment in writing is equally severe
to that in reading. Both the ability to read letters,
words, numbers, and musical notation out loud, and
the ability to comprehend them are impaired.
Patients are often able to copy words; however, they
are unable to spontaneously write them.
Acalculia
The inability to solve simple mathematical problems
observed in patients with angular gyrus syndrome
results from a combination of deficits. There is an
anarithmetia, or basic disorder of computation, that
results from damage to neural structures that store
arithmetic facts and calculation procedures. These
structures are thought to reside within the angular
gyrus. Difficulties with reading and comprehension
of numbers, which are components of extrasylvian
sensory aphasia, also contribute to the acalculia.
Left–Right Confusion
Patients with angular gyrus syndrome have signifi-
cant difficulty in distinguishing their own right from
left as well as comprehending directional informa-
tion in concrete and hypothetical tasks. Experimental
evidence suggests that these deficits result from
difficulties with the mental manipulation of spatial
information.
Finger Agnosia
This is the inability to identify and localize fingers,
both of one’s own hands and those of the examiner.
Finger agnosia appears to be related to autotopag-
nosia, the inability to localize body parts on one’s
own or another’s body; however, the exact relation-
ship is unclear.
GERSTMANN’S SYNDROME
In 1930, Josef Gerstmann (1887–1969), a professor
of neurology and psychiatry at the Maria–Thereisen–
Schlossel in Vienna, described the constellation of
symptoms that has since been referred to as
Gerstmann’s syndrome. He wrote that the syndrome
of finger agnosia, agraphia, acalculia, and right–left
disorientation ‘‘can be related to a focal disturbance
in the area of transition between the angular and
second occipital convolution’’ and is caused by ‘‘a
unilateral lesion in the left hemisphere in right-
handed individuals.’’ Gerstmann believed that the
phenomenological association of the four compo-
nents of the syndrome reflected a common neuro-
psychological factor related to body image (Grund-
störung), which was important for each of these
functions. He postulated that the image of the hands
 ANOMIA 193

and fingers was crucial for mathematical operations
since children initially learn to do arithmetic by
counting fingers.
For many years after its description, there was
much controversy regarding the true nature of
Gerstmann’s syndrome. The debate focused on four
major questions, which were recently summarized by
Benton:
(i) Whether the syndrome exists as a more or less autonomous
combination of symptoms, unaccompanied by other behavioral
indications of brain disease; (ii) whether the combination has
specific neuroanatomic significance ... i.e., that it implies the
presence of a focal lesion in the territory of the angular gyrus;
(iii) whether the syndrome has a special status compared with
other combinations of deficits that are exhibited by patients
with posterior perisylvian lesions of the left hemisphere; and (iv)
whether the combination is the behavioral expression of a single
underlying basic deficit (Grundstörung).
Farah, M. J., and Feinberg, T. E. (2000). Patient-Based
Approaches to Cognitive Neuroscience. MIT Press, Cambridge,
MA.
Mayer, E., Martory, M.-D., Pegna, A. J., et al. (1999). A pure case
of Gerstmann syndrome with a subangular lesion. Brain 122,
1107–1120.
Morris, H. H., Luders, H., Lesser, R. P., et al. (1984).
Transient neuropsychological abnormalities (including Gerst-
mann’s syndrome) during cortical stimulation. Neurology 34,
877–883.
Pearce, J. M. (1996). Gerstmann’s syndrome. J. Neurol. Neuro-
surg. Psychiatry 61, 56.
Anomia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

These objections were based on studies by Benton,

ANOMIA is often defined two ways: (i) word finding
Heimberger, and others that showed that the
difficulty in spontaneous or conversational speech
components of Gerstmann’s syndrome were often
and (ii) a failure to name objects presented on a
associated with other neuropsychological deficits
naming task. Although these two phenomena are not
such as aphasia or apraxia, did not strongly correlate
exactly the same, they are considered to be manifes-
with each other, and were often not associated with
tations of impaired word (lexical) access or lexical
angular gyrus lesions in a number of large series of
representation. Anomia is a universal disturbance of
brain-damaged patients.
aphasia and dementia, and lexical processing is a
A few cases of pure Gerstmann’s syndrome have
major component of language in normals. Questions
been described. All were associated with left parietal
such as the following have interested philosophers,
lobe damage involving the angular gyrus. Of note,
linguistics, and neurologists for centuries: How do
one study used electrical stimulation of the cortex
we access words? Where are they stored in the brain?
(during functional mapping prior to epilepsy surgery)
How do they come to the mind, selected from many
to demonstrate an area in the transition zone
others, and fit into a sentence? Theories of lexical
between the left supramarginal and angular gyri
access postulate that first the idea of the concept or
that, when selectively inactivated, produced an
an object is generated in various frontal, parietal, or
isolated Gerstmann’s syndrome. Nevertheless, the
temporal association areas depending on the stimu-
rarity of isolated Gerstmann’s syndrome led Benson
lus. During conversation or responding to stimuli
and colleagues to use the term angular gyrus
word concepts—‘‘Wortbegriff’’ in Wernicke’s termi-
syndrome to refer to the most common neuropsy-
nology and ‘‘logogens’’ or ‘‘lexemes’’ in recent
chological deficits associated with damage to the
linguistic schemas—are generated at an incredibly
dominant angular gyrus and to reaffirm that their
rapid rate, and a word is selected for further
coincidence has strong localizing value.
processing. The selection process and its relationship
—Adam Boxer
to thought and to phonological output systems are
extremely complex and much studied by the dis-
See also–Agnosia; Agraphia; Alexia cipline of linguistics, particularly lexicosemantics.

Further Reading
Benson, D. F., and Ardila, A. (1996). Aphasia: A Clinical
Perspective. Oxford Univ. Press, New York.
Benson, D. F., Cummings, J. L., and Tsai, S. Y. (1982). Angular
gyrus syndrome simulating Alzheimer’s disease. Arch. Neurol.
39, 616–620.
Benton, A. L. (1992). Gerstmann’s syndrome. Arch. Neurol. 49,
445–447.
ANOMIA IN APHASIA
Anomia is a universal feature of aphasia, or central
language deficit, and disturbances of word retrieval
cut across all diagnostic classifications. Originally,
aphasia was considered amnesia for words. Later,
anomia became regarded as a symptom of various
 ANOMIA 193

and fingers was crucial for mathematical operations
since children initially learn to do arithmetic by
counting fingers.
For many years after its description, there was
much controversy regarding the true nature of
Gerstmann’s syndrome. The debate focused on four
major questions, which were recently summarized by
Benton:
(i) Whether the syndrome exists as a more or less autonomous
combination of symptoms, unaccompanied by other behavioral
indications of brain disease; (ii) whether the combination has
specific neuroanatomic significance ... i.e., that it implies the
presence of a focal lesion in the territory of the angular gyrus;
(iii) whether the syndrome has a special status compared with
other combinations of deficits that are exhibited by patients
with posterior perisylvian lesions of the left hemisphere; and (iv)
whether the combination is the behavioral expression of a single
underlying basic deficit (Grundstörung).
Farah, M. J., and Feinberg, T. E. (2000). Patient-Based
Approaches to Cognitive Neuroscience. MIT Press, Cambridge,
MA.
Mayer, E., Martory, M.-D., Pegna, A. J., et al. (1999). A pure case
of Gerstmann syndrome with a subangular lesion. Brain 122,
1107–1120.
Morris, H. H., Luders, H., Lesser, R. P., et al. (1984).
Transient neuropsychological abnormalities (including Gerst-
mann’s syndrome) during cortical stimulation. Neurology 34,
877–883.
Pearce, J. M. (1996). Gerstmann’s syndrome. J. Neurol. Neuro-
surg. Psychiatry 61, 56.
Anomia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

These objections were based on studies by Benton,

ANOMIA is often defined two ways: (i) word finding
Heimberger, and others that showed that the
difficulty in spontaneous or conversational speech
components of Gerstmann’s syndrome were often
and (ii) a failure to name objects presented on a
associated with other neuropsychological deficits
naming task. Although these two phenomena are not
such as aphasia or apraxia, did not strongly correlate
exactly the same, they are considered to be manifes-
with each other, and were often not associated with
tations of impaired word (lexical) access or lexical
angular gyrus lesions in a number of large series of
representation. Anomia is a universal disturbance of
brain-damaged patients.
aphasia and dementia, and lexical processing is a
A few cases of pure Gerstmann’s syndrome have
major component of language in normals. Questions
been described. All were associated with left parietal
such as the following have interested philosophers,
lobe damage involving the angular gyrus. Of note,
linguistics, and neurologists for centuries: How do
one study used electrical stimulation of the cortex
we access words? Where are they stored in the brain?
(during functional mapping prior to epilepsy surgery)
How do they come to the mind, selected from many
to demonstrate an area in the transition zone
others, and fit into a sentence? Theories of lexical
between the left supramarginal and angular gyri
access postulate that first the idea of the concept or
that, when selectively inactivated, produced an
an object is generated in various frontal, parietal, or
isolated Gerstmann’s syndrome. Nevertheless, the
temporal association areas depending on the stimu-
rarity of isolated Gerstmann’s syndrome led Benson
lus. During conversation or responding to stimuli
and colleagues to use the term angular gyrus
word concepts—‘‘Wortbegriff’’ in Wernicke’s termi-
syndrome to refer to the most common neuropsy-
nology and ‘‘logogens’’ or ‘‘lexemes’’ in recent
chological deficits associated with damage to the
linguistic schemas—are generated at an incredibly
dominant angular gyrus and to reaffirm that their
rapid rate, and a word is selected for further
coincidence has strong localizing value.
processing. The selection process and its relationship
—Adam Boxer
to thought and to phonological output systems are
extremely complex and much studied by the dis-
See also–Agnosia; Agraphia; Alexia cipline of linguistics, particularly lexicosemantics.

Further Reading
Benson, D. F., and Ardila, A. (1996). Aphasia: A Clinical
Perspective. Oxford Univ. Press, New York.
Benson, D. F., Cummings, J. L., and Tsai, S. Y. (1982). Angular
gyrus syndrome simulating Alzheimer’s disease. Arch. Neurol.
39, 616–620.
Benton, A. L. (1992). Gerstmann’s syndrome. Arch. Neurol. 49,
445–447.
ANOMIA IN APHASIA
Anomia is a universal feature of aphasia, or central
language deficit, and disturbances of word retrieval
cut across all diagnostic classifications. Originally,
aphasia was considered amnesia for words. Later,
anomia became regarded as a symptom of various
194 ANOMIA
aphasic syndromes, and anomic aphasia was con-
sidered a diagnostic variety. Anomia is primarily
considered the disturbance in retrieving words from
a lexical store, but another consideration is a
reduction of the lexical store. The first is often the
feature of anomia, due to a focal lesion, and the
second is more applicable in dementia or diffuse
lesions. However, there is considerable overlap and
uncertainty. Although anomia is a sine qua non of
aphasia, anomic aphasia is not synonymous with
aphasic anomia. Furthermore, anomia or word
finding difficulty does not have to be associated with
aphasia.
There is a general restriction of vocabulary, which
is common to most aphasics, and in some there is a
selective loss of the ability to name specific words.
Many patients are anomic for specific items but can
be fluent with relatively preserved conversational
speech. More severely affected anomic patients have
circumlocutory, uninformative empty speech, lacking
the critical substantive words necessary to convey
meaning. However, grammatical words, such as
pronouns and auxiliary verbs, remain relatively
intact, resulting in relatively preserved syntax and
fluency. More severe cases of word finding difficulty
are associated with logopenic or reduced speech
output and decreased fluency.
What is retrieved and in what circumstances is
dependent on the nature and the severity of the
disease process and lesion size and location. For most
patients, the frequent words of language are the best
retained after brain damage or lost last in a
progressive deficit, such as in dementia. There is a
general frequency effect of common words retrieved
better, but this is not as consistent as in reaction time
experiments in normals. Often, features such as
context, priming, stimulus characteristics, metatypi-
cality, concreteness, manipulability, animateness, and
grammatical class contribute to the accessibility of
lexical items.
Clinicians have distinguished several varieties of
anomia. Word production anomia ranges from the
so-called ‘‘tip of the tongue’’ phenomenon, occurring
in normal conversation, to the inability of a patient
with frontal lesions or Broca’s aphasia to produce a
word spontaneously or confrontation with a stimu-
lus. These patients are aware of the naming
disturbance, they often insist they know the desired
word, and prompting and cueing are often effective
in retrieval. It has been postulated that word
production is analogous to initiating nonverbal
movements that may be impaired in frontal lobe
lesions. This physiological activation phase of word
retrieval has been separated experimentally from
word selection, although the clinical boundaries are
less clear. The tip of the tongue phenomenon often
appears in combination with articulatory and pho-
nemic paraphasias and word selection anomia in
patients.
Word selection anomia is another variety char-
acterized by the occasional semantic paraphasias and
improved response to prompting. It is considered a
disturbance at a more central stage of semantic
specification, or a defect of retrieval from the internal
lexicon. The spontaneous speech of these individuals
is often loaded with circumlocutions and they use
functional descriptions as replacement for a word.
Many patients with pure anomia have comprehen-
sion problems in early stages and only with recovery
pass on to the stage of residual anomia. Anomia and
paraphasias may persist even when comprehension
has recovered.
Category-specific anomia has been described for
color-naming disturbance (color anomia and color
agnosia) usually in occipital lesions, for finger
naming (Gerstmann’s syndrome), and for certain
categories of nouns. Some of these were specifi-
cally related to certain anatomical structures. For
instance, the difference in naming of animate and
inanimate objects was based on superior or inferior
location of the pathology in the dominant parietal
lobe. The category specificity of naming was also
demonstrated for nouns with preserved naming of
letters and numbers. Recently, many dissociations
have been found; for example, the loss of the
meaning of vegetables and fruits with retention of
naming of vehicles and tools is one of the most
common dissociations originally described in
association with temporal lesions. Some of these
dissociations extend to the response modality with
astonishing quadruple dissociations for categories
in naming orally and in writing. Categories for
persons were impaired in temporal polar lesions
and for tools in inferior temporal regions. Inter-
mediate temporal lesions resulted in combined
loss of persons and fruits, and fruits and tools, but
never the combination of persons and tools.
Impaired retrieval of words denoting action was
associated with damage to the left prefrontal and
premotor regions. Recent functional activation
studies also indicated that certain perceptual cate-
gories, such as unique persons, animals, and tools,
have separable regions for storage in the left
temporal lobe.
 ANOMIA 195

Other classifications of anomia include word- NAMING

finding problems due to disconnection of cerebral
Naming is a major item in aphasia testing, whether it
structures, nonaphasic misnaming, and psychogenic
is at the bedside using simple objects available to the
misnaming. In the anomia of disconnection, ob-
clinician, such as a pen, comb, book, objects of
served after callosal lesions, blindfolded patients
clothing, and furniture, or items controlled for
cannot name an object placed in the left hand,
frequency, categories, stimulus complexity, phonolo-
although they can select that object from an array of
gical length, etc. presented under experimental
objects, indicating they perceived its characteristics
conditions. The naming task, for instance, in the
without being able to label the object. When they are
Western Aphasia Battery, uses 20 common objects
asked why they selected the object, they may give an
controlled for frequency and selected for easy
explanation that is confabulatory. This indicates that
availability and manipulability. These objects are
the nondominant hemisphere continues to perform
presented visually for 5–10 sec and a score of 3 is
perceptual and matching tasks but cannot access
given for correct naming, 2 for recognizable phone-
verbal labels. Nonverbal recognition of an object can
mic paraphasia, and 1 if a phonemic or tactile cue is
be dissociated from its access to the speaking
required. In the case of no response or an incorrect
hemisphere by the callosal sections. The perception,
response, the patient is allowed to touch and
recognition, and selection of objects does not require
manipulate the object. If this still does not result in
verbal labels.
lexical access, a phonemic prompt or a semantic cue
Nonaphasic misnaming has been described in
is given. This allows not only a total object naming
acute confusional states. It has a confabulatory
score but also analysis of naming deficit and the
flavor, such as calling a physician a ‘‘repairman.’’
discovery of modality deficit anomia, tip of the
The mechanism is considered to be related to
tongue phenomena, and the effectiveness of cueing.
decreased levels of consciousness or inattention
Chronometric or timed, very brief tachistoscopic
interfering with memory and retrieval. Nonaphasic
presentation of visual stimuli is often used for
word-finding difficulty or lexical access inhibition by
psycholinguistic studies of normal individuals. The
anxiety and stress, associated with distractibility or
reaction time measures to altered experimental
decreased level of alertness, is a common phenom-
conditions, such as priming or preceding the stimulus
enon that we all experience occasionally to a lesser or
with a related word, are one of the most important
greater extent. Word finding with reaction times in
tools of cognitive science. Priming can be phonolo-
normals is used in pharmacological experiments
gical, semantic, auditory, or visual. Priming experi-
when medications such as hypnotics, neuroleptics,
ments in normals provide important information
or narcotics are given to influence word retrieval.
concerning the nature of word retrieval and semantic
The results can be used to quantitate the effect of
fields.
psychotropic drugs.
In modality-specific anomia, a dissociation be-
tween the effects of the modalities of presentation
WORD FLUENCY
can be observed in the case of visual agnosia or optic
aphasia when naming cannot be accomplished on Word fluency is a test of word finding in which
visual stimulation but is prompt and clearly pre- patients are required to recall words in a certain
served in the tactile modality. The dissociation of category. This is also called word fluency in associa-
visual and tactile naming is the sine qua non for the tion. Some word fluency tests use initial letters or a
diagnosis of visual agnosia. Cognitive analysis of phonological category, but this is more difficult for
visual agnosia indicates that the deficit is at the level both aphasics and normals than a semantic category
of recognition. Optic aphasia is sometimes also such as naming as many animals as the patient can
called visual anomia. In optic aphasia, the deficit is name in 1 min. Tests of word fluency are very
closer to language processing and the visual naming sensitive to a minimal amount of brain damage, be it
deficit is a modality-specific anomia. It is distin- due to head injury or early dementia. There is a
guished from visual agnosia by preserved description significant difference in the word fluency perfor-
and demonstration of object use or correct answers mance of normals of various intellectual abilities or
to probe questions about it. Even though recognition educational background. Anxiety and distractibility
has taken place, verbal labeling of the visually interfere with word fluency performance to a greater
presented object is deficient. extent than with naming on stimulus.
196 ANOMIA
Sentence completion is similar to word fluency in
using semantic priming or word retrieval in syntactic
association. Responsive speech also uses the context
of the preceding sentence, and responding to it is
easier than spontaneous word finding, or word
fluency generation in categories (‘‘Christmas is in
the month ofy’’). Prompting, cueing, and priming
are various methods of facilitating word retrieval.
Various prompting or cueing of phonological or
semantic associations are an important part of
testing and treating aphasics.
ANOMIC APHASIA
The largest group of aphasics are variously categor-
ized as anomic or amnesic aphasics, characterized by
fluent speech with relatively little, if any, expressive
or receptive difficulty. These patients have word-
finding difficulty and a variable failure to name when
confronted with a stimulus. Occasionally, there are
verbal paraphasia or semantic substitutions, but
usually there is no phonological or syntactic dis-
turbance. Anomic aphasics have normal comprehen-
sion and repetition, and only their naming is
impaired significantly. Anomic aphasia is often seen
de novo, often as a result of recovery from
Wernicke’s, conduction, or transcortical aphasias.
Occasionally, patients with Broca’s aphasia recover
toward the anomic type of aphasia. When anomic
aphasia appears de novo, the etiology may not be a
focal lesion but a metabolic or diffuse abnormality.
Progressive anomic aphasia may be the presenting
feature of degenerative illnesses, most notably
primary progressive aphasia, a component of Pick’s
disease or frontotemporal dementia (FTD), or a
slowly progressive brain tumor. It is also a common
early feature of Alzheimer’s disease (AD), but
language impairment in AD usually follows signifi-
cant episodic memory loss. Anomic aphasia due to
strokes has a good prognosis, and word finding
difficulty may recover with time, except for low-
frequency items.
Goldstein described a variety of amnesic aphasia
as an ‘‘impairment of abstract attitude,’’ when a
patient provided inappropriately specific names
instead of the name of the general, base, or
supraordinate category (polar bear instead of bear).
Semantic specification depends a great deal on the
nature of the stimulus and the circumstances of
naming, such as the instructions given to the subjects.
Typical exemplar from a supraordinate category is
likely to be named as the category, whereas atypical
exemplars or stimuli having specific visual identifica-
tion may be named with a specific, subordinate, or
proper name (A wren will be named a bird, but an
ostrich will be named an ostrich). Henry Head
described naming difficulty as nominal aphasia and
considered it the most important component of
semantic aphasia, which also included impaired
understanding of names as part of the disturbance.
Subsequently, this concept of central semantic
disturbance was extended to semantic dementia, a
progressive two-way loss of semantic fields in which
both naming and comprehension are lost for even
simple nouns.
Most clinicians and researchers of aphasia agree
that naming disturbances are the least localizable
function and, in fact, lesions from many areas of the
brain, even for diffuse pathology such as in AD, can
produce serious naming disturbances. However, very
few would question that temporal, parietal, or
perisylvian lesions interfere with lexical retrieval in
a consistent fashion. Localization studies also suggest
occasional separate but often overlapping regions for
certain categories of items, especially in the temporal
lobes.
ANOMIA IN DEMENTIA
Naming disorders in dementia have been examined
in considerable detail. Alzheimer’s disease patients
initially have very little language disturbance, but
they are forgetful of proper names, which is a
borderline area between semantic and episodic
memory. Although they are poor in generating names
in controlled association, especially with phonologi-
cal tasks such as a word starting with a certain letter,
and they have word-finding difficulty in spontaneous
speech, they still have relatively preserved naming of
presented stimuli. However, later frequency-asso-
ciated loss of naming occurs, and eventually both
comprehension and naming of the same items
indicate loss of semantic field. Much of the con-
troversy regarding the study of naming or loss of
semantic field in AD relates to the inclusion of
patients in group studies at various stages of illness.
Word-finding difficulty is usually the beginning of
the primary progressive aphasia (PPA), but episodic
memory is preserved in contrast to AD. This
condition is now recognized as the dominant
temporal variety of Pick’s disease or FTD. Most of
these patients develop increasing difficulty with word
access in spontaneous speech and also for naming
stimuli. The result is a logopenic speech output that

is relatively well articulated in most instances but
soon becomes nonfluent. Some patients have a
stuttering onset, but others develop agrammatism.
In some cases, this proceeds to mutism without any
development of articulatory disturbance or agram-
matism. Meanwhile, comprehension is retained until
the late stages. Similarly, progressive anomia is seen
after the behavioral presentation, which is usually
with apathy combined with disinhibition.
In contrast, the progressive fluent type of aphasia,
or semantic dementia, retains syntactic organization
and fluency. Although word retrieval may suffer
initially, it is impaired proportionately with loss of
comprehension for words. In fact, whole items
disappear from the semantic field. Such patients
would ask, ‘‘What is a steak?’’ when the word was
mentioned, and they would be unable to name it on
seeing the object. The auditory images or visual input
fail to evoke lexical access, indicating a central loss
of lexicon. Initially, this is restricted to nouns or
things with preserved verbs, objectives, and connect-
ing words; eventually, however, other elements of the
language are affected and these patients also become
logopenic and mute. Primary progressive or non-
fluent aphasia tends to have more anterior atrophy in
the frontotemporal region of the dominant hemi-
sphere, whereas semantic dementia has dominant
temporal atrophy. These anatomical distinctions tend
to blur as the disease progresses.
ANATOMY OF THE MENTAL LEXICON
Storage and memory for words and the representa-
tions of objects and concepts in the brain have been
challenging for the neurological, psychological, and
linguistic disciplines. Linguistic formulations (free
from anatomical constraints) conceptualize a prelex-
ical stage representing a thought. The lexeme is the
selected meaning. The ‘‘lemma’’ in the next stage has
certain grammatical attributes. Words are developed
from the lemma by recursive inhibition from seman-
tic, syntactic, and phonological mechanisms. These
cascades of sequential and parallel processes, inspired
by computer analogies, are a modern-day reincarna-
tion of the steps in naming proposed by Pick a
century ago. The role of internal auditory feedback in
the selection of appropriate phonological and seman-
tic attributes of words was first proposed by
Wernicke. Physiological models postulate the simul-
taneous synthesis from multiple cortical activations
with a major cross-modal link taking place, for
instance, in the parietal lobe. The dominant hemi-
ANOMIA 197
spherical angular gyrus was singled out early as
having a key function in complex, convergent,
auditory–visual–spatial associations before reaching
the motor system or generating words. Other favorite
cortical areas for lexical storage are the inferior and
middle temporal gyri, based on lesion evidence. It is
believed that the representation of certain categories
such as tools is located in the cortex, which is capable
of receiving multiple sensory signals from the hand
area, as well as the cortices of visual motor
processing.
Naming of a word on sensory stimulation such as
seeing an object can elicit a large number of visual,
tactile, auditory, orthographic, olfactory, and emo-
tional associations. Some of these act as inhibitory
feedback to prevent a similar (semantically or phono-
logically) name from being produced. Naming evokes
widespread functional activation in both hemispheres,
as demonstrated by positron emission tomography
scanning of glucose metabolism or cerebral blood
flow and functional activation with magnetic reso-
nance imaging. The results of these studies indicate
the complexity of word selection and access.
A SINGLE LEXICON OR MULTIPLE MENTAL
REPRESENTATION OF NAMES?
Naming disturbances may represent impaired access
(retrieval) or loss (impaired storage) of semantic
information. When word-finding difficulty is variable
and an item cannot be found or it is misnamed on
one occasion and retrieved in another context, an
access problem is postulated. On the other hand, if
both naming and comprehension are impaired for the
same item, loss of the semantic field is assumed. If
anomia occurs consistently for an item in all stimulus
modalities, then the argument is in favor of impair-
ment of a unified, central or supramodality semantic
field. In addition to a supramodality semantic field,
lexicons are assumed in the visual orthographic and
auditory modalities as well as for input and output
modalities as evidenced from clinical and experi-
mental observations.
The occurrence of category-specific and modality-
specific anomia indicates that semantic memories are
represented by categories and by various modalities
of input separately. Interpretations include models of
semantic representations, which are distributed
according to functional, perceptual, and structural
attributes when they are acquired and the modalities
of acquisition, depending on the stimuli and the state
of central processing. The phenomenon of mental
198 ANOSOGNOSIA
imagery led to the dual-code hypothesis of semantic
memory, which assumes that knowledge is repre-
sented internally by a verbal and pictorial code. The
existence of a supramodality semantic field, however,
is equally persuasive from evidence of supramodality
impairment in aphasic anomia and semantic demen-
tia. Thus, the psycholinguistic argument between
dual, even multiple, semantic fields vs a central
unified semantic lexicon continues.
—Andrew Kertesz
See also–Agrammatism; Agraphia; Alexia;
Aphasia; Language and Discourse; Language
Disorders, Overview; Pick, Ludwig; Speech
Disorders, Overview
Further Reading
Caramazza, A., and Hillis, A. E. (1991). Lexical organization of
nouns and verbs in the brain. Nature 349, 788–790.
Dell, G. (1986). A spreading activation theory of retrieval in
sentence production. Psychol. Rev. 93, 283–321.
Glaser, W. R. (1992). Picture naming. Cognition 42, 61–105.
Goodglass, H., Kaplan, E., Weintraub, S., et al. (1976). The
‘‘tip-of-the-tongue’’ phenomenon in aphasia. Cortex 12,
145–153.
Goodglass, H., and Wingfield, A. (1997). Anomia—Neuroana-
tomical and Cognitive Correlates. Academic Press, San Diego.
Kertesz, A. (1982). The Western Aphasia Battery. Grune &
Stratton (Psychological Incorporated), New York.
Levelt, W. J. M. (1989). Speaking. MIT Press, Cambridge, MA.
Pick, A. (1913). Die Agrammatischen Sprachstörungen. Studien
zur Psychologishen Grundlegung der Aphasielehre. Springer,
Berlin.
Warrington, E. K., and Shallice, T. (1984). Category specific
semantic impairments. Brain 107, 829–854.
Wernicke, C. (1874). Der Aphasische Symptomenkomplex. Cohn
& Weigart, Breslau.
Anorexia Nervosa
see Eating Disorders
Anosognosia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANOSOGNOSIA is a common behavioral phenomen-
on seen in people both with and without disease of
the brain. It is a basic feature of human behavior for
people to not readily accept bad things that happen
to them. It has been said that when President George
Bush did not recognize the challenge of Bill Clinton
in the early stages of the campaign in the election of
1992, he suffered from ‘‘denial of presidential
disability.’’ People with serious medical illnesses
often experience a period of varying length in which
they fail to recognize the potential implications of
their problems. This is an important issue in cancer,
for example, when people fail to seek medical atten-
tion in the early stages of tumor growth when treat-
ment is most effective. People with brain disease have
patterns of response to illness that are often profound
exaggerations of the denial seen in healthy people.
In 1924, Babinski and Joltrain coined the term
anosognosia (literally, lack of knowledge of disease)
to describe two patients with unawareness of left
hemiplegia (paralysis of the left limbs), which had
been previously reported by Pick in 1898. One would
ignore commands to move her left hand and the
other stated that she was not paralyzed. When asked
what her trouble was she stated ‘‘pain in the back’’
and ‘‘phlebitis’’ as the difficulty, and when asked to
move her paralyzed left arm she either did not
respond or said ‘‘voilà, c’est fait.’’ In 1918, Marie
contributed to an extension of the concept of
anosognosia, noting the lack of awareness of the
hemianopia (deficit in one visual field) resulting from
brain disease. Since that time, the manifestations of
denial have been widely documented.
Patients may explicitly deny that there is anything
wrong and may also minimize their difficulties.
When asked ‘‘What is your main trouble? Why are
you in the hospital?’’ a patient with left hemiplegia
responds ‘‘My sister thought I should come in for
some tests. I am hungry, when can I eat?’’ These
patients characteristically do not learn from experi-
ence and often reject evidence of their disability as
inconsequential. Other disabilities that patients with
brain disease may deny include incontinence, in-
voluntary movements, aphasia, and the fact of an
operation. Denial syndromes also include lack of
recognition of blindness [Anton’s syndrome (1889),
which was actually first noted by Von Monakow in
1885]. They may deny they are ill in any way and
deny that they are in the hospital. These patients,
despite their denial, remain in the hospital and
usually cooperate in examinations, laboratory in-
vestigations, and even surgery. Patients with brain
disease may deny or fail to recognize any form of
disability.
Denial of illness is often accompanied by asso-
ciated disorders, including unilateral neglect, con-
198 ANOSOGNOSIA
imagery led to the dual-code hypothesis of semantic
memory, which assumes that knowledge is repre-
sented internally by a verbal and pictorial code. The
existence of a supramodality semantic field, however,
is equally persuasive from evidence of supramodality
impairment in aphasic anomia and semantic demen-
tia. Thus, the psycholinguistic argument between
dual, even multiple, semantic fields vs a central
unified semantic lexicon continues.
—Andrew Kertesz
See also–Agrammatism; Agraphia; Alexia;
Aphasia; Language and Discourse; Language
Disorders, Overview; Pick, Ludwig; Speech
Disorders, Overview
Further Reading
Caramazza, A., and Hillis, A. E. (1991). Lexical organization of
nouns and verbs in the brain. Nature 349, 788–790.
Dell, G. (1986). A spreading activation theory of retrieval in
sentence production. Psychol. Rev. 93, 283–321.
Glaser, W. R. (1992). Picture naming. Cognition 42, 61–105.
Goodglass, H., Kaplan, E., Weintraub, S., et al. (1976). The
‘‘tip-of-the-tongue’’ phenomenon in aphasia. Cortex 12,
145–153.
Goodglass, H., and Wingfield, A. (1997). Anomia—Neuroana-
tomical and Cognitive Correlates. Academic Press, San Diego.
Kertesz, A. (1982). The Western Aphasia Battery. Grune &
Stratton (Psychological Incorporated), New York.
Levelt, W. J. M. (1989). Speaking. MIT Press, Cambridge, MA.
Pick, A. (1913). Die Agrammatischen Sprachstörungen. Studien
zur Psychologishen Grundlegung der Aphasielehre. Springer,
Berlin.
Warrington, E. K., and Shallice, T. (1984). Category specific
semantic impairments. Brain 107, 829–854.
Wernicke, C. (1874). Der Aphasische Symptomenkomplex. Cohn
& Weigart, Breslau.
Anorexia Nervosa
see Eating Disorders
Anosognosia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANOSOGNOSIA is a common behavioral phenomen-
on seen in people both with and without disease of
the brain. It is a basic feature of human behavior for
people to not readily accept bad things that happen
to them. It has been said that when President George
Bush did not recognize the challenge of Bill Clinton
in the early stages of the campaign in the election of
1992, he suffered from ‘‘denial of presidential
disability.’’ People with serious medical illnesses
often experience a period of varying length in which
they fail to recognize the potential implications of
their problems. This is an important issue in cancer,
for example, when people fail to seek medical atten-
tion in the early stages of tumor growth when treat-
ment is most effective. People with brain disease have
patterns of response to illness that are often profound
exaggerations of the denial seen in healthy people.
In 1924, Babinski and Joltrain coined the term
anosognosia (literally, lack of knowledge of disease)
to describe two patients with unawareness of left
hemiplegia (paralysis of the left limbs), which had
been previously reported by Pick in 1898. One would
ignore commands to move her left hand and the
other stated that she was not paralyzed. When asked
what her trouble was she stated ‘‘pain in the back’’
and ‘‘phlebitis’’ as the difficulty, and when asked to
move her paralyzed left arm she either did not
respond or said ‘‘voilà, c’est fait.’’ In 1918, Marie
contributed to an extension of the concept of
anosognosia, noting the lack of awareness of the
hemianopia (deficit in one visual field) resulting from
brain disease. Since that time, the manifestations of
denial have been widely documented.
Patients may explicitly deny that there is anything
wrong and may also minimize their difficulties.
When asked ‘‘What is your main trouble? Why are
you in the hospital?’’ a patient with left hemiplegia
responds ‘‘My sister thought I should come in for
some tests. I am hungry, when can I eat?’’ These
patients characteristically do not learn from experi-
ence and often reject evidence of their disability as
inconsequential. Other disabilities that patients with
brain disease may deny include incontinence, in-
voluntary movements, aphasia, and the fact of an
operation. Denial syndromes also include lack of
recognition of blindness [Anton’s syndrome (1889),
which was actually first noted by Von Monakow in
1885]. They may deny they are ill in any way and
deny that they are in the hospital. These patients,
despite their denial, remain in the hospital and
usually cooperate in examinations, laboratory in-
vestigations, and even surgery. Patients with brain
disease may deny or fail to recognize any form of
disability.
Denial of illness is often accompanied by asso-
ciated disorders, including unilateral neglect, con-

fabulation, disorientation, hallucinations, acute con-
fusional states, reduplication, and dementia. Con-
fabulations in which the affected side is represented
in metaphorical or allegorical language may be quite
elaborate. Critchley describes patients who refer to
their affected extremities with terms such as ‘‘silly
Jimmy,’’ ‘‘sloppy Joe,’’ ‘‘fanny Anne,’’ ‘‘the stinker,’’
or ‘‘a piece of dead meat.’’ One of Critchley’s patients
called his paralyzed arm ‘‘the Communist’’ because it
refused to work. In 1974, Critchley coined the term
misoplegia for morbid hatred of hemiplegia. These
patients may also have disinhibited (ludic) behavior
with inappropriate joking, referring to the examiner’s
health when asked how they feel or the examiner’s
vision when asked how well they see. Patients may
also have reduplication for place, time, and person,
nonaphasic misnaming, and marked mood changes
including withdrawal. The disorientation for place
seen in patients with denial usually indicates that the
patient is somewhere else, implying that he or she is
less ill. That is, the patient in the hospital often
believes he or she is at home. As Hughlings Jackson
stated in 1876, disorientation for place cannot be
attributed to ‘‘confusion’’ unless one were to say that
the patient is specifically confused only regarding the
hospital name. In reduplication for place (closely
related to disorientation), the patient usually states
that there are two or more hospitals of the same or
similar names. This phenomenon was described by
Pick as ‘‘reduplicative paramnesia’’ in 1903. In
nonphasic misnaming, the patient selectively mis-
names objects associated with the illness and
personal identity.
In unilateral neglect, also know as hemi-inatten-
tion (a disturbance of the ‘‘body schema’’), patients
are neglectful of events in the external world on one
side of space, usually on the same side as a lateralized
motor or sensory deficit. Although unilateral neglect
often accompanies denial of illness, denial often
occurs without neglect. Neglect is often accompanied
by constructional apraxia and other behavioral
changes seen with denial of illness. Most patients
with hemineglect also have a unilateral motor and
sensory deficit on the same side and evidence of a
disturbance of consciousness and sometimes an acute
confusional state. These patients may also have
dressing apraxia and topographical disorientation.
Unilateral neglect was first reported by Hughlings
Jackson in 1878 as ‘‘imperception.’’ When asked to
read, a patient with left neglect began in the right
lower corner and tried to read backwards. She did
not know places, persons, or objects and was
ANOSOGNOSIA 199
withdrawn. She had difficulty in dressing and finding
her way around the city. At autopsy, Sir William
Gowers found a right temporal lobe glioma.
Patients with denial of illness and hemi-inattention
may fail to recognize the limbs on one side of the
body as their own. They may attend to events and
people only on one side or respond only when
addressed from one side. When drawing a figure,
they may omit details on the neglected side. They
may deviate their head and eyes constantly to the
good side and fail to look at the effected side. Hemi-
inattentive subjects may eat from only one side of the
tray or shave completely only one side of the face.
Critchley reported the case of an orchestra conductor
who ignored the musicians on one side. A hemi-
inattentive radiologist attended to only the right
side of x-rays he was interpreting. This deficit is
not caused solely by a motor or sensory loss because
movement of the head and eyes can correct well
for unilateral homonymous hemianopia when the
patient has sufficient time. Patients with dense
homonymous hemianopia often exhibit no evi-
dence of visual hemineglect and are generally able
to draw and read without asymmetry. The fact that
neglect is not caused by motor or sensory loss alone
is also illustrated by Critchley’s glove test: When a
patient with left neglect is asked to put on a pair of
gloves, he or she characteristically uses the neglected
left hand to put the glove on the ‘‘good’’ right hand.
The defect that the patient denies may or may not be
due to the same lesion in the nervous system that is
necessary for the enduring maintenance of the denial.
Thus, in a stroke patient with diabetes, the impaired
vision of which the patient says he or she has no
knowledge of and disregards may be due to retinal
disease.
Patients may explicitly deny the presence of illness,
such as when a hemiplegic patient states that he or
she does not have any weakness in the affected
extremity. There may also be implicit evidence of
denial of illness as shown by a patient with
hemiparesis who states that he or she has some
stiffness in his or her arm from sleeping on it during
the evening. Implicit denial may also be demon-
strated as indifference or lack of concern. When one
patient was asked if her left arm belonged to her, she
said ‘‘my eyes and my feelings are not in agreement:
and I must believe in what I feel. I sense in looking
that they are as if they are mine, but I feel that they
are not and I cannot believe my eyes.’’ Patients persist
in their misrepresentations and delusions despite
evidence to the contrary because they have personal
200 ANOSOGNOSIA
meaning. Denial, confabulation, reduplication, and
symbolic disorientation may persist in part because
they provide a sense of identity, combat feelings of
unreality, and impart structure to what might
otherwise be a mass of confusing information.
Lesions of the right hemisphere are more likely to
cause denial and unilateral neglect than those of the
left. Both Schilder and Goldstein discussed a
motivational theory for anosognosia, suggesting a
primary instinctive urge toward body integrity
governing behavior. Schilder considered denial to
be a form of ‘‘organic repression.’’ Goldstein believed
that denial represented a psychological defense
mechanism often present in normal individuals, and
that a ‘‘drive to self-actualization’’ was involved in
the production of denial. Denial may be of value to
the patient in assisting in the avoidance of a
catastrophic reaction. Weinstein and associates
found that patients with denial often have premorbid
personalities (before development of altered brain
function) that are compulsive and perfectionistic
with a tendency to deny problems (regarding illness
as a sign of failure and weakness). Weinstein and
associates emphasized the positive, adaptive, con-
ceptual, and symbolic aspects of denial of illness and
unilateral neglect and that these manifestations may
be in part ‘‘gestures in which the patient symbolizes
the affected side, similar to the way he conceptualizes
it verbally with delusions, confabulations, humor,
and other forms of metaphorical expression.’’ These
are patients in whom ‘‘the idea of illness was
incompatible with personal integrity’’ and who are
conscientious, compulsive, efficiency-oriented peo-
ple. Other patients with the same forms of altered
brain function and neurological deficit, without such
premorbid personalities, may show no explicit or
implicit denial.
Denial of illness may occur with a lesion at any
level of the central nervous system as long as there is
an accompanying deficit in mental function. Lesions
related to denial of illness syndromes are most
commonly seen in the right hemisphere, including
especially the parietal lobe, interparietal sulcus,
supermarginal gyrus, and angular gyrus. Focal
lesions causing denial more commonly involve the
parietal–occipital cortex rather than the pre-Roll-
andic cortex or subcortical regions. However, denial
may also be seen with damage to cortical white
matter, frontal and temporal cortex, and occipital
cortex. Mesulam proposed a model of neglect in
which lesions of the cingulate, frontal, and reticular
systems interrupt the ‘‘integrated network of mod-
ulation of directed attention within extrapersonal
space.’’ Heilman and associates proposed that denial
and neglect represent a disorder in the orienting
response caused by a lesion in a corticolimbic
reticular loop.
Denial of illness may also occur in patients with
Alzheimer’s disease. Weinstein and colleagues found
that denial was not related to severity of deficit in
Alzheimer’s disease. They concluded that denial or
unawareness of dementia is not caused by the
cognitive impairment alone because marked denial
was encountered in patients with Mini-Mental Status
Examination scores in the mid-20s (mild dementia),
whereas awareness of disability was expressed by
patients with scores as low as 7 (severe dementia).
Most patients maintained their denial ratings over
the course of the illness, indicating that disease
progression alone does not necessarily produce
denial. Persons with Alzheimer’s disease who have
poor awareness of their deficit may not understand
the need for altered participation in activities, such as
cooking, driving, and performing potentially hazar-
dous tasks at work.
Denial of illness may have important practical
consequences for the daily life of the patient. For
example, a person with hemiplegia may not cooperate
with physical therapy. However, anosognosia after
acute brain lesions is usually a transient phenomenon
and recedes along with the initial clouding of
consciousness (as noted by Babinski). However, the
selectivity of response to questions about disease in
the patient with denial indicates that some discrimi-
nation is occurring. Patients often deny their dis-
abilities in one context of language and acknowledge
them in another. The recognition of disability may
occur when the patient is speaking in anecdotes,
clichés, humor, and other forms of idiomatic speech
or ‘‘social language.’’ Patients may deny illness in
the presence of family members but acknowledge
awareness of disability when interviewed alone.
Denial of illness is often shared by the patient
and the family. This is illustrated by the case of a
man with Alzheimer’s disease who had difficulty
driving because of dementia and needed his wife
to shift for him: He made a left turn at the wrong
time and caused an accident in which his wife died. It
is important to include assessment of denial of illness
in the patient evaluation and to conduct interviews
with both the patient and the family members
separately and together to acquire the needed
information.
—Robert P. Friedland

See also–Alien Limb; Babinski, Josef-Francois-
Felix; Münchausen Syndrome; Neglect Disorders
Acknowledgments
This work was supported in part by Grants PO 263-MO-818915
and UO1 AG1713-01A1 from the NIA, Grant P50 AG 08012
from the Alzheimer’s Disease Research Center, the Mandel
Foundation, the Nickman family, the Institute for the Study of
Aging, and Philip Morris, USA.
Further Reading
Friedland, R. P., and Weinstein, E. A. (1977). Hemi-inattention
and hemisphere specialization: Introduction and historical
review. Adv. Neurol. 18, 1–31.
Heilman, K. M. (1991). Anosognosia: Possible neuropsychological
mechanisms. In Awareness of Deficit after Brain Injury (G. P.
Prigitano and D. L. Schacter, Eds.), pp. 53–62. Oxford Univ.
Press, New York.
Shalev, R. S. (1985). Anosognosia: The neurological correlate of
denial of illness. In Denial: A Clarification of Concepts and
Research (E. L. Edelstein, D. L. Nathanson, and A. M. Stone,
Eds.), pp. 119–127. Plenum, New York.
Weinstein, E. A. (1969). Body schema in organic mental
syndromes. Handb. Clin. Neurol. 4, 241–247.
Weinstein, E. A., and Kahn, R. L. (1955). Denial of Illness:
Symbolic and Physiological Aspects. Thomas, Springfield, IL.
Weinstein, E. A., Friedland, R. P., and Wagner, E. E. (1994).
Denial/unawareness of impairment in symbolic behavior in
Alzheimer’s disease. Neuropsychiatry Neuropsychol. Behav.
Neurol. 7, 176–184.
Anoxic–Ischemic
Encephalopathy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANOXIC–ISCHEMIC ENCEPHALOPATHY is a term that
usually refers to brain dysfunction after total
circulatory (cardiac) arrest. It constitutes a common
problem: 116 per 100,000 citizens suffer cardiac
arrest as a primary event each year. Pooled data of
in- and out-of-hospital cases showed that 444 of
1784 (25%) survived for at least 1 hr, a sufficient
amount of time to be connected to a ventilator in the
intensive care unit (ICU). Of these 444, 126 (28%)
recovered awareness and were discharged from the
hospital. Thus, 72% of comatose survivors of cardiac
arrest did not recover consciousness.
PATHOLOGY AND PATHOGENESIS
Certain neurons show a ‘‘selective vulnerability’’ to
anoxic–ischemic insults. The large cell layers (3, 5,
ANOXIC–ISCHEMIC ENCEPHALOPATHY 201
and 6) of the neocortex and the CA1 and end folium
(CA4–6) of the hippocampus are especially vulner-
able. Other relatively vulnerable regions include the
Purkinje cells of the cerebellum, the putamen,
caudate, and thalamus. If the patient survives for a
sufficient amount of time, the neurons are replaced
by a gliotic reaction. Trans-synaptic degeneration
may affect thalamic nuclei and brainstem nuclei such
as the inferior olivary complex. If the insult is
sufficiently severe, all neurons may die, producing
brain death.
From experimental studies, it is clear that ische-
mia is the essential component in producing
neuronal death in cardiac arrest. Hypoxia alone,
even with arterial oxygen concentrations of o25
mmHg, does not produce neuronal death. Thus, the
term generalized ischemic encephalopathy is more
accurate pathophysiologically. The mechanisms for
neuronal death include release of excitotoxic neuro-
transmitters, activation of N-methyl-d-aspartate
receptors with calcium influx into neurons, perox-
ynitrile production, failure of clearance of hydrogen
ions and lactate, and free radical production on
reperfusion.
MANAGEMENT
The management of patients with anoxic–ischemic
encephalopathy should depend on prognostic deter-
mination. Since the decision to withdraw care cannot
be reversed, a test that has no false positives for a
poor prognosis is needed (Fig. 1).
Until a definitive prognosis can be determined,
patients resuscitated from cardiac arrest require
immediate, high-quality intensive care. Although
evidence-based or even consensus-based guidelines
are not available for neuroprotection in this situa-
tion, some recommendations for preventing further
secondary damage in patients with acute ischemic
stroke may apply. These include (i) preventing
hyperglycemia and hyperthermia; (ii) maintaining
adequate blood pressure: Because of loss of auto-
regulation, adequate systemic blood pressure is
essential; on the other hand, hypertension aggra-
vates vasogenic cerebral edema; and (iii) achieving
normal arterial concentrations of oxygen and carbon
dioxide: Excessive oxygen may contribute to in-
creased free radical damage; hypocapnia reduces
cerebral perfusion, and hypercapnia raises intracra-
nial pressure.

See also–Alien Limb; Babinski, Josef-Francois-
Felix; Münchausen Syndrome; Neglect Disorders
Acknowledgments
This work was supported in part by Grants PO 263-MO-818915
and UO1 AG1713-01A1 from the NIA, Grant P50 AG 08012
from the Alzheimer’s Disease Research Center, the Mandel
Foundation, the Nickman family, the Institute for the Study of
Aging, and Philip Morris, USA.
Further Reading
Friedland, R. P., and Weinstein, E. A. (1977). Hemi-inattention
and hemisphere specialization: Introduction and historical
review. Adv. Neurol. 18, 1–31.
Heilman, K. M. (1991). Anosognosia: Possible neuropsychological
mechanisms. In Awareness of Deficit after Brain Injury (G. P.
Prigitano and D. L. Schacter, Eds.), pp. 53–62. Oxford Univ.
Press, New York.
Shalev, R. S. (1985). Anosognosia: The neurological correlate of
denial of illness. In Denial: A Clarification of Concepts and
Research (E. L. Edelstein, D. L. Nathanson, and A. M. Stone,
Eds.), pp. 119–127. Plenum, New York.
Weinstein, E. A. (1969). Body schema in organic mental
syndromes. Handb. Clin. Neurol. 4, 241–247.
Weinstein, E. A., and Kahn, R. L. (1955). Denial of Illness:
Symbolic and Physiological Aspects. Thomas, Springfield, IL.
Weinstein, E. A., Friedland, R. P., and Wagner, E. E. (1994).
Denial/unawareness of impairment in symbolic behavior in
Alzheimer’s disease. Neuropsychiatry Neuropsychol. Behav.
Neurol. 7, 176–184.
Anoxic–Ischemic
Encephalopathy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANOXIC–ISCHEMIC ENCEPHALOPATHY is a term that
usually refers to brain dysfunction after total
circulatory (cardiac) arrest. It constitutes a common
problem: 116 per 100,000 citizens suffer cardiac
arrest as a primary event each year. Pooled data of
in- and out-of-hospital cases showed that 444 of
1784 (25%) survived for at least 1 hr, a sufficient
amount of time to be connected to a ventilator in the
intensive care unit (ICU). Of these 444, 126 (28%)
recovered awareness and were discharged from the
hospital. Thus, 72% of comatose survivors of cardiac
arrest did not recover consciousness.
PATHOLOGY AND PATHOGENESIS
Certain neurons show a ‘‘selective vulnerability’’ to
anoxic–ischemic insults. The large cell layers (3, 5,
ANOXIC–ISCHEMIC ENCEPHALOPATHY 201
and 6) of the neocortex and the CA1 and end folium
(CA4–6) of the hippocampus are especially vulner-
able. Other relatively vulnerable regions include the
Purkinje cells of the cerebellum, the putamen,
caudate, and thalamus. If the patient survives for a
sufficient amount of time, the neurons are replaced
by a gliotic reaction. Trans-synaptic degeneration
may affect thalamic nuclei and brainstem nuclei such
as the inferior olivary complex. If the insult is
sufficiently severe, all neurons may die, producing
brain death.
From experimental studies, it is clear that ische-
mia is the essential component in producing
neuronal death in cardiac arrest. Hypoxia alone,
even with arterial oxygen concentrations of o25
mmHg, does not produce neuronal death. Thus, the
term generalized ischemic encephalopathy is more
accurate pathophysiologically. The mechanisms for
neuronal death include release of excitotoxic neuro-
transmitters, activation of N-methyl-d-aspartate
receptors with calcium influx into neurons, perox-
ynitrile production, failure of clearance of hydrogen
ions and lactate, and free radical production on
reperfusion.
MANAGEMENT
The management of patients with anoxic–ischemic
encephalopathy should depend on prognostic deter-
mination. Since the decision to withdraw care cannot
be reversed, a test that has no false positives for a
poor prognosis is needed (Fig. 1).
Until a definitive prognosis can be determined,
patients resuscitated from cardiac arrest require
immediate, high-quality intensive care. Although
evidence-based or even consensus-based guidelines
are not available for neuroprotection in this situa-
tion, some recommendations for preventing further
secondary damage in patients with acute ischemic
stroke may apply. These include (i) preventing
hyperglycemia and hyperthermia; (ii) maintaining
adequate blood pressure: Because of loss of auto-
regulation, adequate systemic blood pressure is
essential; on the other hand, hypertension aggra-
vates vasogenic cerebral edema; and (iii) achieving
normal arterial concentrations of oxygen and carbon
dioxide: Excessive oxygen may contribute to in-
creased free radical damage; hypocapnia reduces
cerebral perfusion, and hypercapnia raises intracra-
nial pressure.
202 ANOXIC–ISCHEMIC ENCEPHALOPATHY
Figure 1
This ‘‘decision algorithm’’ has been applied to the management of patients in coma after resuscitation from cardiac arrest.
Prognostic Determination for Anoxic–
Ischemic Encephalopathy
The prognosis of comatose survivors has tradition-
ally been on clinical grounds. Although the loss of
two or more brainstem reflexes at 24 hr is strongly
predictive of a poor outcome, cranial nerve reflexes
return in most patients who have been resuscitated.
Even patients who arrive in the ICU with a Glasgow
Coma Scale score of 3 can recover awareness.
Decerebrate or decorticate posturing is not reliably
predictive. Assessment is also hampered by endo-
tracheal intubation and the use of paralyzing and
sedating drugs. The risk of falsely pessimistic
prediction of a group of comatose survivors ap-
proaches 10%.
Electrophysiological testing offers the best method
of prognostic determination. Although various
biochemical methods, positron emission tomography
(PET), and cerebral blood flow determinations
have been suggested, these are less suitable because
(either one or more may apply to each) there is too
much overlap between survivors and nonsurvivors,
the technology is expensive and not universally
available, and the tests do not examine neuronal
function in isolation from other central nervous
tissue cells.
The cortical N20 response to median nerve
stimulation is practically the ideal prognostic test.
The absence of the N20 response from median nerve
stimulation has a very high predictive value for
nearly 100% of patients for an outcome no better
than persistent vegetative state (PVS). It should be
noted, however, that when the N20 is present, only
half of such patients recover awareness. Thus, the
presence of the N20 does not reliably predict a
favorable outcome. A more sensitive test would be
desirable, but the absence of the N20 meets the main
requirement of a positive predictive value approach-
ing 100%. Other tests must measure up to this gold
standard.
The literature on cardiac arrest victims indicates
that short-latency somatosensory evoked potentials
(SSEPs) are a better test than a single electroence-
phalograph (EEG) recording for determining a
prognosis of no better than PVS: EEG lacks the
specificity of SSEPs in this regard, shows wider
confidence intervals, and is more susceptible to
reversible changes by drugs and metabolic complica-
tions than are SSEPs. Apart from complete EEG

suppression after 24 hr from cardiac arrest, no other
single EEG pattern has a 100% association with an
outcome no better than PVS. The value of single
recordings, taken in isolation, is limited to various
probabilities but never to certainty of poor outcome.
EEGs performed after the first day of arrest may
show deteriorating patterns associated with a fatal
outcome. This is supported by experimental models,
in which it has been shown that the phenomenon of
‘‘delayed neuronal death’’ may take more than 24 hr
to develop. One must be on guard that such later
suppression is not related to drugs, shock, or sepsis,
however.
There is general agreement that the following EEG
patterns found on repeated testing after cardiac
arrest are strongly associated with a poor neurolo-
gical outcome: generalized suppression; generalized
burst suppression; generalized periodic patterns,
especially with epileptiform activity; and alpha or
alpha–theta pattern coma.
COMPLICATIONS OF ANOXIC–ISCHEMIC
ENCEPHALOPATHY
Increased Intracranial Pressure/Cerebral
Edema
Increased intracranial pressure (ICP) following gen-
eralized anoxic–ischemic encephalopathy relates to
cerebral edema. There is evidence from diffusion
weighted magnetic resonance imaging studies that
most of this edema is cytotoxic rather than vaso-
genic, although both likely play a role.
Probably not all patients with cerebral edema and
increased ICP are alike with regard to the mechanism
(relative proportion of vasogenic or cytotoxic edema)
of the edema or the reversibility of the underlying
neuronal insult. It makes sense to vigorously treat the
cerebral edema or presumed increased ICP in those
patients who have the potential for recovery of
neurological functioning. The previously discussed
methods of assessment of prognosis can be applied.
Patients should be treated vigorously if there is
uncertainty of prognosis or if there is evidence of
reasonable outcome.
Some scenarios are promising for reversibility. If
the patient recovers awareness and then deteriorates
coincident with cerebral edema on computed tomo-
graphy scanning, aggressive treatment with mannitol
and other measures is warranted.
Treatment is aimed at reducing further brain
swelling and improving brain perfusion in the face
ANOXIC–ISCHEMIC ENCEPHALOPATHY 203
of increased ICP. In perinatal rats, mannitol can
decrease the amount of water in the brain after
perinatal hypoxia with ischemia (bilateral carotid
ligation). In this experimental study, however, there
was no improvement in alleviation of ischemic
damage.
There are no controlled trials of therapy for
cerebral edema in adults in coma after cardiac arrest.
Thus, it is probably best to borrow from studies of
increased ICP in trauma. In patients with markedly
increased ICP, reduced cerebral perfusion pressure,
and a Glasgow Coma Scale score of r8, the use of
modest hypothermia (to 341C) was shown to be
beneficial in head injury.
POST-ANOXIC–ISCHEMIC
STATUS MYOCLONICUS
Of comatose survivors of cardiac arrest with general-
ized myoclonus, only 3% recover conscious aware-
ness. This mortality of 97% from anoxic–ischemic
encephalopathy myoclonus contrasts sharply with
the rate of 6–35% associated with generalized
convulsive status epilepticus due to other causes.
Most physicians attempt to stop the myoclonus.
The intravenous preparation of valproate or, if this is
not available, valproic acid syrup given down the
nasogastric tube or by retention enema, at 500 mg
every 8 hr, is often efficacious in arresting the
myoclonus. Clonazepam (0.5 mg t.i.d.) administered
per nasogastric tube as crushed tablets dissolved or
suspended in tepid water is probably less useful but is
often better than other benzodiazepines, phenytoin,
or phenobarbital. Lorazepam may work occasion-
ally.
Further management depends on prognostic de-
termination. Vigorous antiepileptic treatment with
anesthetic barbiturates is not warranted if the
prognosis, from the initial ischemic damage, can be
established as hopeless for meaningful recovery. In
the latter situation, skeletal muscle relaxants are
sometimes necessary to stop the myoclonus. The
following indicate that one is treating a patient with
ultimately hopeless prognosis rather than reversible
status epilepticus: (i) partial or complete cranial
nerve areflexia between seizures; (ii) a flat or totally
suppressed EEG during or between seizures (unless
large doses of anesthetic barbiturates are used); (iii)
absent N20 response with SEP testing; and (iv)
o50% of normal ATP stores or low levels of N-
methyl-aspartic acid, a compound found only in
neurons, on nuclear magnetic resonance spectro-
204 ANTERIOR SPINAL ARTERY OCCLUSION

scopy, persistent over several days. It is hoped
that further work on commonly available blood
flow studies (e.g., HMPAO-SPECT) or invariant
patterns on continuous EEG monitoring may be
useful.
In patients for whom the prognosis is uncertain or
favorable, full treatment for status epilepticus,
including midazolam and anesthetic agents if neces-
sary, appears advisable.
—G. Bryan Young
See also–Acute Hemorrhagic Encephalitis;
Brain Death; Cardiac Arrest Resuscitation;
Cerebral Edema; Coma; Intracranial Pressure;
Ischemic Cell Death, Mechanisms; Sepsis-
Associated Encephalopathy; Toxic
Encephalopathy; Uremic Encephalopathy;
Wernicke’s Encephalopathy
Further Reading
Bassetti, C., Bromo, F., Mathis, J., et al. (1996). Early prognosis in
coma after cardiac arrest: A prospective clinical, electrophysio-
logical and biochemical study of 60 patients. J. Neurol.
Neurosurg. Psychiatry 61, 610–615.
Hallett, M., Chadwick, D., Adam, J., et al. (1977). Reticular
reflex myoclonus: A physiological type of human post-
anoxic myoclonus. J. Neurol. Neurosurg. Psychiatry 40,
253–264.
Mujsce, D. J., Towfighi, J., Stern, D., et al. (1990). Mannitol
therapy in perinatal hypoxic–ischemic brain damage in rats.
Stroke 21, 1210–1214.
Pearigen, P., Gwinn, R., and Simon, R. P. (1996). The effects of in
vivo hypoxia on brain injury. Brain Res. 725, 184–191.
Steil, I. G., Hébert, P. C., Wells, G. A., et al. (1996). The Ontario
trial of active compression–decompression cardiopulmonary
resuscitation for in-hospital and prehospital cardiac arrest. J.
Am. Med. Assoc. 275, 1417–1423.
thermal and painful stimuli and sparing position
and vibration senses below the level of the lesion.
Such a clinical picture is sometimes called the ASA
syndrome because it results from involvement of the
territory of distribution of the ASA (i.e., the anterior
two-thirds of the spinal cord).
The ASA is a small-caliber artery of muscular type
and it courses longitudinally into a duplication of
the pial sheet (linea splendens) in front of the
anterior median fissure, extending from the pyra-
mids of the medulla oblongata to the conus
medullaris. It originates from the union of two
intracranial branches of the vertebral arteries, the
right and left anterior spinal branches, at the level of
the pyramids of the medulla oblongata, and it ends
at the conus medullaris. The caliber of the ASA is
not uniform along its course: It ranges from 200 to
500 mm in the cervical region, from 200 to 400 mm
in the thoracic region, and from 500 to 1300 mm in
the lumbar region (Fig. 1). Along its course, the ASA
receives a variable number (3–10) of anterior
radicular arteries, segmental branches arising
bilaterally from extracranial verterbral arteries,
thyrocervical and costocervical arteries, posterior
intercostal arteries, lumbar arteries, and internal
iliac arteries. The more caudal anterior radicular

Anterior Spinal Artery

Occlusion
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

THE OCCLUSION of the main arterial trunk in the

anterior part of the spinal cord, the anterior spinal
artery (ASA), may produce a distinctive clinical
picture, first reported by Spiller at the beginning of Figure 1
the 20th century. It is characterized by flaccid paresis Course and diameter of the anterior spinal artery and arteria
or plegia and dissociated sensory loss, affecting radicularis magna.
204 ANTERIOR SPINAL ARTERY OCCLUSION

scopy, persistent over several days. It is hoped
that further work on commonly available blood
flow studies (e.g., HMPAO-SPECT) or invariant
patterns on continuous EEG monitoring may be
useful.
In patients for whom the prognosis is uncertain or
favorable, full treatment for status epilepticus,
including midazolam and anesthetic agents if neces-
sary, appears advisable.
—G. Bryan Young
See also–Acute Hemorrhagic Encephalitis;
Brain Death; Cardiac Arrest Resuscitation;
Cerebral Edema; Coma; Intracranial Pressure;
Ischemic Cell Death, Mechanisms; Sepsis-
Associated Encephalopathy; Toxic
Encephalopathy; Uremic Encephalopathy;
Wernicke’s Encephalopathy
Further Reading
Bassetti, C., Bromo, F., Mathis, J., et al. (1996). Early prognosis in
coma after cardiac arrest: A prospective clinical, electrophysio-
logical and biochemical study of 60 patients. J. Neurol.
Neurosurg. Psychiatry 61, 610–615.
Hallett, M., Chadwick, D., Adam, J., et al. (1977). Reticular
reflex myoclonus: A physiological type of human post-
anoxic myoclonus. J. Neurol. Neurosurg. Psychiatry 40,
253–264.
Mujsce, D. J., Towfighi, J., Stern, D., et al. (1990). Mannitol
therapy in perinatal hypoxic–ischemic brain damage in rats.
Stroke 21, 1210–1214.
Pearigen, P., Gwinn, R., and Simon, R. P. (1996). The effects of in
vivo hypoxia on brain injury. Brain Res. 725, 184–191.
Steil, I. G., Hébert, P. C., Wells, G. A., et al. (1996). The Ontario
trial of active compression–decompression cardiopulmonary
resuscitation for in-hospital and prehospital cardiac arrest. J.
Am. Med. Assoc. 275, 1417–1423.
thermal and painful stimuli and sparing position
and vibration senses below the level of the lesion.
Such a clinical picture is sometimes called the ASA
syndrome because it results from involvement of the
territory of distribution of the ASA (i.e., the anterior
two-thirds of the spinal cord).
The ASA is a small-caliber artery of muscular type
and it courses longitudinally into a duplication of
the pial sheet (linea splendens) in front of the
anterior median fissure, extending from the pyra-
mids of the medulla oblongata to the conus
medullaris. It originates from the union of two
intracranial branches of the vertebral arteries, the
right and left anterior spinal branches, at the level of
the pyramids of the medulla oblongata, and it ends
at the conus medullaris. The caliber of the ASA is
not uniform along its course: It ranges from 200 to
500 mm in the cervical region, from 200 to 400 mm
in the thoracic region, and from 500 to 1300 mm in
the lumbar region (Fig. 1). Along its course, the ASA
receives a variable number (3–10) of anterior
radicular arteries, segmental branches arising
bilaterally from extracranial verterbral arteries,
thyrocervical and costocervical arteries, posterior
intercostal arteries, lumbar arteries, and internal
iliac arteries. The more caudal anterior radicular

Anterior Spinal Artery

Occlusion
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

THE OCCLUSION of the main arterial trunk in the

anterior part of the spinal cord, the anterior spinal
artery (ASA), may produce a distinctive clinical
picture, first reported by Spiller at the beginning of Figure 1
the 20th century. It is characterized by flaccid paresis Course and diameter of the anterior spinal artery and arteria
or plegia and dissociated sensory loss, affecting radicularis magna.

artery is generally a large vessel located between T9
and L5, with a marked predilection for T12 and L3
levels. This large anterior radicular artery is known
as the arteria radicularis magna (ARM) or artery of
Adamkiewicz. In the past, it has been debated
whether the ASA is a continuous vessel or inter-
rupted at the thoracic level. However, recent
anatomical evidence from our group demonstrates
that the ASA is a continuous vessel and it is the main
arterial blood supply to the spinal cord, forming an
uninterrupted anastomotic channel between the
vertebral arteries, the ARM, and the lumbar ASA.
Throughout its full length, the ASA gives off the
central or sulcocommissural arteries that enter the
anterior median fissure and penetrate into the spinal
white and gray matters. They supply the anterior
two-thirds of the spinal cord (i.e., the anterior horns
and the anterior portion of the posterior horns of the
gray matter and the anterior funiculi of the white
matter). Thus, the territory of distribution of the
ASA corresponds to the areas supplied by the central
arteries.
The blood flow entering the ASA from each
anterior radicular artery divides into two currents,
one ascending and the other descending. The
convergence of opposite flow currents from adjacent
anterior radicular arteries produces a number of
vascular watershed areas along the spinal cord,
localized halfway between anterior radicular arteries.
The watershed area located at the midthoracic
level seems to be particularly vulnerable to con-
sequences of ischemia. Reversals of normal blood
flow patterns have been demonstrated angiographi-
cally when there is stenosis or occlusion of the
ASA.
Occlusion of the ASA accounts for 1 or 2% of all
brain and spinal infarctions. Embolism is the most
frequent cause of occlusion. Various sources of
emboli have been reported: cholesterol emboli from
atherosclerotic plaques of the aorta and main aortic
branches, dislodged spontaneously or during cardio-
pulmonary resuscitation, aortic catheterization, and
aortic surgery; gaseous emboli (caisson syndrome or
decompression sickness); paradoxical embolism
through a patent foramen ovale from deep venous
thrombosis of the lower limbs, mainly in hypercoa-
gulable states; and fibrocartilaginous embolism, both
spontaneous and during physical exercise, from the
nucleus pulposus of intervertebral disks. Moreover,
the ASA can be occluded by vasculitic disease, such
as polyarteritis nodosa, systemic lupus erythemato-
sus, and syphilis. Other causes of thrombotic
ANTERIOR SPINAL ARTERY OCCLUSION 205
occlusion of the ASA are secondary to direct
mechanical trauma to the vessel and include
subluxation of the cervical spine (posttraumatic or
in rheumatoid arthritis), severe cervical spondylosis,
protrusion of cervical intervertebral disks, and
severe stenosis of the vertebral canal. Finally,
paraplegia rarely complicates spinal arteriography.
The proposed mechanisms for such complications
are direct contrast media neurotoxicity, embolism
from an atherosclerotic plaque, spasm, and throm-
bosis of the ASA. Thrombosis over an atherosclero-
tic plaque is a very rare cause of ASA occlusion. In
fact, the ASA is rarely involved in atherosclerotic
disease.
The effects of experimental acute occlusion of the
low-thoracic ASA have been evaluated in rhesus
monkeys. Surgical ligature of the ASA just above the
junction with the ARM did not result in clinically
significant neurological deficit, whereas ligature of
the ASA below the junction with the ARM resulted
in a severe motor deficit in the lower limbs in most
cases. Interestingly, ligature of the ARM did not
cause a clinically significant neurological deficit. The
pivotal role of the anatomical and functional
continuity of the ASA was demonstrated by the fact
that only the occlusion of the lumbar ASA could not
be compensated because such occlusion compromises
the continuity of the lumbar ASA with both thoracic
ASA and ARM.
The exact duration of the acute ASA occlusion
that produces irreversible damage of the spinal cord
is unknown. However, studies have reported that the
risk of irreversible neurological damage approaches
zero percent for spinal cord ischemia lasting for less
than 10 min; the risk increases progressively for
longer ischemic periods. Towfighi and Vannucci
showed that the minimal duration of circulatory
arrest in dogs for spinal cord damage was 10 min
following asphyxiation and 15 min following
cardiac arrest. Neuropathological changes consisted
of neuronal necrosis involving mainly the spinal
cord gray matter. Yamada and coworkers observed
that in cats the occlusion of the thoracic aorta for 10
min did not result in spinal cord injury, but 20-min
and 30-min occlusions produced neurological and
pathological changes in 25 and 100% of cases,
respectively.
The clinical picture produced by the occlusion of
the ASA depends on the rate of vessel occlusion, on
the level and extent of the spinal cord infarction,
and on the collateral flow. The syndrome may
develop abruptly or within a few hours. Rarely,
206 ANTIANXIETY PHARMACOLOGY
transient spinal ischemic attacks may herald the
infarction. Independent from the localization of
the occlusion, spinal infarction in the distribution
of the ASA is characterized by the onset of bilateral
flaccid paresis or plegia below the lesion level, loss of
motor reflexes, and dissociated sensory loss. Bowel
and bladder paresis is frequent. Patients also
commonly complain of neck or back pain and
sometimes of a radicular-type pain. Moreover, if
the ASA gives off branches to the medulla oblongata,
a very high occlusion of the ASA may also produce
symptoms related to ischemia and infarction of the
medulla oblongata. The flaccid paresis or plegia
usually evolves progressively to spasticity with
hyperactive motor reflexes. In some cases, there is a
significant clinical improvement during the following
months, characterized by a partial recovery of
somatic motor function and voluntary sphincter
control.
Treatment is limited to a few etiologies, such as
hyperbaric therapy for caisson syndrome and surgery
for mechanical traumas. The role of heparinization
for ASA thrombosis is not yet defined. However,
supportive care and close neurological survey in a
stroke or intensive care unit are indicated for all
patients. When the acute phase of spinal injury
subsides, it is advisable to begin a rehabilitation
program.
—Paolo Biglioli
See also–Spinal Cord Anatomy; Spinal Stroke
Acknowledgments
This entry was written in cooperation with Maurizio Roberto,
Aldo Cannata, Francesco Grillo, and Rita Spirito.
Further Reading
Biglioli, P., Spirito, R., Roberto, M., et al. (2000). The anterior
spinal artery: The main arterial supply of the human spinal
cord–A preliminary anatomic study. J. Thorac. Cardiovasc.
Surg. 119, 376–379.
Fried, L. C., Di Chiro, G., and Doppman, J. L. (1969). Ligation of
major thoraco-lumbar spinal cord arteries in monkeys. J.
Neurosurg. 31, 608–614.
Mannen, T. (1966). Vascular lesions in the spinal cord of the aged.
Geriatrics 21, 151–160.
Sliwa, J. A., and Maclean, I. C. (1992). Ischemic myelopathy: A
review of spinal vasculature and related clinical syndromes.
Arch. Phys. Med. Rehab. 73, 365–372.
Thron, A. K. (1988). Vascular Anatomy of the Spinal Cord.
Neuroradiological Investigations and Clinical Syndromes.
Springer-Verlag, New York.
Towfighi, J., and Vannucci, R. C. (1997). Neuropathology of
normothermic circulatory arrest in newborn dogs. Acta
Neuropathol. 93, 485–493.
Wang, Y., and Hashizume, Y. (1996). Pathological study of age-
related vascular changes in the spinal cord. Nippon Ronen
Igakkai Zasshi 33, 563–568.
Yamada, T., Morimoto, T., Nakase, H., et al. (1998). Spinal
cord blood flow and pathophysiological changes after
transient spinal cord ischemia in rats. Neurosurgery 42,
626–634.
Antianxiety Pharmacology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TREATMENT of anxiety disorders is a complex
topic, given the number of specific anxiety disorders
and because treatment usually must be highly
tailored to the individual. Many different types of
psychotherapies, especially variants of cognitive and
behavioral psychotherapies, are successfully used in
the treatment of anxiety disorders, but often anti-
anxiety medications are essential for the relief of
symptoms and maintenance of remission. These
medications commonly include benzodiazepines,
serotonin-selective reuptake inhibitors (SSRIs), tri-
cyclic antidepressants (TCAs), monoamine oxidase
inhibitors (MAOIs), and other antidepressants (e.g.,
venlafaxine), buspirone, b-adrenergic blockers, and
antihistamines.
SEROTONIN-SELECTIVE REUPTAKE
INHIBITORS
Serotonin-selective reuptake inhibitors have been
found to be beneficial for a number of anxiety
disorders. Fluoxetine, sertraline, paroxetine, and
citalopram have demonstrated efficacy as antipanic
agents at doses comparable to those for the treatment
of major depressive disorder. A paradoxical activation
may occur in patients with panic disorder when SSRIs
are started, so a low starting dose and slow upward
titration are recommended. SSRIs generally take 2–4
weeks to exert their therapeutic effect. For patients
who respond to any medication for panic disorder, it
remains unclear how long to maintain patients on the
medication; common practice is to continue it for at
least 1 year. Relapse rates of 50–90% after disconti-
nuation of medication have been reported, although
some reports suggest that adjunctive cognitive–beha-
vioral therapy may help prevent relapse.
234 ANTI-PHOSPHOLIPID ANTIBODIES
MacDonald, D. R. (1991). Neurologic complications of che-
motherapy. Neurol. Clin. 9, 955–967.
Young, D. F., and Posner, J. B. (1980). Nervous system toxicity of
the chemotherapeutic agents. In Handbook of Clinical Neurol-
ogy (P. J. Vinken and G. W. Bruyn, Eds.), Vol. 39, pp. 91–130.
North-Holland, Amsterdam.
Anti-Phospholipid Antibodies
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANTI-PHOSPHOLIPIDS are immunoglobulins of the
IgG, IgM, IgA, and mixed classes directed against
negatively charged or neutral phospholipids. They
were first detected as reagin, a type of anti-
phospholipid antibody found in the blood of
patients with syphilis. Later, they were found in
patients without syphilis, some of whom had
systemic lupus erythematosus (SLE), in which
case the anti-phospholipids caused a biological
false-positive serological test for syphilis. Anti-
phospholipid antibodies (aPLs) were termed anti-
coagulants because they were found to prolong
the phospholipid-dependent tests of coagulation;
they were also termed the lupus anticoagulant
(LA), although this was discovered to actually
be a misnomer because the LA was found to be
associated with a thrombotic tendency. A more
specific assay was developed for aPL, with
cardiolipin (a serologically active phospholipid) as
the antigen, using a solid phase radioimmuno-
assay for anticardiolipin (aCL) detection. Subse-
quently, an enzyme-linked immunosorbent assay
(ELISA) was developed and standardized. There
is partial concordance between the assays for aCL
and LA. Some patients may be positive for one
but not the other, and some will harbor both. aCLs
have been identified in approximately 10% of
unselected patients with first ischemic stroke. The
isotype mainly implicated in thrombosis is IgG,
specifically subtype IgG-2. Recent data suggest that
the presence of high titers of aCL immunoreactivity,
mainly the IgG isotype but possibly also IgM,
correlates with an increased risk of thrombosis.
Generally, titers of IgG aCL implicated are 440
GPL units, although this is a somewhat arbitrary
cutoff point and is dependent on the test systems,
which are not standardized.
Table 1 PAPS ASSOCIATED FEATURES
Venous occlusions
Arterial occlusions
Recurrent fetal loss
Thrombocytopenia
Livedo reticularis
Chorea
Migraine
PRIMARY ANTI-PHOSPHOLIPID SYNDROME
Although aPLs can be associated with SLE or lupus-
like disease, a large proportion of patients have
antiphospholipid syndrome (aPS), a term used to
describe arteriovenous thrombosis, sometimes ac-
companied by thrombocytopenia, occurring in the
presence of aPLs.
When aPS occurs without major serological or
clinical features of SLE, it has been described as the
primary aPS or PAPS. The clinical and laboratory
features of PAPS (Table 1) were reviewed in 70
patients by Asherson et al., who found the following:
venous thrombosis (54%); arterial thrombosis
(44%); recurrent fetal loss, usually due to placental
infarction (34%); ANA, usually low titer (46%);
thrombocytopenia, platelet count o150,000 (46%);
VDRL positivity (33%); aCL IgG and LA (86%);
aCL IgM (39%); and positive Coombs test (14%).
Sneddon’s syndrome (i.e., livedo reticularis asso-
ciated with ischemic cerebrovascular disease) has
been associated with the presence of aPLs. Livedo
reticularis has been found to occur alone or in the
presence of stroke or transient ischemic attack or
chorea. Chorea has been noted in patients with aPS.
Some have been found to have caudate or basal
ganglionic strokes on brain imaging, although some
have normal imaging studies or strokes in regions
that do not explain the chorea, and the etiology is
unknown. Headaches, often characterized as mi-
graine and associated with migraine accompani-
ments or more complicated stroke-like features, are
also associated with aPLs.
In many cases of recurrent thrombosis related to
aPLs, those with venous thrombosis will have further
venous thromboses and those with arterial throm-
bosis will have further arteriothrombotic events.
The aPLs are found in a variety of autoimmune
disorders other than SLE, including rheumatoid
arthritis, primary Sjogrens syndrome, and progres-
sive systemic sclerosis. They can also be found in
 ANTI-PHOSPHOLIPID ANTIBODIES 235

malignancy, hematological disorders such as idio- mine. The binding of the different antigens was
pathic thrombocytopenic purpura, hemolytic ane- b2-GPI dependent.
mia, and infections including HIV and Lyme. aPLs
can be found during usage of certain drugs, such as
phenothiazines. In these settings, the association with aPL-ASSOCIATED STROKE
thrombosis is low, and the aPL titers are low and
Studies have suggested that strokes related to aPLs
more likely to be of the IgM isotype.
are caused by thrombotic events as well as embolic
events. Pathological studies have shown noninflam-
ANTI-PHOSPHOLIPID PROTEIN ANTIBODIES, matory thrombotic occlusions of both large and
ANTI-PHOSPHOLIPID/COFACTOR small cerebral vessels. Vasculitis has not been found.
SYNDROME, AND aPLs OTHER THAN aCL Computed tomography and magnetic resonance
imaging (MRI) show cortical and deep infarcts
The concept of a protein target for aPL evolved from
(Fig. 1). Deep infarcts are in the distribution of pial
a series of independent reports in 1990 that identified
branches and have an appearance different from that
b2 glycoprotein I (b2-GPI), also called apolipoprotein
of lacunar infarcts. Progressive white matter disease
H, as a necessary plasma cofactor to bind cardiolipin
can occur and present as multi-infarct dementia.
in vitro on ELISA plates. b2-GPI is a 50-kDa plasma
Angiograms show large-vessel or branch occlu-
protein that has several anticoagulant functions. The
sions, or they are normal. MR angiography from the
aPL protein antibodies (aPL-P), rather than being a
patient whose MRI is shown in Fig. 1 was normal, as
single or even homogeneous group of autoantibodies,
might be expected in those showing deep white
constitute a heterogeneous family of autoantibodies
matter infarcts, likely secondary to small vessel
with different isotypes, different specificities, differ-
occlusions.
ent requirements of cofactor proteins, and different
immunochemical characteristics. They may interfere
with the kinetics of coagulation reactions or stimu-
late the prothrombotic activities of endothelial cells
and monocytes and promote coagulation by complex
molecular interactions.
In addition, patients have recurrent venous and/or
arterial thromboses without aPL as detected by
routine assays, and there is no clinical or serological
evidence of other autoimmune diseases. Some of
these patients also have other features associated
with aPL, such as livedo reticularis, thrombocytope-
nia and valvular heart disease, and serum IgG
reactivity against human and bovine b2-GPI (i.e.,
anti-b2-GPI antibodies).
Although aCLs are directed to a neoepitope
formed by phospholipid and b2-GPI, immunoassays
based on CL as the target antigen are widely used.
Some patients with clinical manifestations of aPS
occasionally have persistently negative conventional
assays for LA and aCL but antibodies directed
against other phospholipids. CL occurs primarily
intracellularly, such as in the mitochondrial mem-
brane; other phospholipids are important constitu-
ents of the cell membrane. Noncardiolipin antigens
and thrombosis are associated. In a study by Toschi Figure 1
et al., phosphatidylinositol had the highest frequency, MRI showing increased signal on a T2-weighted study in the
subcortical white matter of the high left and right parietal lobes,
with the following other PLs detected: phosphati- consistent with subcortical infarction. This is from a 40-year-old
dylserine, phosphatidylglycerol, phosphatidic acid, woman who presented with left hemiparesis and was found to
phosphatidylcholine, and phosphatidylethanola- have livedo reticularis and markedly elevated titers of IgG aCL.
236 ANTI-PHOSPHOLIPID ANTIBODIES

LABORATORY TESTING
The detection of LAs is based on three criteria:
demonstration of an abnormality in an in vitro
phospholipid-dependent coagulation test, proof that
the abnormality is due to an inhibitor (circulating
anticoagulant) through the use of mixing studies, and
proof that the inhibitor activity is directed at
phospholipid. In addition to the aPTT, other screen-
ing tests for LAs are the Kaolin clotting time, the
dilute Russell’s viper venom time, and the plasma
clot time. No single test will identify all patients with
LAs; therefore, it is appropriate to use two different
screening tests to obtain the highest accuracy.
Figure 2 Accepted criteria are outlined by the Subcommittee
Transesophageal echocardiogram showing a large mass attached on Lupus Anticoagulant/Anti-phospholipid Antibody
to the right and left coronary cusps, with frond-like projections of the Scientific and Standardization Committee of
dangling from the valve, prolapsing back and forth into the left
ventricle and aorta.
the ISTH. Anti-phospholipids other than LA, such as
aCL, may exist in the absence of LA and must be
screened for using ELISAs.
One of the major difficulties regarding aPL-P is
Cardiac valvular lesions are often found in patients
laboratory variability. It is imperative that studies on
with aPLs (Fig. 2). Valvular lesions associated with
aPL-P include specific descriptions of the assays used
aPLs occur as valve masses or thickening. Both can
because interpretation of any finding depends on the
be associated with valve dysfunction, although such
microtiter plates used (assays using oxidized or
association is much more common with the latter
irradiated microtiter plates are made to be highly
alteration. The predominant functional abnormality
sensitive, presumably by reconfiguration of protein
is regurgitation; stenosis is rare. Valvular involve-
to expose a neotype) as well as other aspects of the
ment usually does not cause clinical vavular heart
procedure, including buffers, blocking agents, and
disease. The mitral valve is mainly affected, followed
the presence of animal (e.g., bovine) b2-GPI. Retest-
by the aortic valve. The presence of aPLs seems to
ing after 8 weeks for continued persistence of the
increase the risk of thromboembolic complications,
antibody is recommended.
mainly cerebrovascular, posed by valve lesions.
Pathologically, there are fibrin platelet lesions that
may show evidence of inflammation on the valve
cusps, chordae tendineae, and papillary muscles and
resemble the thrombotic vegetations of Libman–
Sacks endocarditis (Fig. 3). Current data suggest a
role for aPLs in the pathogenesis of valvular lesions.
aPLs may promote the formation of valve thrombi.
There is evidence that subpopulations of aPLs or
some other immunoglobins in the sera of patients
with aPS bind to endothelial cells. These antibodies
may also act by another mechanism, as indicated by
the finding of subendothelial deposits of immunoglo-
bulins including aCLs and of colocalized complement
components in deformed valves of patients with aPS.
Some data suggest that immunological factors may
contribute not only to thrombosis but also to atheros-
clerosis, mediated by aPL-P. Patients with aPL have
Figure 3
increased levels of antibodies to oxidized low-density Gross abnormality of the mitral valve in a 40-year-old woman
lipoprotein, associated with progression of athero- with aPS and a new left MCA distribution infarct, showing
sclerosis and risk of thrombo-occlusive events. vegetations.

TREATMENT
Although corticosteroids or other immunosuppres-
sive agents have been used in symptomatic patients
with aPLs, there is no conclusive evidence that
they are effective for preventing thromboembolic
complications. Plasma exchange will lower anti-
body titers, but they return to prior levels within a
few days.
Stroke recurrence in patients who harbor aPLs is
reduced by high levels of warfarin anticoagulation,
resulting in an international normalized ratio of Z3.
Whether aspirin helps is unclear; in studies in which
it was used alone, recurrence rates were unchanged.
When added to warfarin, recurrence rates were
changed by high INR, whether aspirin was used or
not. On the other hand, because cardiac valvular
lesions are platelet-fibrin deposits, the use of ASA
empirically makes sense, at least in those patients
with valvular lesions.
CONCLUSION
The aPLs are associated with arterial and venous
thromboses as well as cardiac valvular lesions. These
autoantibodies, rather than being a single or even a
homogeneous group, constitute a heterogeneous
family with different isotypes, different specificities,
different requirements of cofactor proteins, and
different immunochemical characteristics. The aPL-
P may interfere with the kinetics of coagulation
reactions or stimulate the prothrombotic activities of
endothelial cells and monocytes and promote coagu-
lation by complex molecular interactions. Approxi-
mately 10–15% of patients, despite presenting the
clinical picture of the aPS, have negative tests for
aCL and LA. Thus, in patients with high clinical
suspicion, further testing is indicated, such as
antibodies to b2-GPI, possibly to prothrombin, or
to noncardiolipin phospholipids.
—L. Dana DeWitt
See also–Arterial Thrombosis, Cerebral; Cerebral
Venous Thrombosis; Stroke Risk Factors;
Systemic Lupus Erythematosus (SLE)
Further Reading
Anti-phospholipid Antibodies in Stroke Study (APASS) Group
(1990). Clinical and laboratory findings in patients with anti-
phospholipid antibodies and cerebral ischemia. Stroke 21,
1268–1273.
ANTIPLATELET THERAPY 237
Anti-phospholipid Antibodies in Stroke Study (APASS)
Group (1993). Anticardiolipin antibodies are an independent
risk factor for first ischemic stroke. Neurology 43,
2069–2073.
Asherson, R. A., Khamashta, M. A., Ordi-Ros, J., et al. (1989).
The ‘‘primary’’ anti-phospholipid syndrome: Major clinical and
serological features. Medicine 68, 366–374.
Brandt, J. T., Triplett, D. A., Alving, B., et al. (1995). Criteria
for the diagnosis of the lupus anticoagulants: An update.
On behalf of the Subcommittee on Lupus Anticoagulant/
Anti-phospholipid Antibody of the Scientific and Standardiza-
tion Committee of the ISTH. Thromb. Haemost. 74,
1185–1190.
Hojnik, M., George, J., Ziporen, L., et al. (1996). Heart valve
involvement (Libman–Sacks endocarditis) in the anti-phospho-
lipid syndrome. Circulation 93, 1579–1587.
Khamashta, M. A., Cuadrado, M. J., Mujic, F., et al. (1995). The
management of thrombosis in the anti-phospholipid-antibody
syndrome. N. Engl. J. Med. 332, 993–997.
Tanne, D., Triplett, D. A., and Levine, S. R. (1998). Anti-
phospholipid-protein antibodies and ischemic stroke: Not just
cardiolipin any more. Stroke 29, 1755–1758.
Toschi, V., Motta, A., Castelli, C., et al. (1998). High prevalence of
antiphosphatidylinositol antibodies in young patients with
cerebral ischemia of undetermined cause. Stroke 29, 1759–
1764.
Antiplatelet Therapy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RECENT developments in the use of antiplatelet
therapy for prevention of stroke have been influenced
by two major, but necessarily opposing, trends in
clinical perspective: evidence-based medicine (EBM)
and individualized patient care. The first, concerned
with public health (i.e., the effect of antiplatelet
therapy on the collective of patients), has been
responsible for the widespread acceptance of new
antiplatelet agents. For EBM, the aim is to reduce the
incidence of stroke in the population. Nonetheless, a
few investigators recognize that what is true for the
collective, broadly understood in terms of averages,
may not necessarily apply to the individual patient,
who may be very different from the average patient.
This view derives from the results of tests that can be
done on the individual patient to measure the
antiplatelet effect of the antiplatelet drug at a given
point in time. It also reflects the fact that the
mathematical basis for EBM—probability—was
never meant to predict or reflect the individual
‘‘throw of the die.’’ This latter approach, although
not considered scientific, can be supported by a
206 ANTIANXIETY PHARMACOLOGY
transient spinal ischemic attacks may herald the
infarction. Independent from the localization of
the occlusion, spinal infarction in the distribution
of the ASA is characterized by the onset of bilateral
flaccid paresis or plegia below the lesion level, loss of
motor reflexes, and dissociated sensory loss. Bowel
and bladder paresis is frequent. Patients also
commonly complain of neck or back pain and
sometimes of a radicular-type pain. Moreover, if
the ASA gives off branches to the medulla oblongata,
a very high occlusion of the ASA may also produce
symptoms related to ischemia and infarction of the
medulla oblongata. The flaccid paresis or plegia
usually evolves progressively to spasticity with
hyperactive motor reflexes. In some cases, there is a
significant clinical improvement during the following
months, characterized by a partial recovery of
somatic motor function and voluntary sphincter
control.
Treatment is limited to a few etiologies, such as
hyperbaric therapy for caisson syndrome and surgery
for mechanical traumas. The role of heparinization
for ASA thrombosis is not yet defined. However,
supportive care and close neurological survey in a
stroke or intensive care unit are indicated for all
patients. When the acute phase of spinal injury
subsides, it is advisable to begin a rehabilitation
program.
—Paolo Biglioli
See also–Spinal Cord Anatomy; Spinal Stroke
Acknowledgments
This entry was written in cooperation with Maurizio Roberto,
Aldo Cannata, Francesco Grillo, and Rita Spirito.
Further Reading
Biglioli, P., Spirito, R., Roberto, M., et al. (2000). The anterior
spinal artery: The main arterial supply of the human spinal
cord–A preliminary anatomic study. J. Thorac. Cardiovasc.
Surg. 119, 376–379.
Fried, L. C., Di Chiro, G., and Doppman, J. L. (1969). Ligation of
major thoraco-lumbar spinal cord arteries in monkeys. J.
Neurosurg. 31, 608–614.
Mannen, T. (1966). Vascular lesions in the spinal cord of the aged.
Geriatrics 21, 151–160.
Sliwa, J. A., and Maclean, I. C. (1992). Ischemic myelopathy: A
review of spinal vasculature and related clinical syndromes.
Arch. Phys. Med. Rehab. 73, 365–372.
Thron, A. K. (1988). Vascular Anatomy of the Spinal Cord.
Neuroradiological Investigations and Clinical Syndromes.
Springer-Verlag, New York.
Towfighi, J., and Vannucci, R. C. (1997). Neuropathology of
normothermic circulatory arrest in newborn dogs. Acta
Neuropathol. 93, 485–493.
Wang, Y., and Hashizume, Y. (1996). Pathological study of age-
related vascular changes in the spinal cord. Nippon Ronen
Igakkai Zasshi 33, 563–568.
Yamada, T., Morimoto, T., Nakase, H., et al. (1998). Spinal
cord blood flow and pathophysiological changes after
transient spinal cord ischemia in rats. Neurosurgery 42,
626–634.
Antianxiety Pharmacology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TREATMENT of anxiety disorders is a complex
topic, given the number of specific anxiety disorders
and because treatment usually must be highly
tailored to the individual. Many different types of
psychotherapies, especially variants of cognitive and
behavioral psychotherapies, are successfully used in
the treatment of anxiety disorders, but often anti-
anxiety medications are essential for the relief of
symptoms and maintenance of remission. These
medications commonly include benzodiazepines,
serotonin-selective reuptake inhibitors (SSRIs), tri-
cyclic antidepressants (TCAs), monoamine oxidase
inhibitors (MAOIs), and other antidepressants (e.g.,
venlafaxine), buspirone, b-adrenergic blockers, and
antihistamines.
SEROTONIN-SELECTIVE REUPTAKE
INHIBITORS
Serotonin-selective reuptake inhibitors have been
found to be beneficial for a number of anxiety
disorders. Fluoxetine, sertraline, paroxetine, and
citalopram have demonstrated efficacy as antipanic
agents at doses comparable to those for the treatment
of major depressive disorder. A paradoxical activation
may occur in patients with panic disorder when SSRIs
are started, so a low starting dose and slow upward
titration are recommended. SSRIs generally take 2–4
weeks to exert their therapeutic effect. For patients
who respond to any medication for panic disorder, it
remains unclear how long to maintain patients on the
medication; common practice is to continue it for at
least 1 year. Relapse rates of 50–90% after disconti-
nuation of medication have been reported, although
some reports suggest that adjunctive cognitive–beha-
vioral therapy may help prevent relapse.

Obsessive–compulsive disorder (OCD) is recurring
and persistent thoughts that cause extreme anxiety or
depression. Fluoxetine, sertraline, paroxetine, and
fluvoxamine have been found to be effective in the
treatment of OCD, with approximately 60% of
patients responding at least partially. Efficacious
doses are often higher than those used in the
treatment of major depressive disorder, and it may
take several months before peak efficacy is reached.
Relapse rates are as high as 90% following dis-
continuation of medication, so long-term mainte-
nance treatment may be necessary.
A meta-analysis of published studies found that
clomipramine is significantly more effective than
SSRIs in the treatment of OCD, but direct compar-
isons have suggested equal efficacy. Paroxetine has
been approved in the United States for treatment of
social anxiety disorder, and studies suggest that other
SSRIs may also be effective. Compared to MAOIs,
SSRIs may be the first-line treatment for social
anxiety disorder due to their better side effect profile
and freedom from dietary restrictions. SSRIs have
also been studied as a treatment for post-traumatic
stress disorder (PTSD), although relatively few
randomized controlled trials have been performed.
These trials suggest that fluoxetine, sertraline, and
paroxetine may be beneficial for symptoms of the
disorder.
The therapeutic effects of SSRIs in anxiety
disorders result from the selective blockade of
serotonin reuptake into presynaptic neurons. Their
side effects as a class may include nausea, diarrhea,
insomnia or sedation, jitteriness, dry mouth, and
tremor. Another common side effect is sexual
dysfunction, which may be experienced as decreased
libido or arousal, impairment in erection or ejacula-
tion, or inorgasmia. Compared to TCAs, SSRIs have
fewer anticholinergic, antihistaminergic, and antia-
drenergic side effects; they also do not appear to be
associated with cardiac arrhythmias or conduction
delay, and they are relatively safe in overdose.
TRICYCLIC ANTIDEPRESSANTS
Among tricyclic antidepressants, imipramine and
clomipramine have been found in double-blind,
placebo-controlled studies to be effective as antipanic
medications. Other TCAs, such as desipramine,
amitriptyline, nortriptyline, and doxepin, may also
be effective in treating panic disorder. Patients with
panic disorder may be very sensitive to TCAs and
may initially experience a paradoxical activation,
ANTIANXIETY PHARMACOLOGY 207
with increased anxiety or excitation. Therefore,
TCAs should be started at a low dose, with slow
upward titration. The TCAs imipramine and ami-
triptyline may also be beneficial for addressing the
intrusive symptoms of PTSD, and evidence supports
the efficacy of clomipramine in the treatment of
OCD. It is thought that TCAs are effective for
anxiety disorders largely because these medications
inhibit the reuptake of norepinephrine and serotonin.
However, they also block histamine and muscarinic
acetylcholine receptors, which can cause an array of
side effects. In general, the secondary amines (e.g.,
desipramine and nortriptyline) tend to produce fewer
adverse effects than the tertiary amines (e.g.,
imipramine and amitriptyline).
Orthostatic hypotension is a common side effect
of TCAs, in part due to a1-adrenergic receptor
antagonism. TCAs also commonly cause sedation,
weight gain, and mild anticholinergic side effects,
including dry mouth, blurred vision, constipation,
and urinary hesitancy. TCAs can precipitate an
attack of narrow-angle glaucoma, so they must be
used with caution in patients with glaucoma. More
severe anticholinergic side effects, such as delirium,
agitation, ileus, and urinary retention, may also
occur, particularly if the patient is elderly, has
overdosed, or is taking other anticholinergic drugs.
Sexual dysfunction is another potential adverse
effect of TCAs; males may experience erectile
dysfunction, whereas impaired arousal and orgasm
may occur in both males and females. At therapeutic
doses, cardiac effects of TCAs may include sinus
tachycardia, prolonged QT intervals, flattened T
waves, and depressed ST segments. At higher plasma
levels (e.g., in overdose), TCAs may cause supraven-
tricular tachycardia, ventricular tachycardia or
fibrillation, and varying degrees of heart block.
Because TCAs slow intracardiac conduction, they
should be avoided in patients with preexisting
conduction defects. An overdose of TCAs may be
fatal; in addition to the severe anticholinergic side
effects and cardiac toxicity noted previously, symp-
toms may also include seizures, central nervous
system (CNS) depression, and respiratory arrest.
MONOAMINE OXIDASE INHIBITORS
Monoamine oxidase inhibitors are effective in the
treatment of panic disorder and social anxiety
disorder. Among the MAOIs, phenelzine as an
antianxiety agent has been studied the most, and
data support the efficacy of phenelzine in the
208 ANTIANXIETY PHARMACOLOGY
treatment of PTSD. In panic disorder, phenelzine has
been shown to block panic attacks and may be
slightly more effective than other pharmacological
agents in treating agoraphobia associated with the
illness. In PTSD, phenelzine may be particularly
beneficial in treating intrusive symptoms, such as
distressing dreams or recollections of the traumatic
event. MAOIs increase synaptic norepinephrine,
serotonin, and dopamine by inhibiting the enzyme
monoamine oxidase from metabolizing these mono-
amine transmitters. Adverse effects include ortho-
static hypotension, weight gain, sexual dysfunction,
edema, and insomnia. A life-threatening adverse
reaction is hypertensive crisis, which may occur when
patients ingest tyramine-containing foods or pressor
drugs. Tyramine-containing foods include certain
cheeses, red wine and beer, processed meats, pickled
fish, fava beans, sour cream, and avocado. Stimulants
and sympathomimetics, including nasal deconge-
stants containing pseudoephedrine, can cause hyper-
tensive crisis if they are taken with MAOIs. Because
of MAO inhibition in the gut, pressor substances are
free to enter the systemic circulation, which can result
in a sharp increase in blood pressure; clinical
symptoms may include severe headache, flushing,
palpitations, sweating, and nausea and vomiting. A
hypermetabolic crisis, sometimes called the serotonin
syndrome, can also occur when patients on MAOIs
ingest another agent that can increase serotonin levels
in the brain. Such agents include meperidine, SSRIs,
and some TCAs, especially clomipramine. Also
potentially life threatening, the syndrome may pre-
sent with autonomic instability, hyperthermia, rigid-
ity, myoclonus, altered consciousness, and seizures.
Although MAOIs are a safe, efficacious, and in-
expensive class of drugs, patients on these medica-
tions must have the ability to adhere to strict dietary
and medication restrictions to avoid a hypertensive or
hypermetabolic crisis. An overdose of MAOI is
extremely dangerous and symptoms may take up to
12 hr to appear. Intoxication is characterized by a
phase of agitation and autonomic excitation, which
may result in rhabdomyolysis and renal failure. The
symptoms may then progress to CNS depression,
coma, cardiovascular collapse, and death.
OTHER PHARMACOLOGICAL AGENTS
Other antidepressants that have been studied for the
treatment of anxiety disorders include venlafaxine
and nefazodone. Venlafaxine inhibits the reuptake of
serotonin and norepinephrine, as does nefazodone;
nefazodone also antagonizes the type 2A serotonin
receptor. In the United States, the extended-release
form of venlafaxine is approved for the treatment of
generalized anxiety disorder (GAD). Venlafaxine and
nefazodone have been studied for panic disorder and
social anxiety disorder, but their efficacy is not
currently well established in the literature. Studies
suggest that nefazodone may be helpful in PTSD, but
again, evidence from large-scale randomized con-
trolled trials is lacking.
Buspirone is an azapirone that is effective in the
treatment of GAD and has been found in randomized
clinical trials to be as effective as benzodiazepines for
this indication. The medication is structurally and
chemically unrelated to benzodiazepines, and it does
not act on g-aminobutyric acid receptors, as do the
benzodiazepines. Buspirone acutely has agonist
effects on the presynaptic serotonin 1A receptor
and also increases noradrenergic and dopaminergic
activity. It is thought that the anxiolytic effects of
buspirone might be attributed to the decrease in
serotonergic activity via its agonist effects on the
serotonin 1A receptor, but this is not entirely clear
since the agonist effects are acute, whereas the
clinical effects are delayed. Compared with benzo-
diazepines, buspirone offers several advantages as an
anxiolytic agent. Buspirone does not cause impair-
ment of cognition, and it has little risk of depen-
dence, abuse, or withdrawal. In addition, it is not
associated with sedation and does not potentiate the
effects of alcohol. Buspirone has relatively few
adverse effects, the most common being dizziness,
nausea, and headache. Unlike benzodiazepines,
which provide anxiolysis within hours, buspirone
takes 2–4 weeks to exert its therapeutic effect. It also
appears that buspirone is less effective in patients
who have previously taken benzodiazepines. Buspir-
one has not been found to be effective in the
treatment of panic disorder.
b-Adrenergic blockers (e.g., atenolol, metoprolol,
nadolol, and propanolol) may be effective in patients
with a specific, circumscribed social phobia, com-
monly referred to as performance anxiety. Although
much of the evidence is anecdotal, b-blockers may be
helpful for patients on an as-needed basis if they
develop anxiety in such situations as public speaking
or musical performance. If the specific social phobia
occurs unpredictably, standing doses of b-adrenergic
blockers may be helpful, but standing use has been
even less well studied than as-needed use. In
addition, b-adrenergic blockers have not been found
to be effective for generalized social phobia. In the

brain, these medications block the effects of norepi-
nephrine on postsynaptic b-adrenergic receptors;
peripherally, they inhibit the effects of epinephrine
and norepinephrine on b-adrenergic receptors in the
sympathetic nervous system. Peripheral b1-adrener-
gic receptors modulate chronotropic and inotropic
cardiac functioning, so b-adrenergic blockers de-
crease heart rate and contractility. The blockade of
b2-adrenergic receptors along airways and blood
vessels results in lower blood pressure and greater
airway resistance. It is thought that the anxiolytic
effects of b-adrenergic blockers are primarily asso-
ciated with their ability to decrease peripheral
somatic symptoms of anxiety. b-Adrenergic blockers
should be used with caution in patients with
congestive heart failure, preexisting bradycardia,
first-degree or greater heart block, and hyperthyroid-
ism. Although there are medications relatively
selective for b1-receptor blockade, they still have
some b2-antagonist activity, so caution is recom-
mended when using any b-adrenergic blocker in
patients with bronchial asthma or other obstructive
pulmonary disease. In patients with diabetes melli-
tus, b-adrenergic blockers may interfere with the
normal physiological response to hypoglycemia and
can mask its tachycardic symptoms. Common
adverse effects of b-adrenergic blockers include
hypotension and bradycardia; in some patients,
nausea, erectile dysfunction, dizziness, lethargy,
dysphoria, and fatigue may also develop. b-Adrener-
gic blockers have been associated with depression in
the past, but recent evidence suggests that this
relationship is not causal. When b-adrenergic block-
ers are discontinued, patients with preexisting angina
and hypertension may experience rebound worsening
of these conditions; thus, it is recommended that
these medications be gradually tapered when dis-
continuing treatment.
Antihistamines (e.g., hydroxyzine) are sometimes
used by clinicians to treat acute anxiety, especially if
the patient is at risk for benzodiazepine abuse or
dependence. It appears that the anxiolytic effects of
antihistamines are due to its blockade of central and
peripheral histamine H1 receptors. Possible adverse
effects include sedation, dizziness, hypotension, and
nausea. These medications may also cause mild
anticholinergic effects, such as dry mouth, blurred
vision, and constipation; in elderly patients, confu-
sion and toxicity may occur. The efficacy of
antihistamines in the treatment of anxiety disorders
has not been well studied.
—Kewchang Lee
ANTIBIOTICS 209
See also–Antidepression Pharmacology;
Antipsychotic Pharmacology; Anxiety Disorders,
Overview; Benzodiazepines; Depression; Panic
Disorder; Phobias
Further Reading
Hyman, S. E., Arana, G. W., and Rosenbaum, J. F. (1995).
Handbook of Psychiatric Drug Therapy. Little, Brown,
Boston.
Kaplan, H. I., and Sadock, B. J. (1996). Pocket Handbook of
Psychiatric Drug Treatment. Williams & Wilkins, Baltimore.
Papp, L. A. (2000). Anxiety disorders: Somatic treatment. In
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry VII
(B. J. Sadock and V. A. Sadock, Eds.), pp. 1490–1498.
Lippincott Williams & Wilkins, Philadelphia.
Reiman, E. M. (1997). Anxiety. In The Practitioner’s Guide to
Psychoactive Drugs (A. J. Gelenberg and E. L. Bassuk, Eds.),
pp. 229–242. Plenum, New York.
Antibiotics
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
A LARGE number of antibiotics have been developed
to combat bacterial infections, tuberculosis, and
fungal diseases. Several have significant neurotox-
icological effects that can be confused with primary
neurological infection. Rapid recognition and treat-
ment through withdrawal of the causative agent are
essential to effective therapy.
ANTIBACTERIAL AGENTS
Penicillins, cephalosporins, and imipenem can cause
jerking movements called myoclonus, seizures, con-
fusion, hallucinations, irregular eye movements
called nystagmus, and mental agitation. Of all agents
in this class, imipenem, cefazolin, and benzyl
penicillin are the most likely to promote seizures.
Penicillin gluteal injection may cause sudden and
irreversible paraplegia. The actual incidence of such
a complication is not known, but there have been
eight cases reported in the medical literature. The
proposed mechanism is accidental injection into an
artery, causing vascular spasm. This complication
can be prevented by giving injections in the lateral
thigh. Penicillins and cephalosporins have also been
reported to cause recurrent aseptic meningitis or
noninfectious inflammation of the meningeal lining
of the central nervous system. Ampicillin has been
reported to aggravate weakness in myasthenia gravis.

brain, these medications block the effects of norepi-
nephrine on postsynaptic b-adrenergic receptors;
peripherally, they inhibit the effects of epinephrine
and norepinephrine on b-adrenergic receptors in the
sympathetic nervous system. Peripheral b1-adrener-
gic receptors modulate chronotropic and inotropic
cardiac functioning, so b-adrenergic blockers de-
crease heart rate and contractility. The blockade of
b2-adrenergic receptors along airways and blood
vessels results in lower blood pressure and greater
airway resistance. It is thought that the anxiolytic
effects of b-adrenergic blockers are primarily asso-
ciated with their ability to decrease peripheral
somatic symptoms of anxiety. b-Adrenergic blockers
should be used with caution in patients with
congestive heart failure, preexisting bradycardia,
first-degree or greater heart block, and hyperthyroid-
ism. Although there are medications relatively
selective for b1-receptor blockade, they still have
some b2-antagonist activity, so caution is recom-
mended when using any b-adrenergic blocker in
patients with bronchial asthma or other obstructive
pulmonary disease. In patients with diabetes melli-
tus, b-adrenergic blockers may interfere with the
normal physiological response to hypoglycemia and
can mask its tachycardic symptoms. Common
adverse effects of b-adrenergic blockers include
hypotension and bradycardia; in some patients,
nausea, erectile dysfunction, dizziness, lethargy,
dysphoria, and fatigue may also develop. b-Adrener-
gic blockers have been associated with depression in
the past, but recent evidence suggests that this
relationship is not causal. When b-adrenergic block-
ers are discontinued, patients with preexisting angina
and hypertension may experience rebound worsening
of these conditions; thus, it is recommended that
these medications be gradually tapered when dis-
continuing treatment.
Antihistamines (e.g., hydroxyzine) are sometimes
used by clinicians to treat acute anxiety, especially if
the patient is at risk for benzodiazepine abuse or
dependence. It appears that the anxiolytic effects of
antihistamines are due to its blockade of central and
peripheral histamine H1 receptors. Possible adverse
effects include sedation, dizziness, hypotension, and
nausea. These medications may also cause mild
anticholinergic effects, such as dry mouth, blurred
vision, and constipation; in elderly patients, confu-
sion and toxicity may occur. The efficacy of
antihistamines in the treatment of anxiety disorders
has not been well studied.
—Kewchang Lee
ANTIBIOTICS 209
See also–Antidepression Pharmacology;
Antipsychotic Pharmacology; Anxiety Disorders,
Overview; Benzodiazepines; Depression; Panic
Disorder; Phobias
Further Reading
Hyman, S. E., Arana, G. W., and Rosenbaum, J. F. (1995).
Handbook of Psychiatric Drug Therapy. Little, Brown,
Boston.
Kaplan, H. I., and Sadock, B. J. (1996). Pocket Handbook of
Psychiatric Drug Treatment. Williams & Wilkins, Baltimore.
Papp, L. A. (2000). Anxiety disorders: Somatic treatment. In
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry VII
(B. J. Sadock and V. A. Sadock, Eds.), pp. 1490–1498.
Lippincott Williams & Wilkins, Philadelphia.
Reiman, E. M. (1997). Anxiety. In The Practitioner’s Guide to
Psychoactive Drugs (A. J. Gelenberg and E. L. Bassuk, Eds.),
pp. 229–242. Plenum, New York.
Antibiotics
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
A LARGE number of antibiotics have been developed
to combat bacterial infections, tuberculosis, and
fungal diseases. Several have significant neurotox-
icological effects that can be confused with primary
neurological infection. Rapid recognition and treat-
ment through withdrawal of the causative agent are
essential to effective therapy.
ANTIBACTERIAL AGENTS
Penicillins, cephalosporins, and imipenem can cause
jerking movements called myoclonus, seizures, con-
fusion, hallucinations, irregular eye movements
called nystagmus, and mental agitation. Of all agents
in this class, imipenem, cefazolin, and benzyl
penicillin are the most likely to promote seizures.
Penicillin gluteal injection may cause sudden and
irreversible paraplegia. The actual incidence of such
a complication is not known, but there have been
eight cases reported in the medical literature. The
proposed mechanism is accidental injection into an
artery, causing vascular spasm. This complication
can be prevented by giving injections in the lateral
thigh. Penicillins and cephalosporins have also been
reported to cause recurrent aseptic meningitis or
noninfectious inflammation of the meningeal lining
of the central nervous system. Ampicillin has been
reported to aggravate weakness in myasthenia gravis.
210 ANTIBIOTICS
Aminoglycosides include several drugs that can
damage the hearing system (ototoxicity) and block
the junction between the motor nerve cells and
muscle cells throughout the body. Acute ototoxicity
is based on drug-induced calcium antagonism and
blockade of ion channels, whereas chronic intoxica-
tion is related to tissue-specific toxicity of a noxious
metabolite. The frequency of ototoxicity ranges from
2 to 4% of exposed subjects in retrospective studies
and is up to 25% in studies that examine patients
with specialized audiological and vestibular testing.
The incidence and severity of damage appear to
increase with patient’s age, total drug dose, and
concomitant use of other ototoxic drugs. Auditory
toxicity is more common with the use of amicacin
and kanamycin, whereas vestibular toxicity predo-
minates following gentamycin and streptomycin
therapy. Tobramycin is associated equally with
vestibular and auditory damage. These drugs can
damage the important hearing organ known as the
cochlea. Cochlear toxicity is more often silent
because the hearing loss first affects the high
frequencies (44000 Hz) before involving the
speech-sensitive frequencies. Cochlear toxicity pre-
sents clinically as deafness, ringing of the ears
(tinnitus), and ear pain, whereas vestibular toxicity
symptoms include unsteadiness, dizziness, vertigo or
spinning sensations, a chronic sense of imbalance,
and jerking eye movements known as nystagmus.
Routine audiometry and/or studies of auditory
brainstem evoked responses can be used to monitor
ototoxicity. Monitoring vestibular toxicity is com-
plex and needs even more specialized testing.
Aminoglycoside-induced hearing loss is usually
irreversible and may even progress following dis-
continuation of drug therapy. Careful monitoring of
peak and trough levels in the blood during therapy,
especially in high-risk groups, helps prevent toxicity.
A potentially fatal neurotoxic effect of all amino-
glycosides is neuromuscular blockade; therefore,
these drugs are not used in botulism, myasthenia
gravis, and other disorders in which transmission
between motor nerve cells and muscle cells is already
impaired. They may further potentiate ether and
other drugs used to induce muscular relaxation
during anesthesia. Neomycin and neltimycin are the
most toxic, and tobramycin and kanamycin are the
least toxic for neuromuscular blockade. Sudden or
prolonged respiratory paralysis due to aminoglyco-
sides may be reversed by calcium infusion and by the
use of drugs known as cholinesterase inhibitors and
aminopyridines.
Sulfonamides inhibit the synthesis of tetrahydro-
folinic acid, the one carbon donor needed for the
synthesis of important chemicals including methio-
nine, serine, and purines. Although they are asso-
ciated with a low incidence of neurotoxicity, a
variety of adverse reactions can occur during therapy.
Recurrent noninfectious (aseptic) meningitis is a
well-recognized side effect of sulfonamide therapy,
more specifically trimethoprim-sulfamethoxazole,
and presents clinically with episodes of headache,
neck rigidity, confusion, and muscle aches, called
myalgias. In addition, isolated headache without
meningitis, fatigue, tinnitus, generalized convulsions,
inflammation of the optic nerve, stammering speech,
diffuse inflammation of peripheral nerves (polyneur-
itis), and spinal cord problems (myelopathy) can
occur with sulfonamides. Euphoria, nausea, vomit-
ing, somnolence, concentrational difficulties, and
judgment impairment may be observed on the second
or third day of treatment. The pathophysiology of
the neurotoxic signs may relate to a drug-induced
hypersensitivity reaction since these neurological
problems often occur in the context of a generalized
immune reaction called serum sickness or drug-
induced vasculitis.
Quinolones are associated with the induction of
seizures, and the use of nalidixic acid (the first
clinically useful quinolone) is contraindicated in
patients with a history of epilepsy. The mechanism
of this epileptogenic effect may be due to inhibition
of the binding of the neurochemical, g-aminobutyric
acid (GABA), to its receptor site in the brain. This
effect seems to be related to quinolone concentra-
tions at the receptor site and to particular substitutes
in quinolone structure. Central nervous system side
effects are seen in 1–4% of exposed patients, and
other than seizures, side effects are usually minor,
including dizziness or mild headache. Quinolones
have been reported to cause tremor, restlessness,
hallucinations, delirium, psychosis, and increased
intracranial pressure, especially in high-dose therapy.
Because neurotoxic signs are often dependent on the
blood levels of these drugs, doses should be carefully
monitored to avoid central nervous system toxicity,
especially in patients with renal impairment.
Metronidazole, a nitroimidazole derivative, is used
for certain infections, especially anaerobic bacteria
and protozoa, as well as for the treatment of Crohn’s
disease. Although it is generally well tolerated and
associated with only minor, transient adverse side
effects, metronidazole can induce a severe peripheral
neuropathy. The mechanism of metronidazole per-

ipheral neuropathy is undetermined, but in experi-
mental animal studies the drug binds to the RNA of
nerve cells, which may diminish protein synthesis
and lead to subsequent nerve degeneration. Neuro-
pathy is particularly prevalent in patients who
receive high doses and long treatment. In long-term
administration, 10–50% of patients develop a
sensory neuropathy that is predominantly distal
and symmetrical. Sensory deficits are prominent,
with two nerves in the leg most often affected, the
sural and peroneal nerves. Metronidazole has rarely
been associated with seizures in humans.
Erythromycin and the macrolide group of anti-
biotics are among the safest anti-infective drugs in
clinical use. An uncommon neurological side effect is
temporary hearing loss that occurs at high doses.
Since erythromycin is metabolized by the liver,
patients with hepatic abnormalities may be at higher
risk for this ototoxic reaction. Ringing in the ears, or
tinnitus, is the usual complaint rather than distinct
difficulty hearing. The new macrolides, azithromycin
and clarithromycin, have not been found to cause
ototoxicity.
Erythromycin interacts with the anticonvulsant
drug carbamazepine, which is frequently used to
treat epilepsy. When the two drugs are ingested
simultaneously, carbamazepine levels increase; there-
fore, careful monitoring of the carbamazepine blood
level and clinical symptoms of toxicity should be
performed in patients receiving both drugs. Worsen-
ing of weakness in patients with myasthenia gravis
can also occur due to the antibiotic effect on nerve
cells at the neuromuscular junction.
Tetracycline is relatively devoid of serious neuro-
logical side effects, but its derivative, minocycline,
causes vestibular toxicity in approximately 50% of
patients, more often in women than men. Although
vestibular toxicity is more likely in patients with
preexisting vestibular disease, many patients have no
such history. The symptoms begin a few days after
the initiation of treatment and consist of light-
headedness, dizziness, loss of balance, nausea, and
extreme vertigo or spinning sensations. The reaction
is transient, and even in the most severe cases it
generally resolves within a few days.
Increased intracranial pressure, causing the syn-
drome pseudotumor cerebri, can occur rarely in
subjects taking tetracyclines. Infants, children, and
adults may be affected with headache, optic disk
swelling called papilledema, and elevated cerebrosp-
inal fluid pressure, and bulging fontanelles may occur
in infants. Signs and symptoms disappear a few days
ANTIBIOTICS 211
after drug discontinuation, although papilledema
may persist for weeks. The intravenous administra-
tion of tetracyclines has been rarely reported to
exacerbate myasthenia gravis.
Nitrofurantoin therapy has been associated with
polyneuropathy. Generally, it begins after several
days of therapy and the patient experiences tingling
of the distal extremities (paresthesias) and progres-
sive weakness and loss of deep tendon reflexes.
Although this polyneuropathy clinically resembles
Guillain–Barré syndrome, the spinal fluid evaluation
is usually normal. Recovery is usually complete, but
10–15% of patients will not improve and 15% will
have only partial recovery. The prognosis appears to
the extent of the neuropathy at the time of drug
withdrawal.
ANTITUBERCULOUS DRUGS
Isoniazid interacts with vitamin B6 (pyridoxine) and
can be associated with seizures and peripheral
neuropathy. The incidence of pyridoxine-associated
polyneuropathy is 0.2–2%, and the clinical features
include numbness and tingling of the feet with
diminished or absent deep tendon reflexes and
occasional optic neuropathy. Isoniazid-associated
neuropathy can be prevented by concomitant admin-
istration of pyridoxine, 50 mg/day. Acute isoniazid
intoxication due to overdosage is associated with
generalized seizures, gait instability, psychosis, and
coma. Metabolic acidosis and high blood glucose
levels (hyperglycemia) accompany the acute neuro-
logical syndrome. Pyridoxine should be administered
immediately, along with standard anticonvulsant and
supportive measures. Since seizures are a complica-
tion of isoniazid therapy, the drug is not recom-
mended for patients with preexisting seizure
disorders if another drug can be chosen. More
unusual isoniazid-related neurotoxic syndromes in-
clude drug-induced (aseptic) meningitis, psychosis,
obsessive–compulsive disorder, and acute mania.
Rifampin may induce altered behavior and psy-
chosis. Other rare adverse reactions are dizziness,
headache, drowsiness, confusion, inability to con-
centrate, and unsteadiness. Rarely, paresthesias and
pain suggestive of peripheral neuropathy occur.
Ethambutol is associated with optic neuropathy,
and the nerve loses its myelin covering (demyelinat-
ing neuropathy). Symptoms are seen in as many as
one-third of patients taking doses of 35 mg/kg/day
for 6 months. The safe maintenance dose is 15 mg/
kg/day. Loss of visual acuity develops along with
212 ANTICOAGULANT TREATMENT
diminished color discrimination, constricted visual
fields, and central and peripheral blind spots or
scotoma. The drug should be stopped at the first sign
of visual change, and recovery can be anticipated,
although it may take weeks or even months. Other
side effects include mild peripheral neuropathy and a
metallic taste in the oral cavity.
ANTIFUNGAL DRUGS
Amphotericin B binds to myelin, the substance that
covers nerve axonal projections in the central
nervous system. As a result, the drug causes an
increase in membrane permeability, resulting in
leakage of intracellular components. Clinically,
patients develop a subacutely evolving neurological
disorder characterized by personality change and
confusion that, when severe, can rapidly progress to
a syndrome known as akinetic mutism, in which the
subject appears to be in a coma. Neuroimaging
studies disclose diffuse nonenhancing lesions of the
cerebral white matter where the myelin normally
resides. This amphotericin-associated disorder that
selectively affects the cerebral white matter (leukoen-
cephalopathy) can be fatal, although there have been
cases of slow recovery after drug discontinuation.
Polymyxin B causes neurotoxicity in approxi-
mately 7% of exposed subjects. Most serious is its
inhibitory effect on the neuromuscular junction,
where peripheral nerves activate muscle. Weakness,
even so severe as to provoke respiratory compromise,
can develop, especially in subjects with renal
disorders or when polymyxin B is administered in
combination with other drugs known to block
neuromuscular transmission. Other adverse effects
of polymyxins include paresthesias, peripheral neu-
ropathy, double vision, difficulty swallowing, dizzi-
ness, incoordination, seizures, and confusion.
—Katie Kompoliti and Christopher G. Goetz
See also–Akinetic Mutism; Immune System,
Overview; Neurotoxicology, Overview
Further Reading
Holdiness, M. R. (1987). Neurological manifestations and
toxicities of the antituberculosis drugs. A review. Med. Toxicol.
2, 33–51.
Klein, N. C., and Cunha, B. A. (1995). Tetracyclines. Med. Clin.
North Am. 79, 789–801.
Kompoliti, K. (1998). Drug-induced and iatrogenic neurological
disorders. In Textbook of Clinical Neurology (C. G. Goetz and
E. J. Pappert, Eds.), pp. 1123–1152. Saunders, Philadelphia.
Lortholary, O., Tod, M., Cohen, Y., et al. (1995). Aminoglyco-
sides. Med. Clin. North Am. 79, 761–787.
River, Y., Averbuch-Heller, L., Weinberger, M., et al. (1994).
Antibiotic induced meningitis. J. Neurol. Neurosurg. Psychiatry
57, 705–708.
Sacristan, J. A., Soto, J. A., and de Cos, M. A. (1993).
Erythromycin-induced hypoacusis: 11 new cases and literature
review. Ann. Pharmacother. 27, 950–955.
Thomas, R. J. (1994). Neurotoxicity of antibacterial therapy.
South. Med. J. 87, 869–874.
Walker, R. W., and Rosenblum, M. K. (1992). Amphotericin B-
associated leukoencephalopathy. Neurology 42, 2005–2010.
Anti-Cardiolipid Antibodies
see Anti-Phospholipid Antibodies
Anticoagulant Treatment
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE NORMAL vascular system and circulating blood
elements contain a host of processes that maintain
the fluidity of the blood while having the capability
of forming thrombus to prevent bleeding. The
normal vascular endothelium inhibits adhesion of
platelets and thrombus formation, but immediately
beneath the endothelial surface are powerful stimu-
lants to thrombus formation upon injury that prevent
exsanguination. Prothrombin and fibrinogen are
circulating proteins destined to form the building
blocks of a thrombus at a site of vascular injury.
There are also circulating inhibitors of coagulation,
including antithrombin III, protein S, and protein C.
Heparin is another naturally occurring anticoagulant
that can bind to antithrombin and thereby markedly
accelerate its ability to inactivate procoagulant
enzymes.
HEPARIN
Heparin is the most commonly used parenteral
anticoagulant. This unfractionated heparin is derived
from bovine lung or porcine gut tissue. Heparin is a
glycosaminoglycan of varying molecular weight that
binds to antithrombin III to inactivate factors IIa and
Xa. Its major anticoagulant effect is due to a unique
212 ANTICOAGULANT TREATMENT
diminished color discrimination, constricted visual
fields, and central and peripheral blind spots or
scotoma. The drug should be stopped at the first sign
of visual change, and recovery can be anticipated,
although it may take weeks or even months. Other
side effects include mild peripheral neuropathy and a
metallic taste in the oral cavity.
ANTIFUNGAL DRUGS
Amphotericin B binds to myelin, the substance that
covers nerve axonal projections in the central
nervous system. As a result, the drug causes an
increase in membrane permeability, resulting in
leakage of intracellular components. Clinically,
patients develop a subacutely evolving neurological
disorder characterized by personality change and
confusion that, when severe, can rapidly progress to
a syndrome known as akinetic mutism, in which the
subject appears to be in a coma. Neuroimaging
studies disclose diffuse nonenhancing lesions of the
cerebral white matter where the myelin normally
resides. This amphotericin-associated disorder that
selectively affects the cerebral white matter (leukoen-
cephalopathy) can be fatal, although there have been
cases of slow recovery after drug discontinuation.
Polymyxin B causes neurotoxicity in approxi-
mately 7% of exposed subjects. Most serious is its
inhibitory effect on the neuromuscular junction,
where peripheral nerves activate muscle. Weakness,
even so severe as to provoke respiratory compromise,
can develop, especially in subjects with renal
disorders or when polymyxin B is administered in
combination with other drugs known to block
neuromuscular transmission. Other adverse effects
of polymyxins include paresthesias, peripheral neu-
ropathy, double vision, difficulty swallowing, dizzi-
ness, incoordination, seizures, and confusion.
—Katie Kompoliti and Christopher G. Goetz
See also–Akinetic Mutism; Immune System,
Overview; Neurotoxicology, Overview
Further Reading
Holdiness, M. R. (1987). Neurological manifestations and
toxicities of the antituberculosis drugs. A review. Med. Toxicol.
2, 33–51.
Klein, N. C., and Cunha, B. A. (1995). Tetracyclines. Med. Clin.
North Am. 79, 789–801.
Kompoliti, K. (1998). Drug-induced and iatrogenic neurological
disorders. In Textbook of Clinical Neurology (C. G. Goetz and
E. J. Pappert, Eds.), pp. 1123–1152. Saunders, Philadelphia.
Lortholary, O., Tod, M., Cohen, Y., et al. (1995). Aminoglyco-
sides. Med. Clin. North Am. 79, 761–787.
River, Y., Averbuch-Heller, L., Weinberger, M., et al. (1994).
Antibiotic induced meningitis. J. Neurol. Neurosurg. Psychiatry
57, 705–708.
Sacristan, J. A., Soto, J. A., and de Cos, M. A. (1993).
Erythromycin-induced hypoacusis: 11 new cases and literature
review. Ann. Pharmacother. 27, 950–955.
Thomas, R. J. (1994). Neurotoxicity of antibacterial therapy.
South. Med. J. 87, 869–874.
Walker, R. W., and Rosenblum, M. K. (1992). Amphotericin B-
associated leukoencephalopathy. Neurology 42, 2005–2010.
Anti-Cardiolipid Antibodies
see Anti-Phospholipid Antibodies
Anticoagulant Treatment
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE NORMAL vascular system and circulating blood
elements contain a host of processes that maintain
the fluidity of the blood while having the capability
of forming thrombus to prevent bleeding. The
normal vascular endothelium inhibits adhesion of
platelets and thrombus formation, but immediately
beneath the endothelial surface are powerful stimu-
lants to thrombus formation upon injury that prevent
exsanguination. Prothrombin and fibrinogen are
circulating proteins destined to form the building
blocks of a thrombus at a site of vascular injury.
There are also circulating inhibitors of coagulation,
including antithrombin III, protein S, and protein C.
Heparin is another naturally occurring anticoagulant
that can bind to antithrombin and thereby markedly
accelerate its ability to inactivate procoagulant
enzymes.
HEPARIN
Heparin is the most commonly used parenteral
anticoagulant. This unfractionated heparin is derived
from bovine lung or porcine gut tissue. Heparin is a
glycosaminoglycan of varying molecular weight that
binds to antithrombin III to inactivate factors IIa and
Xa. Its major anticoagulant effect is due to a unique

pentasaccharide with high-affinity binding to antith-
rombin. Unfractionated heparin is quite heteroge-
neous, containing saccharides ranging in molecular
weight from 5 to 30 kDa. Only approximately one-
third of the unfractionated heparin molecules have
anticoagulant activity. This heterogeneity is one of
the reasons for the variability in the anticoagulant
effect of heparin administration among individuals.
The most common side effect of heparin administra-
tion is bleeding. Other complications include throm-
bocytopenia, osteoporosis, skin necrosis, alopecia,
hypersensitivity reactions, and hypoaldosteronism.
Thrombocytopenia is more common with heparin
derived from bovine lung than from porcine gut. The
thrombocytopenia is thought to occur because of the
binding of an immunoglobulin to heparin. Throm-
bocytopenia occurs in between 0.3% (in prophylac-
tic use) and 2.4% (with higher therapeutic doses) of
treated patients. Low-molecular-weight heparin re-
presents a fragment of a standard heparin, with
lower molecular weight, higher bioavailability, long-
er half-life, and more predictable anticoagulant
effects. It is believed to have fewer bleeding
complications and fewer interactions with platelets;
however, this remains controversial. Heparinoids are
analogs of heparin that inhibit factor Xa, have a
longer half-life than that of unfractionated heparin,
and have fewer bleeding complications.
ANTICOAGULATION FOR ACUTE
ISCHEMIC STROKE
Heparin has a long history of use in the setting of
acute ischemic stroke and transient ischemic attack.
Widespread use continues despite a lack of convin-
cing evidence of efficacy from large well-designed
clinical treatment trials. The use of heparin in the
setting of acute ischemic stroke is based on a number
of potential effects, including its antithrombotic
effect, which prevents deep venous thrombosis
(DVT) and pulmonary embolus and is theorized to
prevent recurrent or progressive stroke.
The rationale for early institution of anticoagulant
therapy in acute ischemic stroke is twofold. First,
heparin therapy is associated with a highly significant
reduction in the risk of DVT and pulmonary
embolism. DVT complicates stroke in up to 75%
of patients, and 5% of early deaths are due to
pulmonary emboli. Second, the role that the intra-
arterial thrombus (or embolus) plays regarding
neurological deterioration in the setting of acute
stroke must be considered. The neurological status of
ANTICOAGULANT TREATMENT 213
approximately 30% of patients with minor stroke
who initially appear stable or to be improving will
deteriorate in a gradual or stepwise progression
within 24 hr after the onset of stroke. This
neurological deterioration may be due to one or a
combination of several mechanisms, including pro-
pagation of an intra-arterial thrombus, reemboliza-
tion from a cardiac or proximal arterial source,
evolving cerebral edema, or vasospasm. Systemic
factors, such as hypotension, hypoxia, infection, and
metabolic or drug effect, may also cause neurological
deterioration. An intra-arterial occlusion (thrombus
or embolism) may enlarge due to stagnation of flow,
further compromising the collateral blood supply to
the ischemic region.
The major recent randomized trials that have
examined heparins and acute stroke include the Trial
of ORG 10172 in Acute Stroke Treatment (TOAST),
the International Stroke Trial, and the fraxaripine
trials. The TOAST study showed no difference in
favorable outcome at 3 months. The International
Stroke Trial showed identical 6-month event rates of
death and dependency. The first fraxaripine study
showed a reduction in death and dependency in the
high-dose group but the repeat larger trial failed to
show benefit. Thus, recent randomized trials have
failed to demonstrate an overall benefit to acute
anticoagulation of ischemic stroke. The TOAST
study examined ORG 10172 given intravenously
versus placebo for 7 days in patients with acute
ischemic stroke of less than 24-hr duration. Overall,
there was no benefit to anticoagulant therapy;
however, when subgroups were analyzed there was
a possible benefit in the group of patients with an
atherosclerotic mechanism for their ischemic stroke.
The benefits overall to anticoagulation in the TOAST
trial were offset by an increased risk for major
hemorrhage. The American College of Chest Physi-
cians guidelines addressed the use of heparin for
acute stroke. After a review of studies, it concluded
that the evidence for the routine use of heparin is
inconclusive, with heparin still an option for
cardioembolic and large artery atherothrombotic
stroke, progressing stroke from ongoing presumed
thromboembolism, and cardiac abnormalities with a
high risk for recurrent cardioembolic stroke. In
summary, it indicates that ‘‘there is still a consider-
able debate regarding the appropriate use of heparin
and low-molecular-weight heparin for the treatment
of acute stroke.’’ Acute anticoagulation is commonly
used for a number of conditions, including progres-
sive stroke, cardiac sources with embolus with a high
214 ANTICOAGULANT TREATMENT
risk for recurrence, carotid or vertebral artery
dissection, venous sinus thrombosis, the antipho-
spholipid antibody syndrome, tight stenosis of a
major cerebral artery, and intraluminal thrombus
demonstration. Despite the absence of definitive
proof of its benefit for acute stroke, heparin is widely
endorsed by neurologists.
ORAL ANTICOAGULATION FOR
PREVENTION OF STROKE
During the late 1950s through the 1970s, a number
of studies favored oral anticoagulants (OAs) as
prophylactic therapy for patients with transient
ischemic attack (TIA) or minor stroke. These studies
were largely case series with nonrandomized com-
parisons, making interpretation of the results incon-
clusive. Four very small randomized trials performed
approximately 30 years ago compared OAs to no
therapy in patients with TIA in the carotid and
vertebral artery territories. The total number of
patients treated with OAs in the four studies was
only 93—too small for meaningful statistical analy-
sis. Other methodological flaws included incomplete
OA administration, short and incomplete follow-up,
and poor characterization of stroke subtype (studies
preceded computed tomography and echocardiogra-
phy). Aggregate results suggested a benefit of OAs
for stroke prevention (9%/year control and 3%/year
OA; p40:05), but these results are inconclusive. In
short, no convincing evidence exists to assess the
value of OAs for secondary prevention for patients
with primary occlusive cerebrovascular disease.
ORAL ANTICOAGULANTS FOR
CARDIOGENIC EMBOLISM
Cardiogenic embolism accounts for approximately
20% of all ischemic strokes and as much as 35% in
younger patients. Nonvalvular atrial fibrillation
(NVAF) is the most frequent substrate for cardioem-
bolic stroke. Acute myocardial infarction, ventricular
aneurysm, rheumatic heart disease, and prosthetic
cardiac valves comprise the majority of the remain-
ing causes of cardiogenic emboli leading to brain
ischemia.
Nonvalvular Atrial Fibrillation
Atrial fibrillation is a common arrhythmia that is an
important independent risk factor for stroke. AF is
present in more than 2 million Americans and the
prevalence increases rapidly after the age of 65. Each
year, approximately 50,000 Americans suffer the
devastating consequences of stroke as a result of AF.
The median age of stroke patients with AF is
approximately 75 years. NVAF is the most frequent
cardiac abnormality responsible for cardioembolic
stroke. The stroke rate of patients with AF is
approximately six times that of otherwise similar
people without AF. Within the broad spectrum of
patients with AF, the risk for arterial thromboembo-
lism is not uniform and subgroups at greater and
lesser risk clearly exist. It is critical to identify
subgroups of patients with AF with higher or lower
risk for arterial thromboembolism because it may
influence decisions regarding optimal antithrombotic
prophylaxis. The risk of stroke varies greatly
depending on age and coexisting cardiovascular
disease. Patients younger than 65 years of age with
no hypertension, diabetes, history of TIA or stroke,
or cardiovascular disease have a very low risk of
stroke (annual rate of 1%). In a pooled analysis of
individual patient data by the Atrial Fibrillation
Investigators, four clinical features were identified by
multivariable analysis to be significantly and inde-
pendently associated with increased risk for arterial
thromboembolism: previous stroke or TIA, diabetes
mellitus, history of hypertension, and increasing age.
Six recent randomized clinical trials evaluated the
relative efficacy and safety of warfarin or aspirin
compared to placebo in patients with asymptomatic
NVAF. Overall, these trials demonstrated the super-
ior therapeutic effect of warfarin compared to
placebo in the prevention of thromboembolic events.
Combining the results of these trials by intention-to-
treat analysis revealed an annual stroke rate of 4.5%
for the control patients and 1.4% for the warfarin-
treated patients (risk reduction of 68%). Most of the
patients who suffered strokes in the warfarin group
were not receiving therapy or were significantly
underanticoagulated at the time of the event. Patients
who decline anticoagulation or who are poor
candidates for anticoagulation therapy should be
given 325 mg/day aspirin.
Ischemic Heart Disease
Long-term anticoagulation reduces the rate of
ischemic stroke by approximately 75% in patients
with prior myocardial infarction (MI), but the
absolute rate reduction is only approximately 1%
per year among unselected survivors of MI. Although
OAs [International Normalized Ratio (INR) 2.5–4.8]
effectively lower the rate of ischemic stroke approxi-
mately 1% per year, they increase the rate of more

severe hemorrhagic strokes by approximately 0.4%
per year so that the net benefit to the brain is minimal
for unselected survivors of MI who have received
anticoagulation therapy at these intensities.
Mechanical Prosthetic Valves
Long-term (permanent) anticoagulation therapy is
indicated for patients with mechanical prosthetic
cardiac valves. However, the optimal anticoagulation
intensity that balances embolism prophylaxis with
bleeding complications has not been firmly estab-
lished. An INR in the range of 2.5–3.6 appears to be
effective in reducing the risk of thromboembolic
events and in minimizing the risk of bleeding in
patients with mechanical cardiac valves.
Bioprosthetic Valves
Because the incidence of thromboembolic events is
highest in the first 3 months after surgery, early
anticoagulation is recommended. Among patients
with bioprosthetic valves who are in sinus rhythm,
long-term therapy with 325 mg/day aspirin may offer
protection against thromboembolism. In patients
with AF, left atrial enlargement, or previous throm-
boembolism, the risk of systemic emboli is persis-
tently high, so lifelong anticoagulation is
recommended.
Rheumatic Valve Disease
For patients with rheumatic mitral valve disease with
a history of systemic emboli, atrial fibrillation, or
enlarged left atrium (45.5 cm), long-term warfarin
therapy is recommended. The decision to antic-
oagulate other patients with rheumatic mitral valve
disease is less clear and must be made on an
individual basis guided by comorbid cardiac risk
factors.
Patent Foramen Ovale
The management of patients with ischemic stroke
and a patent foramen ovale remains unclear. For
asymptomatic patent foramen ovale (no stroke), no
antithrombotic therapy is recommended. The risk of
recurrent paradoxical emboli in patients with a
patent foramen ovale in whom no source of emboli
is identified is uncertain. In isolated patent foramen
ovale and unexplained TIA or stroke with no
evidence of venous embolic source, antiplatelet
therapy seems reasonable. If concomitant venous
thrombosis is documented by venogram or Doppler
sonography, it is strongly recommended that patients
be treated with long-term anticoagulation therapy.
ANTICOAGULANT TREATMENT 215
CONCLUSION
Anticoagulation is important in the therapeutic
armamentarium for stroke. In the setting of acute
ischemic stroke, anticoagulation has proven benefit
in preventing DVT and associated pulmonary embo-
lism. Although firm proof of benefit in prevention of
early stroke progression or recurrence is lacking from
modern, large randomized clinical trials, anticoagu-
lation continues to be used in specific stroke
situations. Chronic anticoagulation is definitely of
benefit in preventing stroke in certain cardiac
conditions with a high risk of propelling emboli into
the brain’s arterial tree. The most notable and
uncontroversial cardiac abnormalities benefited by
long-term anticoagulation are atrial fibrillation,
mechanical prosthetic valve placement, and rheu-
matic valvular disease. Use of low-molecular-weight
heparins and heparinoids is increasingly displacing
unfractionated heparin use because of their greater
ease of use and possibly their reduced risk of bleeding
complications. The use of anticoagulants in stroke
management will continue for the foreseeable future.
—David G. Sherman
See also–Antiplatelet Therapy; Arterial
Thrombosis, Cerebral; Embolism, Cerebral;
Stroke, Overview; Stroke, Thrombolytic
Treatment of
Further Reading
Albers, G., Amarenco, P., Easton, J. D., et al. (2001). Antithrom-
botic and thrombolytic therapy for ischemic stroke. Chest 119,
300S–320S.
Atrial Fibrillation Investigators (1994). Risk factors for stroke and
efficacy of antithrombotic therapy in atrial fibrillation. Analysis
of pooled data from five randomized controlled trials. Arch.
Intern. Med. 154, 1449–1457. [published erratum appears in
Arch. Intern. Med. 154, 2254, 1994].
Cairns, J. A., Theroux, P., Lewis, H. D., et al. (2001).
Antithrombotic agents in coronary artery disease. Chest 119,
228S–252S.
Cerebral Embolism Task Force (1989). Cardiogenic brain embo-
lism. The second report of the Cerebral Embolism Task Force.
Arch. Neurol. 46, 727–743.
Harker, L. A., and Mann, K. G. (1998). Thrombosis and
fibrinolysis. In Cardiovascular Thrombosis: Thrombocardiol-
ogy and Thromboneurology (M. Verstraete and V. Fuster, Eds.),
pp. 3–22. Lippincott–Raven, Philadelphia.
Hirsh, J., and Granger, C. (1998). Unfractionated and low mole-
cular weight heparin. In Cardiovascular Thrombosis: Throm-
bocardiology and Thromboneurology (M. Verstraete and V.
Fuster, Eds.), pp. 189–219. Lippincott–Raven, Philadelphia.
International Stroke Trial Collaborative Group (1997). The
International Stroke Trial (IST): A randomised trial of aspirin,
216 ANTIDEPRESSION PHARMACOLOGY

subcutaneous heparin, both, or neither among 19,435 patients Table 1 CLASSES OF ANTIDEPRESSANTS
with acute ischaemic stroke [see Comments]. Lancet 349,
1569–1581. Generic name Brand name
Kay, R., Wong, K. S., Yu, Y. L., et al. (1995). Low-molecular-
weight heparin for the treatment of acute ischemic stroke [see Tricyclic antidepressants (TCAs)
Comments]. N. Engl. J. Med. 333, 1588–1593. Amitriptyline Elavil
Publications Committee for the Trial of ORG 10172 in Acute Clomipramine Anafranil
Stroke Treatment (TOAST) Investigators (1998). Low molecu- Desipramine (Is 21 amine, metabolite of Norpramin
lar weight heparinoid, ORG 10172 (danaparoid), and outcome imipramine)
after acute ischemic stroke: A randomized controlled trial [see
Doxepin Sinequan
Comments]. J. Am. Med. Assoc. 279, 1265–1272.
Salem, D. N., Daudelin, H. D., Levine, H. J., et al. (2001). Imipramine Tofranil
Antithrombotic therapy in valvular heart disease. Chest 119, Nortriptyline (Is 21 amine, metabolite of Pamelor
207S–219S. amitriptyline)
Stein, P. D., Alpert, J. S., Bussey, H. I., et al. (2001).
Antithrombotic therapy in patients with mechanical and Monoamine oxidase inhibitors (MAOIs)
biological prosthetic heart valves. Chest 119, 220S–227S.
Isocarboxazid Marplan
Phenelzine Nardil
Tranylcypromine Parnate

Selective serotonin reuptake inhibitors (SSRIs)

Antidepression Pharmacology Citalopram Celexa
Encyclopedia of the Neurological Sciences Escitalopram Lexapro
Copyright 2003, Elsevier Science (USA). All rights reserved.
Fluoxetine Prozac
Fluvoxamine Luvox
DEPRESSION is a common ailment with a lifetime Paroxetine Paxil
prevalence of 21% in women and 13% in men. Sertraline Zoloft
Although patients with this disorder often feel
hopeless, depression is actually quite amenable to Atypical antidepressants
treatment, with response rates ranging from 60 to Bupropion (slow release) Wellbutrin
80%. Antidepressant medications have been avail- SR (aka
able since the 1960s, and clinicians can choose from Zyban)
a variety of different classes with differing mechan- Bupropion Wellbutrin
isms of action and side effect profiles. Classes include Mirtazapine Remeron
the tricyclic antidepressants (TCAs), the monoamine Nefazodone Serzone
oxidase inhibitors (MAOIs), the selective serotonin Trazodone Desyrel
reuptake inhibitors (SSRIs), and atypical (or ‘‘other’’) Venlafaxine (extended release) Effexor XR
antidepressants (Table 1). Individuals with mild Venlafaxine Effexor
depression often improve with psychotherapy alone;
however, many with moderate depression may
require an antidepressant prescription to effectively
treat their disorder. For those patients with severe They also frequently expect that their depression will
depression, treatment with an antidepressant is begin to improve soon after beginning a course of
almost always indicated. In addition to their utility antidepressant treatment. Patients may view the use
in treating depression, some of the antidepressants of an antidepressant as a ‘‘crutch’’ and a sign of
have demonstrated clear efficacy for premenstrual weakness. They may also have to deal with family
dysphoric disorder, bulimia, chronic pain, and and friends who tell them that antidepressants are
several different anxiety disorders. not necessary and with their own or others’ prejudice
that only ‘‘crazy people’’ take psychoactive medica-
tions. Despite much public education, depression and
GENERALITIES OF ALL ANTIDEPRESSANTS its treatment are still stigmatized in the U.S. culture,
and antidepressants remain the frequent butt of jokes
Myths and Misconceptions and cartoons.
Patients often believe that antidepressant medica- Thus, when a recommendation is made that a
tions will cause an artificial high and are addictive. depressed individual begin an antidepressant trial,
216 ANTIDEPRESSION PHARMACOLOGY

subcutaneous heparin, both, or neither among 19,435 patients Table 1 CLASSES OF ANTIDEPRESSANTS
with acute ischaemic stroke [see Comments]. Lancet 349,
1569–1581. Generic name Brand name
Kay, R., Wong, K. S., Yu, Y. L., et al. (1995). Low-molecular-
weight heparin for the treatment of acute ischemic stroke [see Tricyclic antidepressants (TCAs)
Comments]. N. Engl. J. Med. 333, 1588–1593. Amitriptyline Elavil
Publications Committee for the Trial of ORG 10172 in Acute Clomipramine Anafranil
Stroke Treatment (TOAST) Investigators (1998). Low molecu- Desipramine (Is 21 amine, metabolite of Norpramin
lar weight heparinoid, ORG 10172 (danaparoid), and outcome imipramine)
after acute ischemic stroke: A randomized controlled trial [see
Doxepin Sinequan
Comments]. J. Am. Med. Assoc. 279, 1265–1272.
Salem, D. N., Daudelin, H. D., Levine, H. J., et al. (2001). Imipramine Tofranil
Antithrombotic therapy in valvular heart disease. Chest 119, Nortriptyline (Is 21 amine, metabolite of Pamelor
207S–219S. amitriptyline)
Stein, P. D., Alpert, J. S., Bussey, H. I., et al. (2001).
Antithrombotic therapy in patients with mechanical and Monoamine oxidase inhibitors (MAOIs)
biological prosthetic heart valves. Chest 119, 220S–227S.
Isocarboxazid Marplan
Phenelzine Nardil
Tranylcypromine Parnate

Selective serotonin reuptake inhibitors (SSRIs)

Antidepression Pharmacology Citalopram Celexa
Encyclopedia of the Neurological Sciences Escitalopram Lexapro
Copyright 2003, Elsevier Science (USA). All rights reserved.
Fluoxetine Prozac
Fluvoxamine Luvox
DEPRESSION is a common ailment with a lifetime Paroxetine Paxil
prevalence of 21% in women and 13% in men. Sertraline Zoloft
Although patients with this disorder often feel
hopeless, depression is actually quite amenable to Atypical antidepressants
treatment, with response rates ranging from 60 to Bupropion (slow release) Wellbutrin
80%. Antidepressant medications have been avail- SR (aka
able since the 1960s, and clinicians can choose from Zyban)
a variety of different classes with differing mechan- Bupropion Wellbutrin
isms of action and side effect profiles. Classes include Mirtazapine Remeron
the tricyclic antidepressants (TCAs), the monoamine Nefazodone Serzone
oxidase inhibitors (MAOIs), the selective serotonin Trazodone Desyrel
reuptake inhibitors (SSRIs), and atypical (or ‘‘other’’) Venlafaxine (extended release) Effexor XR
antidepressants (Table 1). Individuals with mild Venlafaxine Effexor
depression often improve with psychotherapy alone;
however, many with moderate depression may
require an antidepressant prescription to effectively
treat their disorder. For those patients with severe They also frequently expect that their depression will
depression, treatment with an antidepressant is begin to improve soon after beginning a course of
almost always indicated. In addition to their utility antidepressant treatment. Patients may view the use
in treating depression, some of the antidepressants of an antidepressant as a ‘‘crutch’’ and a sign of
have demonstrated clear efficacy for premenstrual weakness. They may also have to deal with family
dysphoric disorder, bulimia, chronic pain, and and friends who tell them that antidepressants are
several different anxiety disorders. not necessary and with their own or others’ prejudice
that only ‘‘crazy people’’ take psychoactive medica-
tions. Despite much public education, depression and
GENERALITIES OF ALL ANTIDEPRESSANTS its treatment are still stigmatized in the U.S. culture,
and antidepressants remain the frequent butt of jokes
Myths and Misconceptions and cartoons.
Patients often believe that antidepressant medica- Thus, when a recommendation is made that a
tions will cause an artificial high and are addictive. depressed individual begin an antidepressant trial,

clinicians must educate patients that these medica-
tions are not addictive, typically do not lift one’s
mood within just a few days, and are not a crutch.
Instead, patients can be told that antidepressants are
an effective and proven treatment for a specific
clinical disorder. Due to the stigma attached to
depression and its treatment, patients can benefit
greatly from being educated about this disorder and
from referrals to support organizations and informa-
tive Web sites. Helpful Web sites include the
National Institutes of Mental Health Depression
Awareness Program (http://www.nimh.nih.gov/dart),
the National Mental Health Association site
(NMHA, http://www.nmha.org), and Mental
Health: A Report of the Surgeon General (http://
www.surgeongeneral.gov/library/mentalhealth/).
Choosing an Antidepressant
To date, all antidepressants appear to be fairly
equally effective in the treatment of depression.
Exceptions to this generality are that some indivi-
duals with atypical depression—for example, hyper-
phagia (overeating), hypersomnia (oversleeping), and
rejection sensitivity (high sensitivity to interpersonal
rejection)—may respond better to SSRIs and MAOIs
than to other classes, and that individuals with
treatment-refractory and severe, melancholic depres-
sion may respond better to dual-action antidepres-
sants (TCAs and some of the aytpicals) rather than to
SSRIs. Several factors contribute to a clinician’s
choice of which antidepressant to prescribe. A
clinician considers whether certain adverse effects
must be avoided, such as anticholinergic side effects
in an individual with benign prostatic hypertrophy or
agitation in a patient with an anxious depression.
Conversely, one may select a certain agent specifi-
cally because of its side effects; for example, a more
sedating antidepressant is a common choice in a
patient with severe insomnia. If a patient has a past
history of responding to a particular antidepressant,
that drug should be strongly considered to treat
subsequent episodes. Similarly, if a first-degree
relative responded well to one antidepressant, that
agent should be prescribed (if appropriate) for the
identified patient.
Clinicians should also consider the potential for
interactions with other drugs, both prescribed and
over-the-counter. Adverse reactions can occur due to
elevated serum levels of drugs metabolized by
enzymes inhibited by a second drug. In addition,
effectiveness of a prescribed drug may be diminished
due to lower serum levels if its metabolizing enzyme
ANTIDEPRESSION PHARMACOLOGY 217
is induced by a second drug. The TCAs and MAOIs
have narrow therapeutic windows and can be lethal
if taken as an overdose; thus, if an individual is
suicidal, these classes of agents are best avoided. The
newer classes of antidepressants (SSRIs and atypi-
cals) do not appear to be lethal when overdosed in
isolation. Tricyclic antidepressants are the only
antidepressant class for which excellent correlation
exists between serum levels and efficacy. Thus, TCAs
are worth considering for patients who are treatment
refractory (so that the adequacy of a trial can be
assessed via the serum levels) and for those who may
be noncompliant (so that serum levels can be tracked
to ensure compliance). The final consideration in
selecting an antidepressant may be cost and whether
a particular medication is on the specific formulary
of a patient’s insurance company. The newer anti-
depressants (SSRIs and atypicals) are significantly
more expensive than the older drugs.
Phases of Treatment
Treatment with antidepressants is conceptualized as
having three distinct phases (Fig. 1).
Acute Phase: The goal of this phase is to treat the
depression to the point of remission and to avoid
relapse. Ideally, antidepressant trials should be pre-
scribed at an adequate dose for an adequate length of
time. Symptoms of depression typically respond fully
to an antidepressant after approximately 4–6 weeks
of treatment. If an individual has no or little response
after 4–6 weeks of antidepressant treatment at a
typical therapeutic dose, clinicians should consider
switching to a different agent or augmenting the
antidepressant with a second agent (lithium carbo-
nate, thyroid hormone, a second antidepressant from
a different class, pindolol, or buspirone).
Continuation Phase: Once the patient’s depression
is in remission, treatment then enters the continua-
tion phase. This phase should last for a minimum of
4 months, but ideally it should continue for 9–12
months. The goal of the continuation phase is to
avoid relapse. Prospective studies have shown that by
continuing on medication, relapse risk decreases
from 40–60% to 10–20%.
Maintenance Phase: Individuals with histories of
three or more episodes of major depression, with
chronic depression, or with late-onset depression
should continue on their antidepressant regimen
indefinitely in a maintenance phase of treatment.
For others, the antidepressant can be tapered and
218 ANTIDEPRESSION PHARMACOLOGY

Figure 1
Phases of treatment for major depression. The figure shows mood of an individual changing from ‘‘normal’’ into a major depression (below
the dotted line) and then into remission with treatment. Treatment is divided into three distinct phases: Acute phase: goal is to achieve
remission; Continuation phase: goal is to prevent relapse; and Maintenance phase: goal is to prevent recurrence (Source: Agency for Health
Care Policy and Research Depression in Primary Care, Clinical Guideline Number 5, AHCPR Publication No. 93-0550, April 1993).

discontinued at the termination of the continuation
phase. The goal of the maintenance phase is to
prevent recurrence of another episode of major
depression. Without maintenance treatment, the
recurrence rate for individuals with three or more
past episodes is 90%. If not limited by side effects,
the antidepressant dose prescribed during the con-
tinuation and maintenance phases should be the
same as it was during the acute phase of treatment.
SPECIFIC CLASSES OF ANTIDEPRESSANTS
Tricyclic Antidepressants
The TCAs have been available to treat depression
since the 1960s and are well-studied and highly
effective agents (Table 2). Effects (both therapeutic
and adverse) are exerted through antagonism at
multiple different neurotransmitter receptors. Major
drawbacks to their use include the need to start at a
low dose and titrate upwards slowly, their complex
side effect profile, and their narrow therapeutic index
with a high risk of lethality in overdose. Advantages
include the correlation between serum levels and
efficacy, the possibility of better efficacy in the
treatment of severe, melancholic depression com-
pared to the SSRIs, and the fact that they are
inexpensive.
TCAs are categorized as tertiary amines (amitrip-
tyline, clomipramine, doxepin, imipramine, and
trimipramine) and secondary amines (desipramine,
nortriptyline, amoxapine, and protriptyline). Block-
ade at muscarinic receptors leads to anticholinergic
effects, including dry mouth, constipation, blurry
vision, urinary hesitancy, and tachycardia. Antihis-
taminergic effects include sedation and weight gain.
Blockade at the a1-adrenergic receptor can lead to
orthostatic hypotension, and blockade at the seroto-
nin 5-HT2 receptor may result in sedation. TCAs can
also cause cardiac toxicity because they may slow
conduction through the AV node; thus, they should
be avoided in patients with bifascicular heart block,
left bundle branch block, or a prolonged QT interval.
In general, the tertiary amines cause significantly
more adverse effects than the secondary amines;
thus, secondary amines are the preferred choice.
Monoamine Oxidase Inhibitors
The MAOIs inhibit the action of monoamine
oxidase, which catabolizes monoamines (norepi-
nephrine, dopamine, and serotonin) both in the
 ANTIDEPRESSION PHARMACOLOGY 219

Table 2 TRICYCLIC ANTIDEPRESSANTS

Starting dose Usual dose Maximum dose

Medication (brand name) (mg/day) (mg/day) How supplied (mg) (mg/day)

Amitriptyline (Elavil) 25–50 150–300 10, 25, 50, 75, 100, 150 300
Amoxapin (Ascendin) 50 bid 200–400 25, 50, 100, 150 600
Clomipramine (Anafranil) 25–50 150–200 25, 50, 75 250
Desipramine (Norpramin) (Is 21 amine, 25–50 150–300 10, 25, 50, 75, 100, 150 300
metabolite of imipramine)
Doxepin (Sinequan) 25–50 150–300 10, 25, 50, 75, 100, 150 300
Imipramine (Tofranil) 25–50 150–300 10, 25, 50, 75, 100, 125, 150 300
Nortriptyline (Pamelor) (Is 21 amine, 10–25 50–150 10, 25, 50, 75 150
metabolite of amitriptyline)
Protriptyline (Vivactil) 10 30–60 5, 10 60
Trimipramine (Surmontil) 25 150–200 25, 50, 100 300
Maprotiline (Ludiomil) 50 150–200 25, 50, 75 225

central nervous system (CNS) and elsewhere in the
body (Table 3). Common side effects of these
agents include orthostatic hypotension, insomnia,
agitation, sedation, and sexual side effects. The
most problematic aspect of these medications is
the possibility of rapidly developing hypertension
if a patient eats foods containing tyramine. Patients
must avoid matured cheeses, dried meats, tap beers,
sauerkraut, and soy sauce and other soy products.
Drug interactions are also potentially dangerous
with the MAOIs. Contraindicated drugs include
SSRIs and other serotonergic acting drugs, meper-
idine, and sympathomimetics such as pseudo-
ephedrine and dextromethorphan. An advantage of
the MAOIs is their apparent better efficacy in the
treatment of atypical depression compared to
TCAs. Data are not conclusive in comparing
MAOIs and SSRIs in the treatment of this con-
dition. Overall, MAOIs are prescribed fairly infre-
quently.
Serotonin Reuptake Inhibitors
SSRIs were first introduced in the United States in
1988 with the release of fluoxetine (Table 4).
Currently, six different SSRIs are available in the
United States (citalopram, escitalopram, fluoxetine,
fluvoxamine, paroxetine, and sertraline), and all but
fluvoxamine have Food and Drug Administration
(FDA) approval for the treatment of depression.
These medications are the most widely prescribed
antidepressants due to their ease of use and relatively
benign side effect profile. Unlike the TCAs and
MAOIs, which need to be started at a low dose and
titrated up to a therapeutic level, the SSRIs are often
begun at a therapeutic dose. Most SSRIs can be given
once a day either in the morning or at bedtime,
depending on whether a patient experiences the drug
as activating or sedating.
Frequently, patients report few or no side effects.
However, SSRI adverse effects may include nausea,
diarrhea, insomnia, headache, agitation, sedation,
excessive sweating, and sexual dysfunction. Sexual
dysfunction is particularly problematic: Individuals
may develop decreased libido, anorgasmia, and/or
impotence, and these sexual side effects occur in
B30–60% of patients. Management options for
sexual side effects include switching to a different
antidepressant class or adding a second agent as an
antidote. Bupropion, nefazodone, yohimbine, and
gingko biloba are some of the agents used to
counteract sexual side effects.
If discontinued abruptly, SSRIs can cause a
discontinuation syndrome manifested by tachycar-
dia, irritability, jitteriness, nausea, diarrhea, vivid

Table 3 MONOAMINE OXIDASE INHIBITORS

Medication (brand name) Starting dose (mg/day) Usual dose (mg/day) How supplied (mg) Maximum dose (mg/day)

Phenelzine (Nardil) 15 45–90 15 90

Tranylcypromine (Parnate) 20 20–50 10 60
220 ANTIDEPRESSION PHARMACOLOGY
Table 4 SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Medication (brand names in Starting dose
parentheses) (mg/day)
Citalopram (Celexa) 10
Escitalopram (Lexapro) 10
Fluoxetine (Prozac) 10
Fluvoxamine (Luvox) 50
Paroxetine (Paxil) 10
Sertraline (Zoloft) 25
dreams, and worsening of mood. Fluoxetine has a
much longer half-life than any of the other agents
and therefore is much less likely to cause a
discontinuation syndrome if abruptly stopped.
Although reports were published in the past suggest-
ing increased suicidality and possibly violent beha-
vior in patients taking SSRIs, subsequent research has
disproved the hypothesized associations.
SSRIs and MAOIs should never be prescribed
simultaneously due to the risk of serotonin syn-
drome. Symptoms of this syndrome include tremor,
hyperreflexia, hyperthermia, myoclonus, diarrhea,
and delirium. The combination of other serotonergic
agents, such as tryptophan or St. John’s wort, with an
SSRI also carries the risk of serotonin syndrome. To
varying degrees, the SSRIs inhibit the hepatic
enzymes known as the cytochrome P450 system.
Inhibition of the different isoenzymes in this system
may lead to problematic drug–drug interactions due
to changes in levels of drugs metabolized by the
affected isoenzyme.
Atypical (or Other) Antidepressants
(Table 5)
Bupropion: Bupropion has a unique mechanism
of action in which it appears to increase dopamine
and norepinephrine turnover in the CNS. Advantages
include the lack of sexual or cardiac side effects.
Disadvantages include the need for multiple daily
doses and adverse effects, including agitation,
insomnia, dry mouth, headaches, and constipation.
Bupropion comes in two different forms—immediate
release and sustained release (SR). In the United
States, the SR form has FDA approval for treatment
of depression under the trade name Wellbutrin SR
and for smoking cessation under the trade name
Usual dose How supplied Maximum dose
(mg/day) (mg) (mg/day)
20–40 10, 20, 40 60
10–20 10, 20 30
20 10, 20, 40, and 80
5 mg/ml soln
100 bid 25, 50, 100 300 (divided
dose)
20 10, 20, 30, 40, 60
and 2 mg/ml soln
50–100 25, 50, 100 200
Zyban. A risk of seizures of 4/1000 has been
reported for the immediate release form but not for
the SR form. The risk of seizures with SR bupropion
is reportedly no different than that with other
antidepressants.
Mirtazapine: Mirtazapine is a receptor antagonist
at a2-adrenergic, 5-HT2 and 5-HT3, and histaminer-
gic receptors. Advantages include its dual action and
its ease of use. Adverse effects include sedation and
weight gain, both of which reportedly improve when
the dose is more than 30 mg/day. Additional side
effects include dry mouth, constipation, and ortho-
static hypotension. This drug is typically given once
daily at bedtime.
Nefazodone: Although this agent is related to
trazodone, it has fewer side effects. Nefazodone is
serotonergic in its action. Unlike the SSRIs, it causes
no or few sexual side effects and no change of normal
sleep architecture, but it may be sedating and may
also cause dizziness, dry mouth, nausea, constipa-
tion, and headache. Twice-daily dosing is recom-
mended because it has a relatively short half-life.
Trazodone: A relatively weak antidepressant, tra-
zodone is often prescribed to manage insomnia. It
inhibits serotonin uptake and blocks serotonin 5-
HT2 receptors. In addition, it blocks a1-adrenergic
receptors. Common adverse effects include sedation,
orthostatic hypotension, and headache. A rare side
effect is priapism.
Venlafaxine: Venlafaxine has selective serotonin
reuptake inhibition actions, but unlike the SSRIs it
also blocks norepinephrine uptake. Norepinephrine
reuptake blockade becomes more prominent as the
dose is increased. Venlafaxine has a similar side effect
profile to the SSRIs and may also cause hypertension.
 ANTIDEPRESSION PHARMACOLOGY 221

Table 5 ATYPICAL ANTIDEPRESSANTS

Medication (brand names in Starting dose Usual How supplied Max dose
parentheses) (mg/day) (mg/day) (mg) (mg/day)

Bupropion, slow release 100 bid 150 bid 100, 150, 200 400 (divided dose)
(Wellbutrin SR)
Bupropion (Wellbutrin) 100 bid or 75 150 tid 75, 100 450 (divided dose)
tid
Mirtazapine (Remeron) 15 15–45 15, 30, 45 45
Nefazodone (Serzone) 50–100 200 bid (qd 50, 100, 150, 200, 250 600
if no SE)
Trazodone (Desyrel) 50–100 300–600 50, 100, 150, 300 600
Venlafaxine, extended release 37.5–75 qd 150 qd 37.5, 75, 150 225
(Effexor XR)
Venlafaxine (Effexor) 37.5 bid 75 bid 25, 37.5, 50, 75, 100 375 (divided dose)

Like bupropion, venlafaxine comes in regular and See also–Antianxiety Pharmacology;

extended release (Effexor XR) versions. The XR Antipsychotic Pharmacology; Anxiety Disorders,
preparation can be dosed once daily compared to bid Overview; Bipolar Disorder; Depression;
or tid for the regular preparation. Serotonin

SPECIAL POPULATIONS Further Reading

Depression with Psychotic Features
Antidepressants alone will not fully resolve symp-
toms in patients with psychotic depression. Most
commonly, these individuals are treated with a
combination of an antidepressant and an antipsy-
chotic. Electroconvulsive therapy (ECT) may also be
an effective treatment.
Bipolar Depression
Individuals with bipolar disorder (manic depression)
are at risk for developing a manic state if treated
with an antidepressant but not a mood stabilizer.
Thus, when depressed, combination treatment is
highly recommended for these patients. Due to the
possibility that taking antidepressants may increase
the risk of developing a rapid cycling form of
this disorder, antidepressant exposure should be
minimized.
Depression in the Elderly: Geriatric patients with
depression should be treated as aggressively as their
younger counterparts. Due to changes in metabolism
with aging, however, medications are best started at
lower doses and titrations are best done at a slow
rate. ECT is an effective treatment for depression in
elderly patients who are unable to tolerate adverse
effects of antidepressants.
—Ellen Haller
Alpert, J. E. (1998). Drug–drug interactions: The interface
between psychotropics and other agents. In The MGH Guide
to Primary Care in Psychiatry (T. A. Stern, J. B. Herman, and P.
L. Slavin, Eds.), pp. 519–534. McGraw-Hill, New York.
American Psychiatric Association (2000). Practice guideline for the
treatment of patients with major depressive disorder (revision).
Am. J. Psychiatry 157, 1–36.
Depression Guideline Panel (1993). Clinical practice guideline
number 5: Depression in primary care II (AHRQ Publication
No. 93–0551). U.S. Department of Health and Human Services,
Rockville, MD.
Fava, M., and Kaji, J. (1994). Continuation and maintenance
treatments of major depressive disorder. Psychiatry Ann. 24,
281–290.
Mueller, T. I., Leon, A. C., Keller, M. B., et al. (1999). Recurrence
after recovery from major depressive disorder during 15 years
of observational follow-up. Am. J. Psychiatry 156, 1000–1006.
Pollack, M. H., and Rosenbaum, J. F. (1987). Management of
antidepressant-induced side effects: A practical guide for the
clinician. J. Clin. Psychiatry 48, 3–8.
Reynolds, C. R., Frank, E., Perel, J. M., et al. (1999). Nortriptyline
and interpersonal psychotherapy as maintenance therapies for
recurrent major depression: A randomized controlled trial in
patients older than 59 years. J. Am. Med. Assoc. 281, 39–45.
Snow, V., Lascher, S., and Mottur-Pilson, C. (2000). Pharmacolo-
gic treatment of acute major depression and dysthymia. Ann.
Intern. Med. 132, 738–742.
U.S. Department of Health and Human Services (1999). Mental
health: A report of the surgeon general—Executive summary.
U.S. Department of Health and Human Services, Rockville, MD.
Williams, J. W., Mulrow, C. D., Chiquette, E., et al. (2000). A
systematic review of newer pharmacotherapies for depression
in adults: Evidence report summary. Ann. Intern. Med. 132,
743–756.
222 ANTIEPILEPTIC DRUGS
Antiepileptic Drugs
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE LAST half of the 19th century saw the first steps
made toward pharmacological treatment of epilepsy
with the use of bromide salts. Until the discovery of
the anticonvulsant properties of the barbiturates in
1912, these toxic compounds were the only available
antiepileptic drugs (AEDs).
By 1939, Merritt and Putnam had described the
laboratory and clinical effects of diphenylhydantoin
(phenytoin), a drug that had unprecedented activity
against partial seizures. Phenytoin remained a first-
line AED along with the barbiturates for approxi-
mately 30 years. By the 1950s, acetazolamide was
shown to have some beneficial effects on a pediatric
population with epilepsy, which stimulated studies in
later years but had a lesser impact than any of its
forebears. A decade later, a chance discovery led to
the discovery of the anticonvulsant properties of
sodium valproate: While being used as solvent for
lipophilic calcium channel antagonists, ‘‘control’’
preparations of valproate were shown to have
activity in a wide range of animal seizure models.
Carbamazepine, a modified tricyclic agent, was
introduced in the late 1960s, and it remains a useful
treatment for localization-related epilepsy.
By the late 1980s, a sustained period of intensive
research had resulted in the introduction of a number
of new antiepileptic drugs. Vigabatrin and lamotri-
gine signaled a new era in AED use; the former was
the first AED specifically designed to enhance
cerebral GABAergic activity, whereas lamotrigine
was shown to affect sodium channels in their slow
inactivated state. At approximately the same time,
another sulfonamide derivative, zonisamide, was
selected for further development as an AED on the
basis of preclinical testing results.
In 1992, another novel compound, felbamate, was
licensed for use in the United States and Europe.
Unfortunately, subsequent descriptions of serious
hepatotoxicity and agranulocytosis severely limited
its use. Gabapentin (1992) and topiramate (1995),
two AEDs with novel structure and function, were
released later in the decade. Tiagabine (a nipecotic
acid derivative), oxcarbazepine (a chemical modifi-
cation of carbamazepine), and levetiracetam (a novel
class of agent with unknown mode of action) were
the last AEDs to be licensed as the 20th century drew
to a close.
The past 20 years have seen more compounds
developed than were discovered in the previous
century and a half. In the new century, drug
treatment of epilepsy has never been so complex or
so promising. With even more compounds due to
become available, we may be close to reaching our
goal of maximizing both efficacy and tolerability of
antiepileptic drug treatment.
COMPARATIVE EFFICACY OF AEDS
Comparative efficacy of the AEDs is difficult to
establish with certainty. There are many reasons for
this, the chief one being the paucity of randomized
clinical trials with adequate statistical power. Tradi-
tionally, most initial efficacy trials of AEDs are
placebo-controlled studies in patients with refractory
epilepsy. Only later, once some anticonvulsant
efficacy has been shown, is it considered acceptable
to carry out monotherapy studies. Such studies,
which are usually carried out for regulatory pur-
poses, may show a lack of significant difference
between the compounds but are simply not large
enough to truly determine equivalence.
One way to circumvent these methodological and
ethical difficulties is to combine results of individual
randomized placebo-controlled trials, providing a
larger cohort for each active treatment (Fig. 1).
Although it has deficiencies, meta-analysis provides
a method of extracting data retrospectively from
trials.
Figure 2 shows the average ratio of effectiveness of
drug:placebo with 95% confidence intervals. It can
be seen that there is no clear statistically significant
difference between any of the compounds, each
displaying clear differences compared to placebo.
RECOGNIZED ANTIEPILEPTIC DRUGS
This section provides an alphabetical listing of those
compounds that are used or have been used as AEDs
in clinical practice (Tables 1 and 2). Variations in
licensing restrictions may mean that there will be
international variations in the scope of use of some of
these compounds. Some compounds (e.g., acetazola-
mide and progabide) are included for largely
historical reasons.
Acetazolamide
By chemically inducing hypercapnia, inhibition of
cerebral carbonic anhydrase activity can help to
improve seizure control in patients with refractory
 ANTIEPILEPTIC DRUGS 223

Barbiturates
Although barbiturates have a wide range of effects
on many neurobiological systems, their main anti-
epileptic effect derives from their specific binding to
the GABAA receptor, which increases the frequency
of chloride channel opening and thereby increases
membrane stability in the nervous system.
Phenobarbital and primidone are the two barbitu-
rates most commonly used in clinical practice. A
Veterans Administration study performed by Matt-
son et al. in the mid-1980s confirmed that the
barbiturates are not as well tolerated as their newer
counterparts.
Phenobarbital: Phenobarbital is effective against
partial and generalized tonic–clonic seizures as well
as in prevention of febrile seizures and treatment of
some cases of status epilepticus. Development of
tolerance can also prove problematic, whereas the
risk of withdrawal seizures means that patients
whose seizures are well controlled on phenobarbi-
tone should not have their treatment altered unless
there is good reason.
Phenobarbital is an inexpensive anticonvulsant
and will therefore remain important in developing
countries. In the developed world, in which cost is
less of a determining factor, it will remain less
attractive than its better-tolerated successors.
Primidone: Primidone is a barbiturate prodrug
(converted in the liver to phenobarbitone) that is less
effective and less well tolerated than carbamazepine,
phenytoin, or phenobarbitone. The most common
side effects are drowsiness, gastrointestinal intoler-
ance, and psychosis. Physical dependence and with-
Figure 1
drawal seizures are also barriers to long-term use.

epilepsy. This is the main action of acetazolamide

and is a secondary effect of both zonisamide and
topiramate. Trials support acetazolamide’s use in
either localization-related epilepsy or idiopathic
generalized epilepsy. In man, the development of
tolerance is unpredictable and may limit its use to
intermittent exposure. Dose-related side effects
include dizziness, nausea, and paraesthesiae. Other
less common side effects include dyspnea, metabolic
acidosis, and renal calculus formation. Animal
studies demonstrate this compound’s teratogenicity,
and together with results from case reports indi-
cate that this drug is unsuitable for use during Figure 2
pregnancy. Comparative efficacy of new AEDs.
224 ANTIEPILEPTIC DRUGS

Table 1 THE ESTABLISHED ANTIEPILEPTIC DRUGS

Spectrum of action Adverse events

Acute dose related Acute idiosyncratic Chronic toxicity Teratogenicity

Barbiturates Tonic–clonic seizures Drowsiness, Rashes Tolerance Confirmed in man

unsteadiness Habituation and animals
Withdrawal
seizures
Behavioral change
Phenytoin Tonic–clonic seizures Dose-related Rashes, Gum swelling, acne, Confirmed in man
unsteadiness, lymphadenopathy, hirsutism, folate and animals
slurred speech, hepatitis deficiency
chorea
Carbamazepine Partial epilepsy, 72y, Dizziness, diplopia, Rashes, low white cell ? None definite Confirmed in man
generalization unsteadiness, count and animals
nausea, vomiting
Sodium Idiopathic Tremor, irritability, Gastric intolerance, ? Weight gain, Confirmed in man
Valproate generalized þ partial restlessness, hepatotoxicity (in alopecia and animals
epilepsy occasional children)
confusion

Benzodiazepines of neurochemical and neurophysiological actions:

In 1960, Randall and colleagues demonstrated the
efficacy of the benzodiazepines in animal seizure
models. Benzodiazepines probably exert their anti-
convulsant effect on binding with a specific site on
the g subunit of the GABAA receptor, which increases
hyperpolarization of affected neurons. Additionally,
similar to other established AEDs, effects on sodium
channels have been described.
Benzodiazepines, particularly diazepam and lora-
zepam, still have a place in the immediate, intrave-
nous treatment of status epilepticus. Clobazam is less
sedative than the older benzodiazepines and can be
useful when given as adjunctive treatment. Although
intermittent treatment is more common with benzo-
diazepines, some studies have supported the long-
term use of clonazepam and clorazepate.
Bromide Salts
Bromide salts act by potentiating GABA’s action on
the chloride channel. The high frequency of sedation
and dermatological side effects have ensured that
bromides are considered for use in only the most
refractory of epilepsies.
Carbamazepine
The first AED trials for carbamazepine, a tricyclic
compound, were performed in 1963. It remains a
first-line AED for the treatment of localization-
related epilepsies. Carbamazepine has a wide range
Sodium channel blockade, which limits sustained
repetitive firing, is probably the most important, but
many other synaptic effects have been described.
Carbamazepine is considered the drug of choice for
partial seizures, whether or not there is secondary
generalization. It has no documented efficacy against
generalized absences or myoclonic seizures. The
latter seizure type may on occasion be exacerbated
by carbamazepine.
Although generally well tolerated, carbamaz-
epine’s pharmacokinetics may be disadvantageous,
leading to marked inter- and intraindividual varia-
tion in response. Rashes and hyponatremia may
occur in some patients. The frequency and severity of
the neurological side effects (nausea, headache,
dizziness, and diplopia) correlate with the levels of
both carbamazepine and its active metabolite carba-
mazepine epoxide.
Carbamazepine’s success as an antiepileptic drug
has been augmented by the development of the slow-
release preparation, which leads to an increased
tolerability via a decrease in plasma level variability.
Ethosuximide and Other Succinimides
The succinimides were synthesized as modifications
of the hydantoin–barbiturate heterocyclic ring. Etho-
suximide is the most commonly used succinimide,
the other two (methsuximide and phensuximide)
being little used today. Ethosuximide remains
a useful compound in pediatric practice in the
 ANTIEPILEPTIC DRUGS 225

Table 2 THE NEW ANTIEPILEPTIC DRUGS

Mode of action Efficacy in seizure Adverse events

Type (mode of use)
Acute idiosyncratic Chronic toxicity Teratogenicity

Felbamate Glycine antagonism Partial/generalized Bone marrow, — Unknown

(monotherapy/ suppression,
add-on) hepatic failure
Gabapentin Uncertain Partial (add-on) Behavioral problems — None described
?GABAergic (children)
effect, ?Ca
channel blockade
Lamotrigine Sodium channel Partial/generalized Rash — None described
blockade (monotherapy/
add-on)
Levetiracetam Unknown Partial/?generalized — — None described
(add-on)
Oxcarbazepine Na channel block, Partial (add-on) — Hyponatremia Unknown
Ca channel block
Tiagabine GABA reuptake Partial (add-on) Partial status — Animal models
block
Topiramate GABAergtic, Na Partial/?generalized — Renal calculi, Animal models
channel block, (add-on/ weight loss
kainate receptor ?monotherapy)
block
Vigabatrin GABA-t inhibition Partial (add-on) Psychosis Visual field defects Animal models
Zonisamide Na channel block Partial/?generalized — Renal calculi Animal models and
(add-on/ isolated case
?monotherapy) reports in humans

treatment of absence seizures, but (unlike some other
succinimides) it does not appear to be effective
against other seizure types. Succinimides act on
calcium T channels to block voltage-dependent
calcium conductance in thalamic neurons. Side
effects of ethosuximide are either gastrointestinal
(nausea, vomiting, and abdominal pain) or involve
the central nervous system (lethargy, dizziness, and
ataxia).
Ethosuximide does not alter the metabolism of
other drugs, but its own metabolism is affected by
enzyme-inducing or -inhibiting antiepileptic drugs.
The efficacy and safety of valproate have ensured
that ethosuximide has become a second-line treat-
ment for absence seizures.
Felbamate
Felbamate is structurally unrelated to other anti-
convulsant compounds, and it was approved for use
in adults in the United States in 1992, with
subsequent approval given for use in children with
Lennox–Gastaut syndrome. The mechanisms of
action of felbamate are novel and not completely
understood, but it has been shown to reduce sodium
currents, enhance GABAergic inhibition, and block
the NMDA receptor site, probably via antagonism of
glycine.
Felbamate undergoes hydroxylation by the liver,
although approximately one-half of each dose is
excreted unchanged in the urine. There are signifi-
cant mutual drug interactions between felbamate and
the older AEDs. Add-on studies demonstrated
felbamate’s efficacy in intractable focal seizures,
whereas two trials showed efficacy as monotherapy
during withdrawal of conventional AEDs. Most side
effects were attributed to the interaction of felbamate
with concomitant AEDs. However, by 1995, after
approximately 100,000 felbamate exposures, two
very serious problems arose. Aplastic anemia devel-
oped in 32 patients and hepatic failure in 19 patients.
Five of those with hepatotoxicity and 10 of those
with bone marrow suppression died.
Use is generally restricted to those patients
refractory to all other medications and in whom
226 ANTIEPILEPTIC DRUGS
the risk–benefit relationship is favorable. Weekly or
biweekly blood counts and liver function tests must
be performed, although it is not clear whether early
detection of either of these idiosyncratic reactions
will prevent the most serious outcomes.
Gabapentin
Gabapentin was developed in an attempt to manu-
facture a direct GABA receptor agonist that could be
administered orally. In fact, the full neurobiological
effects of gabapentin have not been clearly defined,
although it is known that there is no direct action on
GABAA or GABAB receptors and no effect on
benzodiazepine receptors. There may be some
specific binding to a subunit of the calcium channel,
and GABAergic effects may be important in its
efficacy. It has also been suggested that gabapentin
could alter transport of other neurotransmitter
amino acids in vivo.
Gabapentin is rapidly absorbed following oral
dosing and undergoes renal excretion with a half-life
of 5–7 hr. The lack of any drug interactions with
gabapentin use has been widely reported. Studies
showed gabapentin to be effective at lower doses
than are currently used. Compared to the upper end
of the licensed doses in most countries, the studied
doses of 900 or 1200 mg/day seem rather low.
However, these studies confirmed the drug’s efficacy
as add-on therapy against refractory partial epilepsy.
In clinical trials, gabapentin has been very well
tolerated: Adverse events are relatively rare and there
are no reports of any life-threatening side effects of
gabapentin use. The most common side effects are
somnolence, fatigue, dizziness, and weight gain.
Gabapentin is also widely used in the management
of chronic pain syndromes.
Lamotrigine
In the 1960s, some AED development programs
concentrated on antagonism of proconvulsive com-
pounds such as folate. Lamotrigine, a phenyltriazine
derivative, is chemically unrelated to other AEDs and
was noted to be both a mild folate antagonist and
anticonvulsant when used in some animal models. It
is now known that these properties are not linked.
Lamotrigine inhibits neuronal burst firing in a
manner similar to that of phenytoin and carbamaze-
pine. Lamotrigine thereby inhibits release of neuro-
nal glutamate and the blockage of sustained
repetitive firing is thought to be a result of the
frequency and voltage-dependent sodium channel
inactivation. This occurs when the channel is in the
slow inactivated state, and this selectivity may
account for the drug’s tolerability.
Lamotrigine metabolism is largely by hepatic
glucuronidation, but lamotrigine does not induce or
inhibit hepatic enzymes. There may be a pharmaco-
dynamic interaction with carbamazepine that results
in an increase in neurotoxicity when the drugs are
combined. Lamotrigine’s half-life is extended by
concomitant valproate, whereas enzyme-inducing
anticonvulsants, such as carbamazepine and pheny-
toin, have the opposite effect.
Several studies have demonstrated success as add-
on treatment of partial seizures with or without
secondary generalization. The drug is also licensed
for use in Lennox–Gastaut syndrome and idiopathic
generalized epilepsies.
In large trials comparing lamotrigine monotherapy
with carbamazepine monotherapy, lamotrigine
showed similar efficacy but improved tolerability. A
comparative trial with phenytoin has been carried
out that shows similar benefits of lamotrigine
monotherapy. Skin rash and mild central nervous
system events, such as dizziness, ataxia, drowsiness,
headache, and diplopia, occur with lamotrigine use.
Levetiracetam
Levetiracetam is a pyrollidine derivative that is
chemically related to piracetam, a nootropic drug.
Levetiracetam is not structurally similar to any
existing AEDs, and the mechanism of action is
unknown.
Initial studies demonstrated efficacy in refractory
partial seizures in man, whereas later studies have
also shown efficacy in animal models of idiopathic
generalized epilepsy. Pharmacokinetics appear to be
linear, and no interactions have been described with
other drugs. Although the drug is a relatively recent
introduction, no serious adverse events have been
described.
Oxcarbazepine
Oxcarbazepine is a chemical analog of carbamaze-
pine that has a different metabolic profile. Oxcarba-
zepine is rapidly and completely reduced in the liver
to the hydroxylated active moiety. The main advan-
tage of oxcarbazepine arises from avoidance of
formation of carbamazepine epoxide, the compound
that accounts for many of the adverse events
experienced during carbamazepine treatment
(Fig. 3).
The mechanism of action of oxcarbazepine is
thought to be closely related to that of carbamaze-

Figure 3
The metabolic pathways of carbamazepine and oxcarbazepine.
pine (Figs. 4–7). Certainly, the effect of both com-
pounds on animal seizure models is similar, although
not identical. Oxcarbazepine’s major effect is in
preventing repetitive firing of neurons by blocking
voltage-dependent Na þ channels. There may be
some differences in the effect of the latter on calcium
currents or in the modulation of corticostriatal
synaptic transmission. In support of the significance
of these, one trial demonstrated that oxcarbazepine
could prove beneficial when added into a regime
containing carbamazepine without provoking toxi-
city. After a rapid presystemic hydroxylation, oxcar-
bazepine is excreted in the urine. Oxcarbazepine
treatment does not result in autoinduction of
metabolism or hepatic enzyme induction. There is
no interaction with the oral contraceptive pill. The
converse does not apply, however, because enzyme
induction by other AEDs decreases OHCBZ con-
centrations.
A number of trials support the idea that the two
compounds have similar efficacy against partial
epilepsy. Like carbamazepine, oxcarbazepine is
ineffective against most idiopathic generalized epi-
lepsies.
ANTIEPILEPTIC DRUGS 227
Side effects associated with oxcarbazepine are
similar to those produced by carbamazepine: Dizzi-
ness, drowsiness, headache, nausea, vomiting, and
diplopia are the most prominent symptoms. Studies
have reported these to be less frequent and less severe
than with carbamazepine. In addition, oxcarbaze-
pine produces fewer rashes and perhaps fewer
idiosyncratic reactions. Hyponatremia is more com-
mon with oxcarbazepine than with carbamazepine.
This can occasionally present clinically but is usually
mild and asymptomatic. There is no evidence of
teratogenesis associated with oxcarbazepine.
Phenytoin
Phenytoin has been used worldwide since its intro-
duction in 1938. Laboratory studies have demon-
strated phenytoin’s effect on many facets of neuronal
physiology and biochemistry, including modification
of Na þ /K þ ATPase in vitro and in vivo, inactivation
of sodium channels, inhibition of neurotransmission,
blockade of L-type calcium channels, and effects on
other neuronal biochemical parameters such as
chloride permeability, cyclic nucleotide metabolism,
and metabolism of GABA, glutamine, and glutamate.
It is unlikely that any one single action is the source
of its anticonvulsant activity. It is more likely that
this depends on a combination of its many effects.
Phenytoin has marked activity against partial
seizures with or without secondary generalization.
In some developed countries, particularly the United
States, it is also the drug of choice for idiopathic
generalized epilepsies. Intravenous phenytoin is still
considered the treatment of choice for status
epilepticus not fully responsive to benzodiazepines.
The zero-order, nonlinear pharmacokinetics ex-
hibited by phenytoin ensure that it demands careful
monitoring during dose titration, particularly when
used as part of AED polypharmacy. In clinical
practice this need for monitoring is a distinct
disadvantage.
Chronic phenytoin use can cause hirsutism, gum
hyperplasia, and facial coarsening. Such cosmetic
effects can make the drug unpleasant to use in young
women. Central nervous system features of pheny-
toin toxicity include cognitive decline and cerebellar
ataxia. Interference with metabolism of folate or
vitamin D can result in a mild macrocytic anemia or
osteomalacia, respectively. There is a recognized risk
of fetal abnormality with phenytoin treatment,
although the risks to the fetus of uncontrolled
epilepsy justify its use in some pregnancies.
228 ANTIEPILEPTIC DRUGS
Figure 4
The new antiepileptic drugs.
Progabide
Progabide is a direct GABA receptor agonist that
underwent clinical evaluation in the 1980s. Conflict-
ing results from these studies and a continuing risk of
hepatotoxicity have combined to stop the drug from
being used outside of France.
Sulthiame
Sulthiame is chemically related to acetazolamide but
has been shown to have a greater inhibitory effect on
the neuronal isoenzyme of carbonic anhydrase. It
was first used in Europe and Australia as adjunctive
treatment of partial and generalized seizures with
some success. Monotherapy trials showed the com-
pound to be less well tolerated than the established
AEDs. Sulthiame cannot be considered to be a first
choice AED.
Tiagabine
Tiagabine, a nipecotic acid derivative, inhibits GABA
reuptake into both neurons and glial cells, enhancing
the synaptic levels and effects of GABA. The large
addition to the nipecotic acid molecule acts as a
lipophilic anchor, helping the compound to cross the
blood–brain barrier following oral administration.
Tiagabine is easily and rapidly absorbed following
oral administration. The half-life is between 5 and
8 hr. Some of each dose is metabolized and excreted
in the urine, with the majority undergoing fecal.
Patients on a regime containing enzyme-inducing
drugs metabolize tiagabine at a faster rate. Coadmi-
nistration of tiagabine does not have an effect on the
pharmacokinetics of concomitant AEDs. Clinical
studies have confirmed the efficacy of this compound
against partial seizures with or without secondary
generalization.
Tolerability seems to compare favorably with that
of the established AEDs. Most adverse events are
mild or moderate, and no serious adverse effects have
been reported. Some reports have suggested an
increase in the incidence of complex partial status
at higher doses, but a particular association has not
been confirmed statistically. There are no reports of
any teratogenicity in animal studies, but not enough
is known to allow risks in humans to be quantified.
Topiramate
Topiramate is chemically unrelated to other AEDs,
deriving as it does from d-fructose. The precise
mechanisms by which it exerts its anticonvulsant
effect are unknown. It is likely that, like the
established AEDs, the anticonvulsant activity de-
pends on a combination of effects.
The three most important mechanisms include a
decrease of sodium channel conductance, potentia-
tion of GABA’s action on chloride channel conduc-
tance, and a modest block of AMPA and kainate
receptors. The drug is known to have some carbonic
anhydrase inhibitory activity, although this is believed
to have little bearing on its anticonvulsant action.

Figure 5
Chemical structure of the established antiepileptic drugs.
When used as monotherapy, topiramate has a
half-life of approximately 20–30 hr. Pharmacoki-
netics are linear, with the plasma level increasing in
proportion to the dose. The established enzyme-
inducing AEDs increase the clearance of topiramate.
Concomitant valproate or phenobarbitone do not
significantly affect topiramate clearance. Topiramate
reduces the total clearance of phenytoin to a variable
degree. Nevertheless, there is usually no change in
phenytoin dose required in patients commencing
topiramate. The clearance of both digoxin and
estrogen is increased by topiramate.
Trials of efficacy in refractory partial epilepsy
have shown the benefits of topiramate at doses up to
1000 mg/day. The drug has also been used as
monotherapy, although more work is needed to
assess this usage.
Figure 6
Levetiracetam.
ANTIEPILEPTIC DRUGS 229
The most commonly described adverse events
involve the CNS and include ataxia, dizziness, poor
concentration, asthenia, paraesthesiae, and weight
loss. Nephrolithiasis is associated with topiramate
use, probably due to a treatment-related decrease in
urinary citrate excretion. Most calculi were passed
spontaneously and asymptomatically.
Teratogenesis has been demonstrated in
animals, and although no specific relationship with
human teratogenicity has been determined, the
drug should only be used during pregnancy when it
is believed that the benefit is greater than any
potential risks.
Valproic Acid
The exact mechanism by which sodium valproate
exerts its anticonvulsant effect is unknown, but it
has several actions that may contribute, including
effects on the GABAergic system as well as those on
sodium channels, Ca2 þ -dependent K þ influx, and
concentrations of excitatory amino acids such as
aspartate.
Valproate’s efficacy has been confirmed against
generalized tonic–clonic seizures and partial sei-
zures. Other seizure types, such as myoclonic
epilepsy and absence attacks, are effectively treated
by valproate.
Valproate does not induce hepatic enzymes, and
since neither efficacy nor toxicity of valproate can be
230 ANTIEPILEPTIC DRUGS
Figure 7
Zonisamide.
correlated with plasma levels, serum level monitoring
is not necessary with valproate monotherapy. Drug
interactions are less troublesome than with enzyme-
inducing AEDs, although valproate has some en-
zyme-inhibiting properties. This is of clinical sig-
nificance when the drug is added to existing
anticonvulsant treatment regimes, particularly those
containing lamotrigine.
Adverse effects of valproate include tremor, hair
loss, and weight gain. Dose reduction may partially
solve these, but withdrawal of the drug may be
necessary in some patients. There is a recognized risk
of teratogenicity with valproate use, although the
subsequent risk to childhood cognition (the so-called
fetal valproate syndrome) is less well defined. Rare,
though more serious, are episodes of hepatitis,
hepatic failure, pancreatitis, risk thrombocytopenia,
and coma that have been associated with valproate.
Serious adverse effects are more common in chil-
dren, but their rarity has ensured that valproate is
still considered safe. Use of the compound in
countries such as the United States is still limited
as a result of concerns regarding these adverse
effects.
Vigabatrin
Vigabatrin is structurally very similar to GABA, and
it was the first ‘‘designer’’ AED (i.e., a drug
specifically designed to enhance a single biochemical
action). When a molecule of vigabatrin binds to the
enzyme responsible for GABA breakdown, an
irreversible covalent bond is formed that inactivates
GABA-transaminase. This mechanism of action
inspired the term ‘‘suicide inhibitor’’ of GABA-T.
The resultant increase in GABA leads to an increase
in synaptic GABA levels and augmentation of
neuronal inhibition.
Vigabatrin is rapidly absorbed after oral adminis-
tration and, being a small water-soluble molecule,
the majority of each dose is excreted unchanged in
the urine. The plasma half-life is approximately 8 hr,
but the mode of action ensures that the pharmaco-
logical effect of vigabatrin is much longer than its
pharmacokinetic half-life.
No clinically important interactions with other
anticonvulsants have been described. Many studies
have confirmed the efficacy of vigabatrin as add-on
therapy for refractory epilepsy in adults. There has
been one monotherapy in comparison with carba-
mazepine, which showed that vigabatrin was better
tolerated but somewhat less efficacious than carba-
mazepine. The reported effect on generalized seizures
is variable.
In controlled comparative testing, vigabatrin has
been shown to be superior to steroids in the
treatment of infantile spasms (West syndrome). The
most common side effects are dizziness, headache,
diplopia, ataxia, and vertigo. Psychiatric side effects,
such as anxiety, depression, and aggression, are well
recognized; the precipitation of psychosis at high
dose or following sudden withdrawal of the drug
should lead to cautious use of vigabatrin in those
with a history of psychiatric illness. Recent descrip-
tions of visual field defects associated with vigabatrin
use have severely limited the use of vigabatrin in
adults.
Zonisamide
Zonisamide’s actions in blocking sodium and
calcium channels may help explain its effects
in a number of animal models of epilepsy. The
drug also has an inhibitory effect on carbonic
anhydrase.
Studies have shown benefit in both localization-
related and idiopathic generalized epilepsies. The
drug undergoes hepatic metabolism and has reduced
plasma concentrations when used concurrently
with either enzyme-inducing AEDs or valproate.
The frequency of adverse events is similar to that
for carbamazepine. Drowsiness and ataxia are the
most common side effects. These occur with both
monotherapy and polypharmacy. Renal calculus
formation is more prominent in patients in Eur-
opean- and U.S.-based studies than in Japanese
populations.
Animal studies have shown the rate of
spontaneous abortions to be increased at the
equivalent of the maximal human daily dose.
Teratogenic effects were noted in various species
at higher doses. There are only isolated case
reports of human teratogenicity when zonisamide
is part of a regime of AED polypharmacy, but the
drug is recommended for use during pregnancy only
if the therapeutic benefit outweighs the potential
risks.
—John Paul Leach and David W. Chadwick
 ANTINEOPLASTIC CHEMOTHERAPY 231

See also–Epilepsy, Basic Mechanisms; Epilepsy, ALKYLATING AGENTS

Diagnosis of; Epilepsy, Drug Treatment
Principles; Epilepsy, Genetics; Epilepsy,
Overview; Epilepsy, Precipitating Factors;
Epilepsy, Prognosis; Epilepsy Treatment
Strategies
Further Reading
Bialer, M., Johannessen, S. I., Kupferberg, H. J., et al. (1999).
Progress report on new antiepileptic drugs: A summary of the
fourth Eilat Conference (EILAT IV). Epilepsy Res. 34, 1–41.
Brodie, M. J., and Dichter, M. (1996). Anticonvulsant drugs. N.
Engl. J. Med. 334, 168–175.
Dichter, M. A., and Brodie, M. J. (1996). The antiepileptic drugs—
2. N. Engl. J. Med. 334, 1583–1590.
Engel, J., and Pedley, T. A. (1995). Antiepileptic Drug Treatment.
Epilepsy: A Comprehensive Textbook. Lippincott Williams &
Wilkins, Philadelphia.
Marson, A. G., Kadir, Z. A., Hutton, J. L., et al. (1996). The new
antiepileptic drugs; A systematic review of their efficacy and
tolerability. Br. Med. J. 313, 1169.
White, H. S. (1997). Clinical significance of animal seizure models
and mechanism of action studies of potential antiepileptic
drugs. Epilepsia 38, 9–17.
The alkylating agents are drugs that chemically react
with purines and pyrimidines through alkylation,
thereby altering synthesis of nucleotides and subse-
quently impairing the synthesis of DNA. Nitrogen
mustard (NM) is the prototype of this class,
although other drugs have been developed to
improve therapeutic benefit and to reduce toxicity.
Currently, cyclophosphamide is the most widely
used alkylating agent, and thiotepa, melphalan,
chlorambucil, and busulfan are the other important
drugs of this class. The major toxicity of this
group is bone marrow suppression with resultant
damage to the production process for red
blood cells, white blood cells, and platelets. Neuro-
toxicity is not a prominent feature. In very large
doses given intravenously, NM can cause hearing
loss, dysequilibrium, and tinnitus (noises in the
ears such as buzzing and clicking), presumably
from damage to the eighth cranial nerve. Intracar-
otid NM injection has been associated with
weakness or paralysis, seizures, coma, and death.
Damage to the lower motor neurons, located in the
spinal cord and brainstem, has also been reported

Antineoplastic Chemotherapy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved. Table 1 ANTICANCER DRUGS AND NEUROTOXICITY

Alkylating agents
ANTICANCER drugs destroy tumor cells but induce a Eight cranial neuropathy
variety of effects that are toxic to the cells in the Seizures
body. Rapidly growing tissues, such as bone marrow Stroke
Myelopathy
and gastrointestinal mucosa, are highly vulnerable,
Encephalopathy
whereas the nervous system is rather resistant to such Peripheral neuropathy
incidental toxicity. Nevertheless, significant morbi- Nitrosureas
dity and, rarely, mortality relate directly to drug- Encephalopathy
induced toxic damage to the nervous system, either Local pain
peripheral or central. Additionally, indirect or Antimetabolites
secondary nervous system effects can occur in the Meningitis
Myelopathy
form of either drug-induced hepatic or kidney
Encephalopathy
damage. Finally, drug-induced immune suppression Cerebellar dysfunction
can similarly lead to neurological syndromes, includ- Natural products (vinka alkaloides, l-asparaginase, antimetabolic
ing secondary opportunistic infections that cause agents)
encephalitis or meningitis. These indirect conse- Peripheral neuropathy
quences of chemotherapy are not discussed in this Encephalopathy
Strokes
entry, which instead focuses on direct and established
Cerebellar syndrome
drug-induced neurotoxic syndromes.
Other chemotherapeutic agents (cis-platinum, procarbazine,
Chemotherapy often involves more than one drug hexamethylmelamine)
and the combinations are said to be based on Eight cranial nerve dysfunction
a logical consideration of cell biological phases. Encephalopathy
Table 1 summarizes the drugs and syndromes Parkinsonism
Peripheral neuropathy
discussed here.
 ANTINEOPLASTIC CHEMOTHERAPY 231

See also–Epilepsy, Basic Mechanisms; Epilepsy, ALKYLATING AGENTS

Diagnosis of; Epilepsy, Drug Treatment
Principles; Epilepsy, Genetics; Epilepsy,
Overview; Epilepsy, Precipitating Factors;
Epilepsy, Prognosis; Epilepsy Treatment
Strategies
Further Reading
Bialer, M., Johannessen, S. I., Kupferberg, H. J., et al. (1999).
Progress report on new antiepileptic drugs: A summary of the
fourth Eilat Conference (EILAT IV). Epilepsy Res. 34, 1–41.
Brodie, M. J., and Dichter, M. (1996). Anticonvulsant drugs. N.
Engl. J. Med. 334, 168–175.
Dichter, M. A., and Brodie, M. J. (1996). The antiepileptic drugs—
2. N. Engl. J. Med. 334, 1583–1590.
Engel, J., and Pedley, T. A. (1995). Antiepileptic Drug Treatment.
Epilepsy: A Comprehensive Textbook. Lippincott Williams &
Wilkins, Philadelphia.
Marson, A. G., Kadir, Z. A., Hutton, J. L., et al. (1996). The new
antiepileptic drugs; A systematic review of their efficacy and
tolerability. Br. Med. J. 313, 1169.
White, H. S. (1997). Clinical significance of animal seizure models
and mechanism of action studies of potential antiepileptic
drugs. Epilepsia 38, 9–17.
The alkylating agents are drugs that chemically react
with purines and pyrimidines through alkylation,
thereby altering synthesis of nucleotides and subse-
quently impairing the synthesis of DNA. Nitrogen
mustard (NM) is the prototype of this class,
although other drugs have been developed to
improve therapeutic benefit and to reduce toxicity.
Currently, cyclophosphamide is the most widely
used alkylating agent, and thiotepa, melphalan,
chlorambucil, and busulfan are the other important
drugs of this class. The major toxicity of this
group is bone marrow suppression with resultant
damage to the production process for red
blood cells, white blood cells, and platelets. Neuro-
toxicity is not a prominent feature. In very large
doses given intravenously, NM can cause hearing
loss, dysequilibrium, and tinnitus (noises in the
ears such as buzzing and clicking), presumably
from damage to the eighth cranial nerve. Intracar-
otid NM injection has been associated with
weakness or paralysis, seizures, coma, and death.
Damage to the lower motor neurons, located in the
spinal cord and brainstem, has also been reported

Antineoplastic Chemotherapy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved. Table 1 ANTICANCER DRUGS AND NEUROTOXICITY

Alkylating agents
ANTICANCER drugs destroy tumor cells but induce a Eight cranial neuropathy
variety of effects that are toxic to the cells in the Seizures
body. Rapidly growing tissues, such as bone marrow Stroke
Myelopathy
and gastrointestinal mucosa, are highly vulnerable,
Encephalopathy
whereas the nervous system is rather resistant to such Peripheral neuropathy
incidental toxicity. Nevertheless, significant morbi- Nitrosureas
dity and, rarely, mortality relate directly to drug- Encephalopathy
induced toxic damage to the nervous system, either Local pain
peripheral or central. Additionally, indirect or Antimetabolites
secondary nervous system effects can occur in the Meningitis
Myelopathy
form of either drug-induced hepatic or kidney
Encephalopathy
damage. Finally, drug-induced immune suppression Cerebellar dysfunction
can similarly lead to neurological syndromes, includ- Natural products (vinka alkaloides, l-asparaginase, antimetabolic
ing secondary opportunistic infections that cause agents)
encephalitis or meningitis. These indirect conse- Peripheral neuropathy
quences of chemotherapy are not discussed in this Encephalopathy
Strokes
entry, which instead focuses on direct and established
Cerebellar syndrome
drug-induced neurotoxic syndromes.
Other chemotherapeutic agents (cis-platinum, procarbazine,
Chemotherapy often involves more than one drug hexamethylmelamine)
and the combinations are said to be based on Eight cranial nerve dysfunction
a logical consideration of cell biological phases. Encephalopathy
Table 1 summarizes the drugs and syndromes Parkinsonism
Peripheral neuropathy
discussed here.
232 ANTINEOPLASTIC CHEMOTHERAPY
following arterial perfusion to treat pelvic or limb
tumors.
Cyclophosphamide, currently one of the most
widely used alkylating agents, is associated with
very little neurological toxicity. Rapid intravenous
infusion has occasionally caused dizziness, a poster-
ior pharyngeal tingling sensation, and a feeling of
euphoria.
Chlorambucil can cause acute severe and rarely
drowsiness and incoordination, and even seizures
and coma. Progressive multifocal leukoence-
phalopathy, a disease characterized by multiple
areas of myelin-covered axon tracts caused by JC
virus, can develop as a late complication of
chlorambucil treatment in both cancer and non-
cancer subjects.
Thiotepa has particularly low neurotoxicity; thus,
it can be intrathecally injected into the fluid
compartment surrounding the spinal cord. Rarely, a
syndrome of progressive lower extremity weakness,
back and leg pain, loss of deep tendon reflexes, and
an impairment of the spinal cord function occur.
Diagnostic studies using electrical recording of nerve
and muscle functions revealed diffuse lower motor
neuron abnormalities.
Busulfan, also considered neurologically safe, as
been associated with generalized seizures when given
at a high dose.
NITROSOUREAS
The nitrosoureas are a group of cancer chemother-
apeutic agents that have alkylating properties but
probably inhibit protein synthesis. The most com-
mon agents in this group are BCNU and CCNU.
Currently, these drugs produce minimal neurological
toxicity and, in fact, have been used extensively in
the management of central nervous system malig-
nancies. Encephalopathy with confusion and seizures
may follow high-dose (600–800 mg/m2/day or more)
intravenous BCNU. Intracarotid BCNU (usually
100–200 mg/m2/day) will produce severe local pain
in the ipsilateral face, eye, and head during infusion
and sometimes blindness. Intracarotid infusions
above the ophthalmic artery may prevent ocular
toxicity.
ANTIMETABOLITES
Methotrexate (MTX) is an alkylating agent but acts
primarily during DNA synthesis (S phase) as an
antifolate antineoplastic drug. The synthesis of
purine is thereby diminished. As an oral or intra-
venous drug in the usual prescribed doses, MTX has
long been regarded as a neurologically safe agent.
When given by alternate routes or in high doses,
however, MTX is associated with a number of
neurological syndromes. MTX neurotoxicity in-
cludes (i) acute chemical meningitis (fever, headache,
nuchal rigidity, and cerebrospinal fluid leukocytosis)
that lasts 1–3 days, although it may persist for 2
weeks and resolves spontaneously; (ii) stroke-like
encephalopathy with seizures, confusion, limb weak-
ness, and coma; and (iii) spinal cord damage with
weakness or paralysis of the legs, which may be
permanent, and transient radiculopathies (lesions of
the spinal nerves). Delayed neurotoxicity is more
frequent than acute intoxication, and encephalopa-
thy is the most important late effect. Magnetic
resonance imaging and computed tomography usual-
ly show extensive, patchy white matter lesions, with
cortical atrophy.
5-Fluorouracil is a pyrimidine analog used mainly
in the treatment of cancer of the breast, ovary,
and gastrointestinal tract. The mechanism of 5-
fluorouracil neurotoxicity is unknown. It is asso-
ciated with a characteristic cerebellar syndrome
including incoordination and wide-based gait and
eye movement disturbances. Other neurotoxic reac-
tions associated with 5-fluorouracil include encepha-
lopathy and a parkinsonian syndrome (slowness,
tremor, stiffness, and gait disturbances) in 40% of
patients. The encephalopathy is usually mild to
moderate but can range from lethargy to coma in
high-dose infusions.
Cytosine arabinoside (Ara-C) is an analog of
pyrimidine nucleosides and acts by competing for
natural cytidine nucleotides and subsequently inter-
feres with the synthesis of DNA. Although the drug
has little neurotoxicity following usual intravenous
doses, in high doses it can cause a cerebellar
syndrome and, less commonly, seizures and ence-
phalopathy. Parkinsonism induced by high-dose
Ara-C has been reported, as has spinal cord
dysfunction. Intravenous therapy may cause peri-
pheral nervous system damage and possible optic
atrophy.
NATURAL PRODUCTS
Vinca alkaloids, vincristine, and vinblastine
are alkaloid derivatives of the periwinkle plant.
 ANTINEOPLASTIC CHEMOTHERAPY 233

Vincristine is the more widely used drug and is OTHER CHEMOTHERAPEUTIC AGENTS
effective against several neoplasms, including breast
Cis-platinum neurotoxicity is common and dose
cancer and leukemia. The major limiting factor in its
limiting. The most frequent side effect is hearing
use in cancer therapy is its neurotoxicity attributed to
dysfunction. Deafness often begins within 3 or 4 days
axonal damage. The average required dose of
of the initial treatment, slowly improving over
vincristine results in a predictable peripheral nervous
succeeding weeks after treatment is stopped. In most
system dysfunction including cranial nerves with
cases, deafness is reversible; when profound, how-
weakness of the limbs and facial muscles, loss of deep
ever, it may be permanent. Direct toxicity of the drug
tendon reflexes, and sensory disturbances. Vincris-
on the organ of Corti appears to be the cause of the
tine is also associated with an autonomic nervous
induced deafness. An additional side effect of cis-
system dysfunction, in which constipation is the most
platinum is peripheral neuropathy. Occasional spinal
common problem, mild abdominal pain occurs in the
cord dysfunction has been seen in association with
first 72 hr after treatment, and, less commonly,
neuropathy. Encephalopathy with confusion and
bladder dysfunction, impotence, and hypotension
seizures can occur, especially with high doses that
occur. Vinblastine has similar neurotoxic reactions,
may be due to fluid or electrolyte disturbances that
but only at doses that are usually not pres-
accompany cis-platinum therapy, including hypo-
cribed because of concomitant severe hematological
natremia, hypocalcemia, and hypomagnesemia. Pro-
reactions.
carbazine is a monoamine oxidase inhibitor that acts
l-Asparaginase is an enzymatic inhibitor of
primarily as an alkylating agent. Although procar-
protein synthesis and is used in the treatment of
bazine is technically neurotoxic, central nervous
acute lymphoblastic leukemia. General side effects
system and peripheral nervous system alterations
are often dose limiting and include nausea, vomiting,
are not prominent clinically. At usual doses, procar-
and bone marrow suppression. Central nervous
bazine can cause a mild reversible encephalopathy, or
system neurotoxicity, however, may also be dose
peripheral neuropathy will develop in as many as
limiting. Although encephalopathy has usually been
20% of the patients. Because of its monoamine
related to dosage, significant mental changes have
oxidase inhibition, procarbazine can predispose
been seen in some patients on very low doses.
patients receiving it to a variety of drug interactions,
Seizures are not a usual accompaniment of this
including increased sedative effects with tranquili-
encephalopathic syndrome. Strokes have been re-
zers, as well as alcohol intolerance. Procarbazine has
ported secondary to clots because of blood distur-
not been associated with the ‘‘tyramine effect’’ of
bances.
severe hypertensive crisis when cheese or wine is
Antibiotic–antineoplastic agents are antimicrobial
consumed. Hexamethylmelamine can act as an
drugs with cytotoxic properties that have been used
alkylating agent or as an antimetabolite. It has both
in the treatment of various cancers, often with
central and peripheral neurotoxic effects. In the usual
excellent results. Several of these agents appear to
doses administered, neurological problems are seen
act as alkylating agents, although the mechanism of
in up to 20% of patients. The clinical manifestations
action of some antibiotic–antineoplastic agents is
include encephalopathy, parkinsonism, and peri-
not clear. Bleomycin in mainly used to treat tumors
pheral neuropathy. In the case of the peripheral
of the head and neck, testis, and lung. Because the
neuropathy, pyridoxine may be beneficial.
drug is ordinarily used with other chemotherapeutic
—Esther Cubo and Christopher G. Goetz
agents, pure bleomycin-related neurotoxicity is
uncertain. Mental status abnormalities and peri-
pheral nervous system disturbances have been
See also–Cell Death; Neurooncology, Overview;
associated with bleomycin therapy. Adriamycin
Neurotoxicology, Overview; Radiation Therapy
and actinomycin D, in the usual prescribed doses,
and Chemotherapy, Neurological Complications of
produce no neurological side effects in man. How-
ever, neurotoxicity has been produced with both
drugs in experimental animals. Adriamycin has been Further Reading
associated with cerebellar disturbances. Actinomy- Chang, L. W., and Dyer, R. S. (Eds.) (1995). Handbook of
cin D causes tremors, jerky movements, and spinal Neurotoxicology. Dekker, New York.
cord disturbances with weakness of the limbs and Goetz, C. G. (1985). Neurotoxins in Clinical Practice. Spectrum,
sensory deficits. New York.
234 ANTI-PHOSPHOLIPID ANTIBODIES
MacDonald, D. R. (1991). Neurologic complications of che-
motherapy. Neurol. Clin. 9, 955–967.
Young, D. F., and Posner, J. B. (1980). Nervous system toxicity of
the chemotherapeutic agents. In Handbook of Clinical Neurol-
ogy (P. J. Vinken and G. W. Bruyn, Eds.), Vol. 39, pp. 91–130.
North-Holland, Amsterdam.
Anti-Phospholipid Antibodies
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANTI-PHOSPHOLIPIDS are immunoglobulins of the
IgG, IgM, IgA, and mixed classes directed against
negatively charged or neutral phospholipids. They
were first detected as reagin, a type of anti-
phospholipid antibody found in the blood of
patients with syphilis. Later, they were found in
patients without syphilis, some of whom had
systemic lupus erythematosus (SLE), in which
case the anti-phospholipids caused a biological
false-positive serological test for syphilis. Anti-
phospholipid antibodies (aPLs) were termed anti-
coagulants because they were found to prolong
the phospholipid-dependent tests of coagulation;
they were also termed the lupus anticoagulant
(LA), although this was discovered to actually
be a misnomer because the LA was found to be
associated with a thrombotic tendency. A more
specific assay was developed for aPL, with
cardiolipin (a serologically active phospholipid) as
the antigen, using a solid phase radioimmuno-
assay for anticardiolipin (aCL) detection. Subse-
quently, an enzyme-linked immunosorbent assay
(ELISA) was developed and standardized. There
is partial concordance between the assays for aCL
and LA. Some patients may be positive for one
but not the other, and some will harbor both. aCLs
have been identified in approximately 10% of
unselected patients with first ischemic stroke. The
isotype mainly implicated in thrombosis is IgG,
specifically subtype IgG-2. Recent data suggest that
the presence of high titers of aCL immunoreactivity,
mainly the IgG isotype but possibly also IgM,
correlates with an increased risk of thrombosis.
Generally, titers of IgG aCL implicated are 440
GPL units, although this is a somewhat arbitrary
cutoff point and is dependent on the test systems,
which are not standardized.
Table 1 PAPS ASSOCIATED FEATURES
Venous occlusions
Arterial occlusions
Recurrent fetal loss
Thrombocytopenia
Livedo reticularis
Chorea
Migraine
PRIMARY ANTI-PHOSPHOLIPID SYNDROME
Although aPLs can be associated with SLE or lupus-
like disease, a large proportion of patients have
antiphospholipid syndrome (aPS), a term used to
describe arteriovenous thrombosis, sometimes ac-
companied by thrombocytopenia, occurring in the
presence of aPLs.
When aPS occurs without major serological or
clinical features of SLE, it has been described as the
primary aPS or PAPS. The clinical and laboratory
features of PAPS (Table 1) were reviewed in 70
patients by Asherson et al., who found the following:
venous thrombosis (54%); arterial thrombosis
(44%); recurrent fetal loss, usually due to placental
infarction (34%); ANA, usually low titer (46%);
thrombocytopenia, platelet count o150,000 (46%);
VDRL positivity (33%); aCL IgG and LA (86%);
aCL IgM (39%); and positive Coombs test (14%).
Sneddon’s syndrome (i.e., livedo reticularis asso-
ciated with ischemic cerebrovascular disease) has
been associated with the presence of aPLs. Livedo
reticularis has been found to occur alone or in the
presence of stroke or transient ischemic attack or
chorea. Chorea has been noted in patients with aPS.
Some have been found to have caudate or basal
ganglionic strokes on brain imaging, although some
have normal imaging studies or strokes in regions
that do not explain the chorea, and the etiology is
unknown. Headaches, often characterized as mi-
graine and associated with migraine accompani-
ments or more complicated stroke-like features, are
also associated with aPLs.
In many cases of recurrent thrombosis related to
aPLs, those with venous thrombosis will have further
venous thromboses and those with arterial throm-
bosis will have further arteriothrombotic events.
The aPLs are found in a variety of autoimmune
disorders other than SLE, including rheumatoid
arthritis, primary Sjogrens syndrome, and progres-
sive systemic sclerosis. They can also be found in

TREATMENT
Although corticosteroids or other immunosuppres-
sive agents have been used in symptomatic patients
with aPLs, there is no conclusive evidence that
they are effective for preventing thromboembolic
complications. Plasma exchange will lower anti-
body titers, but they return to prior levels within a
few days.
Stroke recurrence in patients who harbor aPLs is
reduced by high levels of warfarin anticoagulation,
resulting in an international normalized ratio of Z3.
Whether aspirin helps is unclear; in studies in which
it was used alone, recurrence rates were unchanged.
When added to warfarin, recurrence rates were
changed by high INR, whether aspirin was used or
not. On the other hand, because cardiac valvular
lesions are platelet-fibrin deposits, the use of ASA
empirically makes sense, at least in those patients
with valvular lesions.
CONCLUSION
The aPLs are associated with arterial and venous
thromboses as well as cardiac valvular lesions. These
autoantibodies, rather than being a single or even a
homogeneous group, constitute a heterogeneous
family with different isotypes, different specificities,
different requirements of cofactor proteins, and
different immunochemical characteristics. The aPL-
P may interfere with the kinetics of coagulation
reactions or stimulate the prothrombotic activities of
endothelial cells and monocytes and promote coagu-
lation by complex molecular interactions. Approxi-
mately 10–15% of patients, despite presenting the
clinical picture of the aPS, have negative tests for
aCL and LA. Thus, in patients with high clinical
suspicion, further testing is indicated, such as
antibodies to b2-GPI, possibly to prothrombin, or
to noncardiolipin phospholipids.
—L. Dana DeWitt
See also–Arterial Thrombosis, Cerebral; Cerebral
Venous Thrombosis; Stroke Risk Factors;
Systemic Lupus Erythematosus (SLE)
Further Reading
Anti-phospholipid Antibodies in Stroke Study (APASS) Group
(1990). Clinical and laboratory findings in patients with anti-
phospholipid antibodies and cerebral ischemia. Stroke 21,
1268–1273.
ANTIPLATELET THERAPY 237
Anti-phospholipid Antibodies in Stroke Study (APASS)
Group (1993). Anticardiolipin antibodies are an independent
risk factor for first ischemic stroke. Neurology 43,
2069–2073.
Asherson, R. A., Khamashta, M. A., Ordi-Ros, J., et al. (1989).
The ‘‘primary’’ anti-phospholipid syndrome: Major clinical and
serological features. Medicine 68, 366–374.
Brandt, J. T., Triplett, D. A., Alving, B., et al. (1995). Criteria
for the diagnosis of the lupus anticoagulants: An update.
On behalf of the Subcommittee on Lupus Anticoagulant/
Anti-phospholipid Antibody of the Scientific and Standardiza-
tion Committee of the ISTH. Thromb. Haemost. 74,
1185–1190.
Hojnik, M., George, J., Ziporen, L., et al. (1996). Heart valve
involvement (Libman–Sacks endocarditis) in the anti-phospho-
lipid syndrome. Circulation 93, 1579–1587.
Khamashta, M. A., Cuadrado, M. J., Mujic, F., et al. (1995). The
management of thrombosis in the anti-phospholipid-antibody
syndrome. N. Engl. J. Med. 332, 993–997.
Tanne, D., Triplett, D. A., and Levine, S. R. (1998). Anti-
phospholipid-protein antibodies and ischemic stroke: Not just
cardiolipin any more. Stroke 29, 1755–1758.
Toschi, V., Motta, A., Castelli, C., et al. (1998). High prevalence of
antiphosphatidylinositol antibodies in young patients with
cerebral ischemia of undetermined cause. Stroke 29, 1759–
1764.
Antiplatelet Therapy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RECENT developments in the use of antiplatelet
therapy for prevention of stroke have been influenced
by two major, but necessarily opposing, trends in
clinical perspective: evidence-based medicine (EBM)
and individualized patient care. The first, concerned
with public health (i.e., the effect of antiplatelet
therapy on the collective of patients), has been
responsible for the widespread acceptance of new
antiplatelet agents. For EBM, the aim is to reduce the
incidence of stroke in the population. Nonetheless, a
few investigators recognize that what is true for the
collective, broadly understood in terms of averages,
may not necessarily apply to the individual patient,
who may be very different from the average patient.
This view derives from the results of tests that can be
done on the individual patient to measure the
antiplatelet effect of the antiplatelet drug at a given
point in time. It also reflects the fact that the
mathematical basis for EBM—probability—was
never meant to predict or reflect the individual
‘‘throw of the die.’’ This latter approach, although
not considered scientific, can be supported by a
238 ANTIPLATELET THERAPY
broader mathematical approach that includes but is
not limited to probability-based statistics. Because
the mathematics of chance (probability) defines
science today, other mathematical approaches have
not been presented in the EBM-based medical
literature. This is a paradox because it is the
individual patient and his or her biological response
to the antiplatelet agent that determine thrombus
formation and the event of vascular occlusion with
subsequent stroke.
In order to understand thrombus formation in any
given individual, one must be able to find and gage
the components of Virchow’s triad in that person
using available laboratory tests. Virchow’s triad is the
accepted biological model for thrombus formation. It
refers to the interaction between endothelial lining,
blood components, and flow that results in thrombus
formation. EBM does not deal with the biology of the
individual patient. Thus, the physician is faced with
having to use antiplatelet therapy in a given patient
using the information available from both EBM and
known biological mechanisms of thrombosis. There-
fore, for any given patient, when considering the
prescription of an antiplatelet agent the physician
must ask what and how much effect will an agent
have on the patient compared to the ‘‘odds.’’
Despite the individual patient-shallow and non-
mechanistic stance of EBM, hypothesis generation
regarding the mechanism of antiplatelet effect for
stroke prevention has in part caused and resulted
from unexpected results in large double-blind ran-
domized trials. An example of this is the case of the
ESPS-2 trial, in which a combination of very low-
dose aspirin (25 mg bid) and extended-release dipyr-
idamole (200 mg bid) was shown to result in a far
more protective effect against stroke occurrence than
that previously shown to be afforded by higher doses
of aspirin combined with non-extended-release di-
pyridamole. Specific reasons for these findings in this
study are mechanistically lacking because individual
measured response to platelet or endothelial action
of the drug was not performed. However, hypotheses
can be generated. One hypothesis is that the
extended-release form of dipyridamole worked di-
rectly at the endothelial level by affecting endothelial
function (vasodilatation) or adhesion and aggrega-
tion of platelets. Another possibility is that aspirin in
lower doses is more effective in terms of inhibition of
platelet aggregation than in higher doses, suggesting
a nonlinear biological response to this agent on
platelet aggregation possibly related to its effect at
the level of the endothelium. No studies have been
done directly measuring inhibition of platelet aggre-
gation in patients to prevent stroke at lower doses of
aspirin in order to confirm the nonlinear response to
aspirin. Although not unexpected from in vitro
studies showing a prostacyclin sparing effect of
aspirin at low dosage, it is still not known what
happens in the individual patient regarding either
this mechanism or inhibition of platelet aggregation
in vivo or ex vivo when small (50–150 mg) to larger
(325 mg) doses of aspirin are given. A third hypoth-
esis that may be generated from the ESPS-2 study is
that it is not the sole action of either nor the additive
effect of aspirin or dipyridamole ER that is respon-
sible for the clinical benefit on the collective of
patients but rather the interaction of the two agents
at this level or at the level of each patient individually
that is synergistic by measurable mechanism.
Interaction between antiplatelet agents that work
to inhibit platelet participation in thrombus forma-
tion is possible when the agents have different
mechanisms of action. Dipyridamole, aspirin, clopi-
dogrel, and ticlopidine affect platelet aggregation in
different ways. Interactions can be described as
synergistic, additive, or incompatible. Combination
antiplatelet therapy can be chosen for the purpose of
achieving a particular effect.
A synergistic interaction of antiplatelet agents at
the biological level has been studied for ticlopidine
and aspirin and for clopidogrel and aspirin. Using the
probability-based statistical analysis of EBM, these
studies may be found in the cardiology literature and
concern the use of these agents in patients with
coronary stent placement. Although shown to be
more than additive, no measurement of the degree of
synergy is reported in any given patient or for the
collective in these reports. Other studies exist in the
scientific but nonmedical literature and use a
different mathematical basis for measurement of
synergy, additivity, and incompatibility. Using fuzzy
mathematics, the synergistic, additive, and incompa-
tible interactions of clopidogrel–aspirin and ticlopi-
dine–aspirin have been measured. These studies have
shown that in some individuals there is a synergistic
interaction on inhibition of platelet aggregation
when epinephrine is the agonist in ex vivo testing,
and that the interaction is incompatible in some
when adenosine diphosphate is used. These inter-
active responses may be important in certain
physiological contexts. Because of the non-probabil-
ity-based mathematical approach used in these
studies, they do not fit into the scientific or EBM
literature.

Therefore, despite the fact that biological response
to antiplatelet therapy can be measured, a mechan-
istic approach to the efficacy of antiplatelet therapy
does not exist in the stroke literature that uses
probability-based statistics and level 1 evidence of
EBM. Interest has focused on the statistical relevance
of the data: the number of patients needing to be
treated, the cost of a given therapy to the community
at large, and all-or-none statistical response for the
collective. However, it is the individual patient who
must be treated by the physician, and physicians
cannot afford to base treatment decisions on chance
if they want to determine a particular effect of
therapy. Only by ensuring continued desired measur-
able biological effect can the physician do so, and
this requires initial and repeated measurements of the
effect of antiplatelet therapy in individual patients. It
is a pity that there is no level 1 evidence to suggest
that a particular biological effect of antiplatelet
therapy is effective for stroke prevention in the
collective. Nonetheless, the assurance of individual
patient response to antiplatelet therapy will depend
on technological advances for measurement of
antiplatelet effect and on basic science advances in
the understanding of the role of platelets in vascular
occlusion and thrombosis. These advances can be the
basis for proof of efficacy at the population level or
for patient-specific assured measurement of effect.
Because the patient is their own control over time,
controlled studies of collective patients will never
address individual responses to antiplatelet therapy
and the phenomenon of nonresponse to any parti-
cular agent.
Human physiology is complex and context depen-
dent. For this reason, what is true at one point in
time may not be true at another, even at the level of
the collective. The complexity of one patient’s
physiology and context may not be generalizable to
any given imaginary ‘‘average’’ patient. Ultimately,
however, the interaction of the individual expert
physician and the individual patient that will
determine outcome for stroke prevention.
—Cathy M. Helgason
See also–Anticoagulant Treatment; Arterial
Thrombosis, Cerebral; Cerebral Metabolism and
Blood Flow; Coagulopathies and Stroke; Stroke
Risk Factors
Further Reading
Diener, H. D., Cunha, L., Forbes, C., et al. (1996). European
Stroke Prevention Study: II. Dipyridamole and acetylsalicylic
ANTIPSYCHOTIC PHARMACOLOGY 239
acid in the secondary prevention of stroke. J. Neurol. Sci. 143,
1–13.
Helgason, C. M., Hoff, J. A., Kondos, G. T., et al. (1993). Platelet
aggregation in patients with atrial fibrillation taking aspirin or
warfarin. Stroke 24, 1458–1461.
Helgason, C. M., Tortorice, K. L., Winkler, S. R., et al. (1993).
Aspirin response and failure in cerebral infarction. Stroke 24,
345–350.
Helgason, C. M., Bolin, K. M., Hoff, J. A., et al. (1994).
Development of aspirin resistance in persons with previous
ischemic stroke. Stroke 25, 2331–2336.
Helgason, C. M., Jobe, T. H., Brace, L. D., et al. (1999). The
fuzzification of platelet aggregation response for interpretation
of interactive effect of combination aspirin–ticlopidine therapy
in patients with stroke. Proc. Int. Conf. North Am. Fuzzy Inf.
Process. Soc. 18th, 283–288.
Helgason, C. M., Mordeson, J. N., Jobe, T. H., et al.
(2000). Inhibition of platelet aggregation alone and in
combination with clopidogrel: Synergy, incompatibility and
additivity. Proc. Int. Conf. North Am. Fuzzy Inf. Process. Soc.
19th, 215–218.
Herbert, J. M., Bernat, A., Samama, M., et al. (1996). The anti
aggregating effect and antithrombotic activity of ticlopidine is
potentiated by aspirin in the rat. Thromb. Haemost. 76, 94–98.
Kosko, B. (1992). Neural Networks and Fuzzy Systems. A
Dynamical Approach to Machine Intelligence. Prentice-Hall,
Englewood Cliffs, NJ.
Moussa, I., Oetgen, M., Roubin, G., et al. (1999). Effectiveness of
clopidogrel and aspirin versus ticlopidine and aspirin in
preventing stent thrombosis after coronary stent implantation.
Circulation 99, 2364–2366.
Patrono, C., Coller, B., Dalen, J. E., et al. (2001). Platelet active
drugs: The relationships among dose, effectiveness, and side
effects. Sixth ACCP Consensus Conference on Antithrombotic
Therapy. Chest 119, 39S–63S.
Antipsychotic Pharmacology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANTIPSYCHOTICS are medications that ameliorate
psychotic symptoms, including hallucinations, delu-
sions, paranoia, disordered thinking, bizarre beha-
vior, abnormalities of affect and motivation, and
cognitive impairments. Although mainstays in treat-
ing schizophrenia, they can be effective in treating
psychotic symptoms associated with other psychia-
tric disorders or with other medical and neurological
conditions, such as dementia and delirium. As a
general class of drugs, antipsychotics are effective,
well researched, and have a high ratio of efficacy to
safety. The use of antipsychotic medications during
the latter half of the 20th century was largely
responsible for the ability to treat individuals with
psychotic disorders in their communities and with

Therefore, despite the fact that biological response
to antiplatelet therapy can be measured, a mechan-
istic approach to the efficacy of antiplatelet therapy
does not exist in the stroke literature that uses
probability-based statistics and level 1 evidence of
EBM. Interest has focused on the statistical relevance
of the data: the number of patients needing to be
treated, the cost of a given therapy to the community
at large, and all-or-none statistical response for the
collective. However, it is the individual patient who
must be treated by the physician, and physicians
cannot afford to base treatment decisions on chance
if they want to determine a particular effect of
therapy. Only by ensuring continued desired measur-
able biological effect can the physician do so, and
this requires initial and repeated measurements of the
effect of antiplatelet therapy in individual patients. It
is a pity that there is no level 1 evidence to suggest
that a particular biological effect of antiplatelet
therapy is effective for stroke prevention in the
collective. Nonetheless, the assurance of individual
patient response to antiplatelet therapy will depend
on technological advances for measurement of
antiplatelet effect and on basic science advances in
the understanding of the role of platelets in vascular
occlusion and thrombosis. These advances can be the
basis for proof of efficacy at the population level or
for patient-specific assured measurement of effect.
Because the patient is their own control over time,
controlled studies of collective patients will never
address individual responses to antiplatelet therapy
and the phenomenon of nonresponse to any parti-
cular agent.
Human physiology is complex and context depen-
dent. For this reason, what is true at one point in
time may not be true at another, even at the level of
the collective. The complexity of one patient’s
physiology and context may not be generalizable to
any given imaginary ‘‘average’’ patient. Ultimately,
however, the interaction of the individual expert
physician and the individual patient that will
determine outcome for stroke prevention.
—Cathy M. Helgason
See also–Anticoagulant Treatment; Arterial
Thrombosis, Cerebral; Cerebral Metabolism and
Blood Flow; Coagulopathies and Stroke; Stroke
Risk Factors
Further Reading
Diener, H. D., Cunha, L., Forbes, C., et al. (1996). European
Stroke Prevention Study: II. Dipyridamole and acetylsalicylic
ANTIPSYCHOTIC PHARMACOLOGY 239
acid in the secondary prevention of stroke. J. Neurol. Sci. 143,
1–13.
Helgason, C. M., Hoff, J. A., Kondos, G. T., et al. (1993). Platelet
aggregation in patients with atrial fibrillation taking aspirin or
warfarin. Stroke 24, 1458–1461.
Helgason, C. M., Tortorice, K. L., Winkler, S. R., et al. (1993).
Aspirin response and failure in cerebral infarction. Stroke 24,
345–350.
Helgason, C. M., Bolin, K. M., Hoff, J. A., et al. (1994).
Development of aspirin resistance in persons with previous
ischemic stroke. Stroke 25, 2331–2336.
Helgason, C. M., Jobe, T. H., Brace, L. D., et al. (1999). The
fuzzification of platelet aggregation response for interpretation
of interactive effect of combination aspirin–ticlopidine therapy
in patients with stroke. Proc. Int. Conf. North Am. Fuzzy Inf.
Process. Soc. 18th, 283–288.
Helgason, C. M., Mordeson, J. N., Jobe, T. H., et al.
(2000). Inhibition of platelet aggregation alone and in
combination with clopidogrel: Synergy, incompatibility and
additivity. Proc. Int. Conf. North Am. Fuzzy Inf. Process. Soc.
19th, 215–218.
Herbert, J. M., Bernat, A., Samama, M., et al. (1996). The anti
aggregating effect and antithrombotic activity of ticlopidine is
potentiated by aspirin in the rat. Thromb. Haemost. 76, 94–98.
Kosko, B. (1992). Neural Networks and Fuzzy Systems. A
Dynamical Approach to Machine Intelligence. Prentice-Hall,
Englewood Cliffs, NJ.
Moussa, I., Oetgen, M., Roubin, G., et al. (1999). Effectiveness of
clopidogrel and aspirin versus ticlopidine and aspirin in
preventing stent thrombosis after coronary stent implantation.
Circulation 99, 2364–2366.
Patrono, C., Coller, B., Dalen, J. E., et al. (2001). Platelet active
drugs: The relationships among dose, effectiveness, and side
effects. Sixth ACCP Consensus Conference on Antithrombotic
Therapy. Chest 119, 39S–63S.
Antipsychotic Pharmacology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ANTIPSYCHOTICS are medications that ameliorate
psychotic symptoms, including hallucinations, delu-
sions, paranoia, disordered thinking, bizarre beha-
vior, abnormalities of affect and motivation, and
cognitive impairments. Although mainstays in treat-
ing schizophrenia, they can be effective in treating
psychotic symptoms associated with other psychia-
tric disorders or with other medical and neurological
conditions, such as dementia and delirium. As a
general class of drugs, antipsychotics are effective,
well researched, and have a high ratio of efficacy to
safety. The use of antipsychotic medications during
the latter half of the 20th century was largely
responsible for the ability to treat individuals with
psychotic disorders in their communities and with
240 ANTIPSYCHOTIC PHARMACOLOGY
psychosocial rehabilitation services rather than in
chronic psychiatric hospitals.
MECHANISM OF ACTION
Current data suggest that primary antipsychotic
effect is due to antagonism at D2 dopamine receptors
or at receptors of the D2 dopamine family. The
relationship between D2 dopamine receptor antag-
onism and clinical potency of antipsychotic drugs
continues to be one of the most vigorous and
informative correlations in clinical pharmacology.
Theories and research on the pathophysiology of
schizophrenia and related psychoses need to take this
action into account. Clinical action parallels the
development of ‘‘depolarization blockade,’’ or down-
regulation of dopamine neurotransmission, in meso-
limbic dopamine neurons. Older agents cause this
downregulation in nigrostriatal dopamine pathways
as well; hence, they produce more motor side effects.
Antipsychotic effects continue to develop over weeks
to months, and D2 dopamine receptor antagonism
and effects on dopamine neurotransmission are likely
only first steps in a cascade of complex, long-term
changes in multiple neurotransmitter systems. The
antipsychotic agents differ in their spectrum of action
on dopamine receptor subtypes and their other
receptor activities [mainly serotonin (5-HT), choli-
nergic, adrenergic, and histaminic receptors]; thus,
they differ in the subtleties of their actions and their
side effects. Newer antipsychotics, with improved
side effect profiles and possibly improved efficacy, are
better tolerated by many patients and are thus largely
supplanting older agents.
TYPICAL ANTIPSYCHOTICS
For more than 25 years, the mainstay of treatment of
psychotic symptomatology has been the typical
antipsychotics, or neuroleptics. Even though they
represented eight different chemical classes of drugs,
the typical antipsychotics had very similar efficacy
but differed in their potencies and side effect profiles.
Original studies in the 1950s first demonstrated the
antipsychotic effects of 300–400 mg chlorpromazine
(CPZ) per day. Antipsychotic potencies continue to
be compared to CPZ equivalents.
Typical antipsychotics are absorbed orally within
60 min, with intramuscular effects within 10 min.
They are highly lipid soluble. They are extensively
metabolized, sometimes to active metabolites, by the
hepatic cytochrome P450 system. Patients exhibit
great variations in how they metabolize these drugs,
which may account for the huge variation in plasma
concentrations found among patients treated with
the same dose. Most have half-lives of more than 24
hr and can be given once a day. Because of
alterations in metabolism and pharmacokinetics,
half-lives are extended in the elderly and doses
should be reduced.
Although the mode of action is similar through D2
dopamine receptor antagonism, side effects result
from various affinities at other receptors, particu-
larly noradrenergic, cholinergic, and histaminic
receptors. In general, high-potency drugs produce
less anticholinergic effects, sedation, or hypotension
but more extrapyramidal symptoms. Extrapyrami-
dal motor side effects of neuroleptics can often be
effectively treated with anticholinergic agents, but
side effects of these agents (including dry mouth,
blurred vision, urinary retention, and negative
effects on concentration and memory) may limit
their use.
Tardive dyskinesia (TD) is a potentially more
severe side effect usually associated with long-term
use of antipsychotics. It is an involuntary movement
disorder characterized by choreoathetoid movements
of bucco-oral areas, extremities, or trunk. It appears
to be due to long-term changes in GABA neuro-
transmission in the striatonigral pathways. It gen-
erally requires longer term exposure to
antipsychotics (usually on the order of a few
months), but the dose–duration–response relation-
ships are not vigorous. The liability for typical agents
to produce TD is approximately 4% per year of
exposure, with symptoms waxing and waning and
sometimes remitting. After more than a decade of
exposure, approximately 40% of patients on typical
antipsychotics will have some symptoms (usually
minimal). The risk for TD from atypical antipsycho-
tics appears to be only a fourth that from typical
agents. Neuroleptic malignant syndrome is another
side effect of neuroleptics that is uncommon; it is
much less likely produced by atypical agents.
NEWER ATYPICAL AGENTS
Antipsychotics made available during the past
decade are often termed ‘‘atypicals’’ because, unlike
the older ‘‘typical’’ neuroleptics, they fail to produce
cataplexy in preclinical animal studies at doses
producing behaviors suggestive of antipsychotic
effects. These newer agents were designed to have
high 5-HT-2:D2 receptor binding ratios and do not

produce as much reduction in dopamine neurotrans-
mission in nigrostriatal dopamine pathways com-
pared to mesolimbic dopamine pathways. Hence,
they have a lower frequency of extrapyramidal
motor side effects (EPS) [parkinsonism, akathisia
(motor restlessness), or acute dystonic reactions]
compared to the older, typical antipsychotics—the
neuroleptics. Atypicals have a complex mixture of
pharmacological properties and relative differences
in receptor binding and actions that account for
subtle differences in their efficacy and side effects
(Table 1).
The prototypical atypical antipsychotic is cloza-
pine, but it remains in a class by itself because newer
atypical agents have not shown similar activity in
treating patients with schizophrenia who are treat-
ment refractory to other agents. Approximately 30%
of patients fail to have an adequate response to
nonclozapine antipsychotics, some with tormenting
auditory hallucinations and paranoid delusions and
severe thought disorganization that make daily living
impossible without extensive supervision and assis-
tance. Clozapine has shown significant benefit for
30–50% of otherwise treatment refractory patients.
Clozapine is essentially devoid of EPS side effects
and TD.
The mechanism of the unique nature of clozapi-
ne’s actions is not understood, but it is active at
multiple receptor systems. This aspect of clozapine
makes it prone to non-EPS side effects, all of which
can often be effectively monitored or managed. The
most serious side effect is the 1–2% frequency of
agranulocytosis (cessation of production of white
blood cells that fight infection), which can result in
death. Drug administration requires weekly or
biweekly blood tests to monitor white blood cell or
neutrophil levels for as long as the patient is on the
medicine. With active monitoring, the risk of
morbidity or mortality is minimal. Other side effects
Table 1 ATYPICAL ANTIPSYCHOTICS
Standard clinical dose Prolactin
Atypical agent range (mg) EPS elevation
Risperidone 4–9 þþ þþþ
Olanzapine 5–30 þ 7
Quetiapine 300–900 7 7
Ziprasidone 40–160 7 7
Clozapine 300–900 0 7
ANTIPSYCHOTIC PHARMACOLOGY 241
include a dose-dependent increased risk of seizures
compared to other agents, tachycardia, orthostatic
hypotension, and constipation. Some patients re-
spond remarkably to this drug, but it is still
underutilized due to concerns about side effects.
Tragically, there are also many patients with schizo-
phrenia who do not respond to any of the current
medications.
Risperidone is an effective antipsychotic with a low
frequency of EPS. Its relatively high D2 binding
results in EPS emerging at higher doses. Studies
support improvement in deficit or negative symptoms
of schizophrenia (poverty of speech and thought
content, apathy, flat affect, and cognitive impairment)
compared to the typical antipsychotic haloperidol. Its
side effect profile is remarkable for a relatively lower
frequency of weight gain. However, it does produce a
relatively higher elevation of the pituitary hormone
prolactin, which can cause impotence, amenorrhea,
osteoporosis, and galactorrhea.
Olanzapine has also been shown to be equivalent
to haloperidol in treating the positive symptoms of
psychosis in schizophrenia (hallucinations, thought
disorder, and delusions), and it demonstrates in-
creased efficacy in treating negative symptoms. There
is evidence that it has effects on mood, and it has
been approved for use as a single agent in treating
acute mania. Its half-life of 31 hr makes once-a-day
dosing feasible, and its low affinity for various
hepatic cytochromes results in few drug interactions.
Of the atypicals, side effects of weight gain (probable
histaminic effects) and effects on glucose and lipid
levels sometimes limit its use.
Quetiapine has been shown to be comparable to
haloperidol in treating both positive and negative
symptoms in schizophrenia. It has a high 5-HT-2:D2
binding ratio, but studies have failed to show
improved efficacy for negative symptoms. This may
be due to study populations, design, or rating scales
Relative side effects
Weight
gain Sedation Orthostasis Anticholinergic
þþ þ þþ þþ
þþþþ þþ þ þþ
þ þþþ þþ þ
þ þþ þ þ
þþþ þþþþ þþþþ þþþþ
242 ANXIETY DISORDERS, OVERVIEW
used. Due to its shorter half-life and rapid dissocia-
tion from the D2 dopamine receptor, it may require
more than once-a-day dosing. It undergoes extensive
metabolism in the liver and interactions with other
drugs need to be considered. Side effects include
orthostatic hypotension (primarily during titration)
and sedation. An association with cataract develop-
ment in dogs is unlikely to be relevant to humans. Its
lower frequency of weight gain is an advantage in
some cases.
Ziprasidone is an antipsychotic with both high 5-
HT-2 and D2 binding. Drug interactions may be
minimal due to limited effect on the cytochrome
P450 system, but a short half-life may indicate a need
for twice-a-day dosing. It also promises to have a
lower frequency of weight gain, and 5-HT-1A
agonism and significant serotonin and norepinephr-
ine reuptake inhibition may indicate mood-elevating
effects. Ziprasidone appears to increase the QT
interval more than the other atypicals do, but there
is no evidence this increases the risk of cardiac
arrhythmias or sudden death.
Although there are less data supporting the use of
atypicals in psychoses associated with diagnoses
other than schizophrenia, such as delirium, psychotic
symptoms associated with depression, or agitation
and psychosis in dementia, there is no reason to
believe that they are any less effective than tradi-
tional neuroleptics.
CONCLUSION
Idiosyncratic primary responses in individuals make
theoretically favoring one antipsychotic drug over
another difficult. If a patient fails to adequately
respond to one, they may respond to another.
Outcome studies, although not definitive, suggest
that although newer drugs are more expensive,
overall there are system-wide cost savings and
improvement in the quality of life. Although under
development, long-acting, injectable atypicals are not
currently available. The most common cause of
treatment failure and morbidity from psychotic
disorders is noncompliance. Although side effects of
medications play a role, it is multifactorial and
includes the stigma of the illnesses, lack of insight
as a primary symptom, and lack of educational
interventions that are appropriately tailored to
the cognitive deficits in the illnesses. Schizophrenia
is a common (at least 1% of the population),
devastating psychotic illness that awaits the devel-
opment of more effective antipsychotics with
fewer side effects. New research in such areas
as pharmacogenetics and functional brain imaging
may eventually make individualized treatment more
effective.
—Catherine A. Leslie
See also–Antianxiety Pharmacology;
Antidepression Pharmacology; Delusions;
Hallucinations; Mania; Paranoia; Schizophrenia,
Treatment; Tardive Dyskinesia
Further Reading
Beasley, C. M., Tollefson, G., Tran, P., et al. (1997). Olanzapine
versus placebo and haloperidol: Acute phase results of the
North American double-blind olanzapine trial. Neuropsycho-
pharmacology 16, 88–90.
Borison, R. L., Pathiraja, A. P., Diamond, B. I., et al. (1992).
Risperidone: clinical safety and efficacy in schizophrenia.
Psychopharmacol. Bull. 28, 213–218.
Goodman, L. S., Gilman, A., Hardman, J. G., et al. (1996). The
Pharmacological Basis of Therapeutics, 9th ed. McGraw-Hill,
New York.
Kane, J. M., Honigfeld, G., Singer, J., et al. (1988). Clozapine in
treatment-resistant schizophrenics. Psychopharmacol. Bull. 24,
62–67.
Peuskens, J., and Link, C. G. (1997). A comparison of quetiapine
and chlorpromazine in the treatment of schizophrenia. Acta
Psychiatr. Scand. 96, 265–273.
Stahl, S. (1996). Essential Psychopharmacology. Cambridge Univ.
Press, New York.
Anxiety Disorders, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
PATHOLOGICAL ANXIETY is a common symptom with
a broad differential diagnosis. Clinicians should first
investigate for possible medication or substance-
induced anxiety. Second, a number of medical
illnesses can present with anxiety, notably hypogly-
cemia, complex partial seizures, and cardiopulmon-
ary disease. Finally, the clinician should evaluate for
the presence of a primary psychiatric disorder, such
as panic disorder, major depression, personality
disorder, or an adjustment disorder in response to a
stressor.
SUBSTANCE-INDUCED ANXIETY DISORDERS
Drug toxicity and withdrawal commonly cause
anxiety. Table 1 lists a number of drugs that may
242 ANXIETY DISORDERS, OVERVIEW
used. Due to its shorter half-life and rapid dissocia-
tion from the D2 dopamine receptor, it may require
more than once-a-day dosing. It undergoes extensive
metabolism in the liver and interactions with other
drugs need to be considered. Side effects include
orthostatic hypotension (primarily during titration)
and sedation. An association with cataract develop-
ment in dogs is unlikely to be relevant to humans. Its
lower frequency of weight gain is an advantage in
some cases.
Ziprasidone is an antipsychotic with both high 5-
HT-2 and D2 binding. Drug interactions may be
minimal due to limited effect on the cytochrome
P450 system, but a short half-life may indicate a need
for twice-a-day dosing. It also promises to have a
lower frequency of weight gain, and 5-HT-1A
agonism and significant serotonin and norepinephr-
ine reuptake inhibition may indicate mood-elevating
effects. Ziprasidone appears to increase the QT
interval more than the other atypicals do, but there
is no evidence this increases the risk of cardiac
arrhythmias or sudden death.
Although there are less data supporting the use of
atypicals in psychoses associated with diagnoses
other than schizophrenia, such as delirium, psychotic
symptoms associated with depression, or agitation
and psychosis in dementia, there is no reason to
believe that they are any less effective than tradi-
tional neuroleptics.
CONCLUSION
Idiosyncratic primary responses in individuals make
theoretically favoring one antipsychotic drug over
another difficult. If a patient fails to adequately
respond to one, they may respond to another.
Outcome studies, although not definitive, suggest
that although newer drugs are more expensive,
overall there are system-wide cost savings and
improvement in the quality of life. Although under
development, long-acting, injectable atypicals are not
currently available. The most common cause of
treatment failure and morbidity from psychotic
disorders is noncompliance. Although side effects of
medications play a role, it is multifactorial and
includes the stigma of the illnesses, lack of insight
as a primary symptom, and lack of educational
interventions that are appropriately tailored to
the cognitive deficits in the illnesses. Schizophrenia
is a common (at least 1% of the population),
devastating psychotic illness that awaits the devel-
opment of more effective antipsychotics with
fewer side effects. New research in such areas
as pharmacogenetics and functional brain imaging
may eventually make individualized treatment more
effective.
—Catherine A. Leslie
See also–Antianxiety Pharmacology;
Antidepression Pharmacology; Delusions;
Hallucinations; Mania; Paranoia; Schizophrenia,
Treatment; Tardive Dyskinesia
Further Reading
Beasley, C. M., Tollefson, G., Tran, P., et al. (1997). Olanzapine
versus placebo and haloperidol: Acute phase results of the
North American double-blind olanzapine trial. Neuropsycho-
pharmacology 16, 88–90.
Borison, R. L., Pathiraja, A. P., Diamond, B. I., et al. (1992).
Risperidone: clinical safety and efficacy in schizophrenia.
Psychopharmacol. Bull. 28, 213–218.
Goodman, L. S., Gilman, A., Hardman, J. G., et al. (1996). The
Pharmacological Basis of Therapeutics, 9th ed. McGraw-Hill,
New York.
Kane, J. M., Honigfeld, G., Singer, J., et al. (1988). Clozapine in
treatment-resistant schizophrenics. Psychopharmacol. Bull. 24,
62–67.
Peuskens, J., and Link, C. G. (1997). A comparison of quetiapine
and chlorpromazine in the treatment of schizophrenia. Acta
Psychiatr. Scand. 96, 265–273.
Stahl, S. (1996). Essential Psychopharmacology. Cambridge Univ.
Press, New York.
Anxiety Disorders, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
PATHOLOGICAL ANXIETY is a common symptom with
a broad differential diagnosis. Clinicians should first
investigate for possible medication or substance-
induced anxiety. Second, a number of medical
illnesses can present with anxiety, notably hypogly-
cemia, complex partial seizures, and cardiopulmon-
ary disease. Finally, the clinician should evaluate for
the presence of a primary psychiatric disorder, such
as panic disorder, major depression, personality
disorder, or an adjustment disorder in response to a
stressor.
SUBSTANCE-INDUCED ANXIETY DISORDERS
Drug toxicity and withdrawal commonly cause
anxiety. Table 1 lists a number of drugs that may
 ANXIETY DISORDERS, OVERVIEW 243

Table 1 DRUGS THAT CAN CAUSE ANXIETYa prominent symptom. For example, patients with
paranoid schizophrenia may have anxiety associated
Stimulants Dopaminergics
Amphetamines Amantadine with paranoid delusions. The Diagnostic and Statis-
Aminophylline Bromocriptine tical Manual of Mental Disorders, fourth edition
Caffeine l-DOPA (DSM-IV), describes eight distinct disorders in which
Cocaine Carbidopa-leuodopa anxiety is the primary problem: panic disorder with
Methylphenidate Metoclopramide
agoraphobia, agoraphobia without history of panic
Theophylline Neuroleptics
Pergolide disorder, specific phobia, social phobia, generalized
Sympathomimetics
Ephedrine Miscellaneous anxiety disorder, post-traumatic stress disorder, acute
Epinephrine Baclofen stress disorder, and obsessive–compulsive disorder.
Phentermine Cycloserine
Phenylpropanolamine Hallucinogens Panic Disorder
Pseudoephedrine Indomethacin
Panic attacks can present in any of the primary
Drug withdrawal Anobolic steroids
Benzodiazepines Captopril anxiety disorders as well as in some neurological,
Narcotics Disopyramide endocrine, cardiovascular, and other organ system
Barbiturates Dronabinol disease. Panic attacks are characterized as discrete
Sedatives Estrogens episodes of intense, unfounded fear accompanied by
Alcohol Fluoroquinolone antibiotics
at least 4 of the following 13 somatic or cognitive
Anticholinergics Metrizamide
Metronidazole symptoms: abrupt-onset palpitations, sweating,
Trihexyphenidyl
Procaine derivatives shaking, shortness of breath, choking, chest pain,
Benztropine
Diphenhydramine Progestins abdominal distress, dizziness, lightheadedness, fear
Oxybutynin Sumatriptan of dying, paresthesias, and chills or hot flushes. The
Propantheline Other attacks may be unexpected or may be situationally
Meperidine SSRIs cued (e.g., attacks occur while in crowds or speaking
Tricyclics Interferon
in public). They typically have a crescendo/decres-
Pilocarpine
cendo course, building to a peak within 10 min or
a
This is a partial listing. Reprinted with permission from less, and are often accompanied by a sense of
Goldberg and Posner (2000). impending doom and an urgency to escape.
Panic disorder comprises recurrent, unexpected
cause anxiety. Urine toxicology may reveal the panic attacks with at least one of the following:
presence of anxiogenic stimulants, such as cocaine persistent concern about having additional attacks,
and amphetamines. Patients with underlying anxiety worry about the implications or consequences of the
disorders may be particularly sensitive to the attacks, and a significant alteration in behavior as a
activating effects of caffeine use, and caffeine result of the attacks. The attacks are often associated
abstinence in chronic users may produce anxiety. with particular situations, but at least two of the
Alcohol withdrawal may present with anxiety, attacks must be unexpected (‘‘out of the blue’’) for
tremulousness, and insomnia. When accompanied the diagnosis. Panic disorder does not include panic
by autonomic arousal, alcohol withdrawal may attacks due to the effects of a drug of abuse,
progress to delirium and require intensive medical medication, or other psychiatric or medical condi-
management. Serotonin reuptake inhibitors, tradi- tion. Frequency and severity of attacks vary sig-
tional neuroleptics, and other dopamine blockers nificantly. Some patients attribute the attacks to an
frequently induce akathisia that may be described by undiagnosed, life-threatening medical condition that
the patient as anxiety or restlessness. If dose may lead to excessive visits to health care facilities.
reduction or switching to another agent are not Concerns about the attacks may also lead to the
possible, low-dose beta-blockers, anticholinergics, development of avoidant behavior that may meet the
and benzodiazepines may be effective in reducing criteria for agoraphobia. Numerous medical condi-
the symptoms. tions appear with significant comorbidity with panic
disorder, including dizziness, cardiac arrhythmias,
hyperthyroidism, asthma, chronic obstructive pul-
PRIMARY PSYCHIATRIC DISORDERS
monary disease, and irritable bowel syndrome. The
Anxiety may be present in a number of psychiatric lifetime prevalence of panic disorder in most studies
disorders as an associated feature of another more is between 1 and 2%, with 1-year prevalence rates
244 ANXIETY DISORDERS, OVERVIEW
between 0.5 and 1.5%. In vestibular, respiratory, and
neurology clinics, the frequency rates vary from 10 to
30%. The disorder is as much as twice as prevalent in
women compared to men. The typical age of onset
for panic disorder is late adolescence to the mid-30s
but varies widely. First-degree relatives of patients
with panic disorder are as much as eight times more
likely to develop panic disorder.
Agoraphobia
Phobias are characterized by excessive fear of a
specific object or circumstance. The DSM-IV distin-
guishes three classes of phobia: agoraphobia, specific
phobia, and social phobia. Agoraphobia is defined as
fear of being in situations from which escape might
be difficult or in which help may not be available in
the event of a full or partial panic attack. The fear
may result in phobic avoidance of crowds or travel
outside the home while alone. In moderate cases,
exposure to the feared situations may be endured. In
more severe cases of agoraphobia, the person may
become completely housebound in order to avoid all
feared situations.
Specific and Social Phobias
In both specific and social phobias, exposure to the
feared stimulus provokes intense anxiety, which may
take the form of a situationally predisposed panic
attack. In both phobic conditions, individuals recog-
nize that their fear is excessive and avoid the feared
stimulus or endure it with great difficulty. The
avoidance or anxiety associated with the feared
stimulus causes significant distress and interferes
significantly with the person’s social or occupational
functioning. Common types of specific phobias
include fears of animals (e.g., mice and spiders),
heights, blood or injection, or of enclosed spaces
such as planes and elevators (claustrophobia).
Individuals with intense fear of enclosed spaces
may be unable to tolerate medical procedures such
as magnetic resonance imaging examination without
sedation, and those with blood or injection phobias
commonly have vasovagal fainting in response to
blood draws or injections. In social phobia, there is
marked fear of social situations in which embarrass-
ment may occur. The feared social situations may be
generalized and include many social interactions
(e.g., in small groups, dating, attending parties, and
public speaking). Others experience intense fear in a
narrower range of circumstances, such as only during
public speaking (stage fright). The lifetime preva-
lence of specific phobia and social phobia is 7–11%
and 3–13%, respectively. In community-based sam-
ples, both disorders are more common in women
than in men. The duration of phobias is frequently
lifelong but may vary depending on life stressors and
demands.
Generalized Anxiety Disorder
Generalized anxiety disorder is characterized by
uncontrollable and excessive anxiety about a number
of issues, occurring more days than not for a period
of at least 6 months. The worry is associated with at
least three of six of the following somatic symptoms:
restlessness, irritability, fatigue, poor concentration,
muscle tension, restlessness, and sleep disturbance.
The focus of the anxiety is not confined to features of
another mental disorder, such as fear of having a
panic attack as seen in panic disorder, having
multiple physical complaints as in somatization
disorder, or having a serious illness as in hypochon-
driasis. The symptoms cause distress or functional
impairment and are not attributable to substance use
or a medical condition. Similarly, the symptoms are
not restricted to a concurrent mood, psychotic, or
developmental disorder. The lifetime prevalence in
community samples is approximately 5%, with a
1-year prevalence rate of 3% and significantly higher
rates for women than for men. More than half of
patients report an onset of symptoms in childhood or
adolescence, but onset may occur at any age. Twin
studies suggest at least a moderate genetic contribu-
tion to the disorder.
Post-Traumatic Stress Disorder and Acute
Stress Disorder
Post-traumatic stress disorder (PTSD) develops in
response to exposure to an extreme traumatic
stressor that involves actual or threatened death or
serious injury to oneself or another. The person’s
response to the stressor includes extreme fear, help-
lessness, or horror. The traumatic exposure results in
a triad of symptoms in which the patient (i)
reexperiences the event through nightmares, flash-
backs, or intrusive thoughts; (ii) avoids stimuli
associated with the trauma and experiences a
numbing of general responsiveness; and (iii) has
heightened arousal manifested, for example, by
hypervigilance and angry outbursts. The full symp-
tom complex must be present for more than 1 month
and must cause significant distress or impairment in
functioning. Patients with PTSD have increased rates
of comorbid major depression, bipolar disorder,
substance abuse disorders, and other anxiety dis-

orders. The lifetime prevalence rate of PTSD in
community samples is approximately 8% of the
adult population in the United States. The disorder
resolves within 3 months in approximately half of
cases but persists beyond 12 months after the
traumatic event in many cases. The likelihood of
developing the disorder after exposure to an event is
likely related to the severity of the event, the absence
of social supports, and the presence of preexisting
mental disorders. Women are more likely to develop
the disorder but are also more likely to be exposed to
high-impact trauma such as rape.
The clinical features of acute stress disorder
resemble those of PTSD but last less than 1 month
after a trauma. Although many individuals exhibit
features of acute stress disorder prior to the devel-
opment of PTSD, the course is variable.
Obsessive–Compulsive Disorder
Obsessive–compulsive disorder (OCD) consists of
recurrent obsessions or compulsions that consume at
least 1 hr a day or cause marked distress or
significant impairment. At some point in the disorder
the person recognizes that the obsessions or compul-
sions are unreasonable or excessive. If another major
mental disorder is present, the contents of the
obsessions and compulsions are not restricted to
the other condition. The obsessions and compulsions
are not caused by the effects of a substance or a
general medical condition. The DSM-IV defines
obsessions as recurrent and persistent thoughts,
impulses, or images that are experienced as intrusive,
inappropriate, and causing marked distress. Compul-
sions are repetitive behaviors or mental acts that the
person feels driven to perform in response to an
obsession or according to rigid rules. The most
common obsessions include fears about contamina-
tion (‘‘my hands are dirty’’) or doubts (‘‘I forgot to
lock the door’’). Common compulsions include hand
washing, checking behaviors, and silently counting
or repeating words. Performing the compulsion
reduces the anxiety associated with the obsession.
In its more severe forms, the obsessions and
compulsions can be all-consuming and can severely
limit the person’s ability to function. There is a 35–
50% frequency of OCD in children and adults with
Tourette’s disorder and, conversely, a 5–7% fre-
quency of Tourette’s in patients with OCD. In
children, the disorder is more common in boys than
girls, but there is no sex difference in adults. In
community samples, adults have a lifetime preva-
lence of 2.5% and a 1-year prevalence of 0.5–2.1%.
ANXIETY DISORDERS, OVERVIEW 245
The disorder usually begins in adolescence or early
adulthood, but it may begin earlier. The majority of
patients have a waxing and waning course that may
be related to stressful life events. Results of twin and
family studies have been mixed but suggest that at
least a subset of cases have a heritable contribution.
Treatment of Primary Psychiatric Disorders
Clinicians should first rule out general medical
conditions and substance-induced anxiety in indivi-
duals presenting with prominent anxiety symptoms.
The diagnosis is commonly confounded by the
coexistence of anxiety disorders with substance
abuse, mood disorders, or other psychiatric diag-
nosis. Treatment recommendations for anxiety dis-
orders include combinations of medications and
psychotherapy. Response of anxiety disorders to
treatment can be highly successful, with response
rates up to 80% in panic disorder and lower but
improving rates for other disorders.
The selection of appropriate pharmacotherapy is
informed by our understanding of the neural basis of
anxiety. The amygdala appears to be the central
mediator of the stress response, fear, and possibly
anxiety, using corticotropin-releasing factor as an
effector neuropeptide. The other major neurotrans-
mitter systems most strongly associated with anxiety
are norepinephrine, serotonin, and g-aminobutyric
acid (GABA), particularly the GABA subsystem
associated with the benzodiazepine receptor. Medica-
tions effective for the treatment of anxiety commonly
target one or more of these neurotransmitter systems.
The first-line medication treatment for panic
disorder, PTSD, OCD, and social phobia is generally
any of the available selective serotonin reuptake
inhibitors (SSRI), with results for PTSD generally less
promising. In the absence of data supporting greater
efficacy of one SSRI compared to another, selection is
typically determined by side effect profiles. Patients
with anxiety disorders may be particularly sensitive
to medication side effects. Consequently, current
consensus is to start treatment with one-fourth to
one-half the usual starting doses for major depression
and to gradually titrate the dose.
For panic disorder, high-potency benzodiazepines,
particularly alprazolam and clonazepam, are also
effective and have the advantage of faster onset of
action. Benzodiazepines may also be useful in the
rapid treatment of other anxiety disorders, although
they have the disadvantage of risks for tolerance and
dependence. Tricyclic antidepressants are also effica-
cious in panic disorder and, in some cases, OCD, but
246 ANXIETY DISORDERS, OVERVIEW

they have poorer tolerability. Buspirone is a potential Table 2 MEDICAL CONDITIONS ASSOCIATED
alternative for the treatment of generalized anxiety WITH ANXIETY SYMPTOMSa
disorder but has little effect in the treatment of other Cardiovascular conditions Neurological conditions
anxiety disorders. It carries no risk for tolerance and Angina pectoris Akathisia
dependence and has a generally benign side effect Arrhythmias Encephalopathy
profile, but it may take several weeks to demonstrate Congestive heart failure Mass lesion
Hypovolemia Postconcussion syndrome
effect. Myocardial infarction Seizure disorder
Among psychotherapies, there is growing evidence Valvular disease Vertigo
for the efficacy of cognitive behavioral therapy (CBT). Endocrine conditions Peptic ulcer disease
For example, in panic disorder, CBT focuses on Carcinoid syndrome Respitory conditions
overcoming catastrophic thinking errors (e.g., ‘‘I am Hyperadrenalism Asthma
having a heart attack’’) as well as graduated exposure Hypercalcemia Chronic obstructive pulmonary
Hyperthyroidism disease
to feared situations and events. The clinician’s Hypocalcemia Pneumothorax
reassurance that the somatic symptoms do not reflect Pheochromocytoma Pulmonary edema
a grave illness may be particularly helpful. Metabolic conditions Pulmonary embolism
Hyperkalemia Immunological conditions
Hyperthermia Anaphylaxis
ANXIETY DISORDERS DUE TO GENERAL Hypoglycemia Systemic lupus erythematosus
MEDICAL CONDITIONS Hyponatremia
Hypoxia
Table 2 lists a number of medical conditions that Porphyria
may present with prominent anxiety. The conditions a
This is a partial listing. Reprinted with permission of Goldberg
most likely to be accompanied by anxiety are
and Posner (2000).
described in more detail here.
Hyperthyroidism
Psychiatric complaints of nervousness, irritability, tremor, palpitations, and faintness. A history of
affective instability, and concentration difficulties postprandial episodes, attacks accompanied by hun-
may be the initial complaint in hyperthyroidism ger, or gastric surgery should prompt laboratory
and may lead to misdiagnosis. The presence of testing of blood sugar.
typical physical manifestations, such as diaphoresis,
heat intolerance, diarrhea, palpitations, tachycardia, Pheochromocytoma
and weight loss, should prompt evaluation of serum This rare catecholamine-secreting tumor in the
thyroid-stimulating hormone, which should help adrenal gland may include prominent anxiety symp-
distinguish the disorder from a psychiatric anxiety toms. Anxiety symptoms accompanied by a combi-
disorder. nation of hypertension, headaches, diaphoresis, and
palpitations should prompt an evaluation of plasma
Partial Simple Seizures catecholamines.
This type of epilepsy, unassociated with amnesia,
may mimic panic attacks. Both can occur suddenly Cardiopulmonary Disease
without clear precipitants and may be accompanied Panic disorder is a common cause of chest pain and
by intense fear. Epilepsy may be distinguished from palpitations in patients with normal cardiac evalua-
panic disorder by the presence of electroencephalo- tions. Arrhythmias need to be evaluated since they
graph spike discharges as well as the occurrence of can be mistaken for anxiety. Recurrent pulmonary
stereotyped behavioral changes, automatisms, and emboli (PE) may mimic panic attacks with associated
hallucinations. Unlike seizures, panic attacks are hyperventilation and dyspnea. Conditions that pre-
often associated with particular environmental situa- dispose to the development of PE, such as hypervis-
tions and therefore can be readily induced. cous states, should alert the clinician to this etiology.
Hypoglycemia Hyperventilation Syndrome
Serum glucose levels lower than 50 mg/dl may result Hyperventilation syndrome is commonly encoun-
in a number of symptoms also present in panic tered in neurology and general medical practices and
attacks, such as anxiety, tachycardia, sweating, is probably a variant of panic disorder. Anxiety,

faintness, visual changes, nausea, palpitations, dys-
pnea, and diaphoresis may all be present and often
lead to a full-blown panic attack. Behavioral
modification to control breathing is useful in the
management of the disorder.
—Robert B. Daroff Jr.
See also–Alcohol-Related Neurotoxicity;
Antianxiety Pharmacology; Cognitive Behavioral
Psychotherapy; Obsessive–Compulsive Disorder;
Panic Disorders; Post-Traumatic Stress Disorder
(PTSD); Substance Abuse
Further Reading
American Psychiatric Association (2000). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed., text revision.
American Psychiatric Association, Washington, DC.
Goldberg, R., and Posner, D. (2000). Anxiety in the medically ill.
In Psychiatric Care of the Medical Patient (A. Stoudemire, B.
Fogel, and D. Greenberg, Eds.), 2nd ed., pp. 165–180. Oxford
Univ. Press, New York.
Gorman, J. (1999). Anxiety disorders. In Comprehensive Text-
book of Psychiatry (H. Kaplan and B. Sadock, Eds.), 7th ed.,
pp. 1441–1503. Williams & Wilkins, Baltimore.
Kornstein, S., Sholar, E., and Gardner, D. (2000). Endocrine
disorders. In Psychiatric Care of the Medical Patient (A.
Stoudemire, B. Fogel, and D. Greenberg, Eds.), 2nd ed., pp.
801–819. Oxford Univ. Press, New York.
Weinberger, D. R. (2001). Anxiety at the frontier of molecular
medicine. N. Engl. J. Med. 344, 1247–1249.
Aphasia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
APHASIA is a language impairment caused by injury
to the brain in a previously normal language user.
The deficits may range from minor problems in
finding the desired words to more profound deficits
in all language modalities. Speech production,
auditory comprehension, word finding, repetition,
reading, and writing may all be affected to varying
degrees.
Language functions are asymmetrically disrupted
by injury to the brain: Left hemisphere lesions can
interfere with the core mechanisms of language in
nearly all right-handed people and a vast majority of
left-handers. Prosody and intonation, as well as other
pragmatic language skills, are more typically affected
after right hemisphere injury.
Each year, approximately 80,000 Americans de-
velop chronic aphasia as a result of stroke, head
APHASIA 247
injury, or other neurological insults. Approximately
1 million people in the United States are affected by
aphasia, a prevalence rate similar to that of
Parkinson’s disease.
APHASIA SYNDROMES
The description of aphasia syndromes has its roots in
the early localization studies of physicians working
in the mid-1800s. Paul Broca, a French surgeon, first
published a series of papers in the 1860s in which he
suggested that the loss of articulate speech was
caused by damage to the posterior inferior frontal
gyrus of the left hemisphere. A decade later, Carl
Wernicke, a 26-year-old German physician, put forth
a more extensive model of language processing and
localization. His model suggested that the compre-
hension and formulation of language takes place in
the posterior superior temporal gyrus, after which
the information is transmitted to the inferior frontal
gyrus, where it is prepared for articulation. Wer-
nicke’s model was revived by Norman Geschwind in
the 1960s, who saw the relevance of the model to
modern neurology. Geschwind also noted the pre-
sence of the arcuate fasciculus, a fiber tract that
connects Wernicke’s and Broca’s area as Wernicke’s
model predicted.
Geschwind’s revival of this early language proces-
sing model led to the classification of seven major
aphasia syndromes. These syndromes are typically
defined by deficits in fluency, auditory comprehension,
repetition and naming (Table 1). Tests such as the
Boston Diagnostic Aphasia Examination and the
Western Aphasia Battery (WAB) measure performance
in these four areas and provide profiles or classifica-
tions of the patient’s language abilities in terms of one
of the aphasia types mentioned in this entry.
The most common form of aphasia, anomic
aphasia, is characterized by word-finding problems,
with relatively intact fluency, comprehension, and
repetition. Although mild, anomic aphasia can be
very frustrating to patients who find that their slowed
ability to retrieve words disrupts the natural flow of
conversation. Interestingly, word-finding problems
exist across all forms of aphasia, although in anomic
aphasia they are the predominant problem.
Anomic patients may present with mispronuncia-
tions, misnamings, or a complete block in retrieving
the target word. Some patients will produce mostly
phonemic paraphasias, substituting the target words
with words that sound similar (e.g., ‘‘fetter’’ instead
of ‘‘letter’’). Others will produce more semantic

faintness, visual changes, nausea, palpitations, dys-
pnea, and diaphoresis may all be present and often
lead to a full-blown panic attack. Behavioral
modification to control breathing is useful in the
management of the disorder.
—Robert B. Daroff Jr.
See also–Alcohol-Related Neurotoxicity;
Antianxiety Pharmacology; Cognitive Behavioral
Psychotherapy; Obsessive–Compulsive Disorder;
Panic Disorders; Post-Traumatic Stress Disorder
(PTSD); Substance Abuse
Further Reading
American Psychiatric Association (2000). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed., text revision.
American Psychiatric Association, Washington, DC.
Goldberg, R., and Posner, D. (2000). Anxiety in the medically ill.
In Psychiatric Care of the Medical Patient (A. Stoudemire, B.
Fogel, and D. Greenberg, Eds.), 2nd ed., pp. 165–180. Oxford
Univ. Press, New York.
Gorman, J. (1999). Anxiety disorders. In Comprehensive Text-
book of Psychiatry (H. Kaplan and B. Sadock, Eds.), 7th ed.,
pp. 1441–1503. Williams & Wilkins, Baltimore.
Kornstein, S., Sholar, E., and Gardner, D. (2000). Endocrine
disorders. In Psychiatric Care of the Medical Patient (A.
Stoudemire, B. Fogel, and D. Greenberg, Eds.), 2nd ed., pp.
801–819. Oxford Univ. Press, New York.
Weinberger, D. R. (2001). Anxiety at the frontier of molecular
medicine. N. Engl. J. Med. 344, 1247–1249.
Aphasia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
APHASIA is a language impairment caused by injury
to the brain in a previously normal language user.
The deficits may range from minor problems in
finding the desired words to more profound deficits
in all language modalities. Speech production,
auditory comprehension, word finding, repetition,
reading, and writing may all be affected to varying
degrees.
Language functions are asymmetrically disrupted
by injury to the brain: Left hemisphere lesions can
interfere with the core mechanisms of language in
nearly all right-handed people and a vast majority of
left-handers. Prosody and intonation, as well as other
pragmatic language skills, are more typically affected
after right hemisphere injury.
Each year, approximately 80,000 Americans de-
velop chronic aphasia as a result of stroke, head
APHASIA 247
injury, or other neurological insults. Approximately
1 million people in the United States are affected by
aphasia, a prevalence rate similar to that of
Parkinson’s disease.
APHASIA SYNDROMES
The description of aphasia syndromes has its roots in
the early localization studies of physicians working
in the mid-1800s. Paul Broca, a French surgeon, first
published a series of papers in the 1860s in which he
suggested that the loss of articulate speech was
caused by damage to the posterior inferior frontal
gyrus of the left hemisphere. A decade later, Carl
Wernicke, a 26-year-old German physician, put forth
a more extensive model of language processing and
localization. His model suggested that the compre-
hension and formulation of language takes place in
the posterior superior temporal gyrus, after which
the information is transmitted to the inferior frontal
gyrus, where it is prepared for articulation. Wer-
nicke’s model was revived by Norman Geschwind in
the 1960s, who saw the relevance of the model to
modern neurology. Geschwind also noted the pre-
sence of the arcuate fasciculus, a fiber tract that
connects Wernicke’s and Broca’s area as Wernicke’s
model predicted.
Geschwind’s revival of this early language proces-
sing model led to the classification of seven major
aphasia syndromes. These syndromes are typically
defined by deficits in fluency, auditory comprehension,
repetition and naming (Table 1). Tests such as the
Boston Diagnostic Aphasia Examination and the
Western Aphasia Battery (WAB) measure performance
in these four areas and provide profiles or classifica-
tions of the patient’s language abilities in terms of one
of the aphasia types mentioned in this entry.
The most common form of aphasia, anomic
aphasia, is characterized by word-finding problems,
with relatively intact fluency, comprehension, and
repetition. Although mild, anomic aphasia can be
very frustrating to patients who find that their slowed
ability to retrieve words disrupts the natural flow of
conversation. Interestingly, word-finding problems
exist across all forms of aphasia, although in anomic
aphasia they are the predominant problem.
Anomic patients may present with mispronuncia-
tions, misnamings, or a complete block in retrieving
the target word. Some patients will produce mostly
phonemic paraphasias, substituting the target words
with words that sound similar (e.g., ‘‘fetter’’ instead
of ‘‘letter’’). Others will produce more semantic
248 APHASIA
Table 1 APHASIA TYPE AND CRITERIA FOR CLASSIFICATION
Aphasia type Fluency
Broca’s Nonfluent
Global Nonfluent
Transcortical motor Nonfluent
Wernicke’s Fluent
Conduction Fluent
Anomic Fluent
Transcortical sensory Fluent
paraphasias with related words substituted for target
words (e.g., ‘‘table’’ for ‘‘chair’’). When the desired
word cannot be retrieved at all, cueing the patient
with the first sound will often facilitate word finding.
In these cases, recognition of the target word is also
immediate when alternatives are provided. Some of
these patients may perseverate on an incorrect choice
and be unable to select another one unless provided
with the correct word. Although anomic aphasic
patients are usually fluent, a coexisting apraxia of
speech can add to the deficit and slow the conversa-
tion further, making the combination easy to mistake
for a nonfluent Broca’s aphasia.
The syndrome of Broca’s aphasia typically results
in slow or halting, effortful speech that lacks
grammatical information. Patients often talk in a
series of nouns and some verbs strung together
without function words, exemplified in the following
transcription of a Broca’s aphasic patient describing a
picture of a picnic scene from the WAB:
Some y sunny day y some trees y two off y ‘sa girl, ‘sa boy,
blankets, radio y boy, books y some pouring cup y ‘sa dog
y some boy, kite y docks y some fish, some flag, some
beach, play, sand y some sailboat y some house.
Word finding and repetition are also impaired and
motor speech disorders such as apraxia of speech and
dysarthria frequently coexist. Patients with Broca’s
aphasia can participate in conversation by their
understanding of single words and grammatically
simple sentences. Impairments in the comprehension
of grammatically complex structures, however, may
result in difficulty following complex commands.
Broca’s aphasics typically present with deficits in
reading and writing as well. As with all aphasic
syndromes, there is a range of severity within Broca’s
aphasia. More severe forms result in such profound
language production deficits that speech is restricted
to recurring utterances, such as a single word or
phrase.
Auditory comprehension Repetition Naming
Relatively good Impaired Impaired
Impaired Impaired Impaired
Relatively good Good Impaired
Impaired Impaired Impaired
Good Impaired Impaired
Good Good Impaired
Impaired Good Impaired
In contrast to Broca’s aphasia, Wernicke’s aphasia
is characterized by impaired auditory comprehension
accompanied by well-articulated, fluent speech that
maintains appropriate prosody but lacks the words
that are necessary to convey meaning to a listener.
Speech is rife with semantic paraphasias, and
neologisms, or nonsense words, are also common.
This style of speech is evident in the following
description of the WAB picnic scene given by a
patient with Wernicke’s aphasia:
There was one group that was kind of one to this, a little bit but
it was pointing me about children who worked in at a food y
And it congenital and active with other children and had their
own interest in special meeting akwaited people, children y
Patients with severe Wernicke’s aphasia may
understand very little in conversation because their
comprehension of even single words may be im-
paired. This deficient auditory comprehension,
coupled with empty speech, can make communica-
tion with Wernicke’s aphasics challenging. Patients
often demonstrate an unawareness of the severity of
their communication deficit. Writing key words,
drawing simple pictures, or using gestures are vital
to communicative success.
Conduction aphasia is a fluent form of aphasia
marked by a striking inability to repeat phrases and
sentences while auditory comprehension remains
relatively intact. High-frequency words, such as
common nouns, are apt to be repeated accurately,
whereas low-frequency words or phrases (e.g., ‘‘The
pastry cook was elated’’) are not. Patients present
with speech that is understandable but contains
frequent phonemic paraphasias. Other extraneous
words may also intrude into the speech of a
conduction aphasic, as is the case in the following
sentences from a patient describing the picnic scene:
There’s a house and there’s a garage and . . . there’s a guy with
his foot off (pointing to man with his shoes off) and he’s looking
at a book. There’s a woman pouring a drink and . . . there’s a guy
pushing a tree (pointing to a boy flying a kite), no, I can’t say it.

Global aphasia, the most severe of aphasic
syndromes, is characterized by profound impair-
ments in all aspects of language. Patients with global
aphasia typically present with little or no productive
output, a near total lack of auditory comprehension,
and an inability to repeat. Occasionally, automatic
words and phrases, such as salutations and counting,
may be preserved. Although some global aphasics
may appear to comprehend simple conversation,
thorough psycholinguistic testing generally reveals
severe impairments in all modalities. To commu-
nicate, global aphasics must rely heavily on a
combination of facial cues, gestures, and drawing.
The rare syndrome of transcortical motor aphasia
is characterized by nonfluent, meaningful speech,
similar to Broca’s aphasia. The difference, however,
lies in a preserved ability to repeat phrases and
sentences even when the patient’s spontaneous output
is halting and effortful. Initially, some patients may be
reluctant to initiate speech and are erroneously
diagnosed as demented or depressed. As spontaneous
speech improves, it is often contaminated by perse-
verations and echolalia. These patients respond well
to prompting when they initially fail to name items.
In contrast to transcortical motor aphasia, patients
with transcortical sensory aphasia present with
overly fluent output and impaired auditory compre-
hension, similar to Wernicke’s aphasia but with
preserved repetition skills. In conversation, patients
may talk rapidly, but the meaning of what they say is
lost due to paraphasic errors. Although they may do
poorly on confrontation naming tasks, patients with
transcortical sensory aphasia have an uncanny ability
to repeat even long, complex sentences. Preserved
oral reading with impaired reading comprehension
also occurs in these rare cases.
LOCALIZATION OF APHASIC SYMPTOMS
AND SYNDROMES
Textbook descriptions of the aphasias localize the
deficits of Broca’s aphasia to lesions in Broca’s area
and those of Wernicke’s aphasia to Wernicke’s area,
as stipulated by the Wernicke–Geschwind model.
Recent work with modern neuroimaging techniques
and more sophisticated behavioral testing has mod-
ified this localization model. For example, lesions to
Broca’s area alone are now known to produce only a
transient mutism that resolves in 3–6 weeks. A much
larger lesion is necessary to produce the symptoms
that result in a persisting Broca’s aphasia. Chronic
Broca’s aphasia occurs as a result of a lesion that
APHASIA 249
typically encompasses Broca’s area as well as
adjacent frontal areas, underlying white matter, the
insula, the anterior superior temporal gyrus, and the
arcuate/superior longitudinal fasciculus in more
severe cases.
Similarly, the lesion site associated with Wernicke’s
aphasia has also been controversial. Recent studies
have found that persisting cases of Wernicke’s
aphasia arise not from lesions to Wernicke’s area
but from near total destruction of the middle
temporal gyrus and significant involvement of under-
lying white matter. Patients with such lesions have a
poor prognosis for recovery. Lesions restricted to
Wernicke’s area tend to resolve to a milder form of
aphasia, typically conduction aphasia. Acute Wer-
nicke’s aphasics whose lesions spare the superior and
middle temporal gyri as well as underlying white
matter typically evolve into anomic aphasics with a
tendency toward semantic paraphasic errors.
Attempts to localize aphasia syndromes have
probably failed because these syndromes are collec-
tions of many individual language deficits or symp-
toms. Broca’s aphasia, for example, is a syndrome
with symptoms such as apraxia of speech, deficits in
word finding, relatively spared auditory comprehen-
sion, and poor repetition skills. Instead of localizing
entire syndromes, it has been more fruitful to study
the relationship of lesions to the individual symptoms
that exist across aphasia types. For example, any
lesion that involves the superior portion of the pre-
central gyrus of the insula will result in an apraxia of
speech, a disorder of articulatory planning. Patients
with such lesions have difficulty in coordinating
articulatory movements so that the tongue, lips, and
larynx make the correct movement at the appropriate
time. Apraxia of speech can present in isolation or in
conjunction with Broca’s aphasia, anomic aphasia,
and conduction aphasia. Regardless of aphasia type,
the lesion always involves this part of the insula.
Whether or not apraxia of speech is part of the deficit
depends on whether this area has been injured.
Similarly, lesion site can predict other specific
deficits. Patients with problems in repeating low-
frequency words and phrases tend to have lesions
involving the posterior superior temporal gyrus and,
in more severe cases, also the inferior parietal
lobule. Because the most apparent deficit in conduc-
tion aphasia is the repetition disorder, it is not
surprising that these patients all have lesions invol-
ving these two regions. However, some patients with
Broca’s aphasia whose lesions include these regions
also demonstrate the same pattern of repetition
250 APHASIA
deficits in addition to their other deficits in fluency,
auditory comprehension, and naming. In general,
larger lesions tend to encompass several of these
critical areas and hence result in a more extensive
disorder.
Although anomia is common in all types of
aphasia, lesions to different brain areas lead to
different patterns of symptoms. Lesions to dorsolat-
eral frontal regions can lead to difficulty in retrieving
words from the lexicon, as evidenced in confronta-
tion naming tasks as well as in free conversation.
Recognition of the correct word, when provided, is
instantaneous. This pattern is seen with chronic
anomic aphasics with frontal lesions as well as acute
transcortical motor aphasic patients, who also
typically resolve into anomic aphasics. Frontal
anomic patients are likely to improve their naming
skills relatively quickly, suggesting that frontal brain
regions may assist in word retrieval but not in lexical
storage per se.
On the other hand, posterior lesions, particularly
those involving the middle temporal gyrus and
underlying white matter, tend to result in misnaming
of objects with less chance of recognizing the correct
name when it is offered. These patients have a more
central deficit in the language system than do their
frontal counterparts. Their deficits are severe and
persisting and generally result in classifications of
Wernicke’s or, if frontal areas are also involved,
global aphasia. When the lesion is small and
involves only part of the middle temporal gyrus, a
transcortical sensory aphasia may result, with
temporary auditory comprehension problems and
intact repetition skills. However, as the comprehen-
sion problems resolve, the classification changes to
anomic aphasia.
Lesions resulting in symptoms of conduction
aphasia were thought to involve the arcuate fas-
ciculus. It is now known that damage to this fiber
tract can cause a much more severe production
deficit. It appears that information processed in
posterior language areas cannot pass through to
motor speech mechanisms in the frontal lobe. When
the arcuate fasciculus is lesioned, the result is
repetitive recurring words or phrases with little or
no productive output.
When all the aforementioned speech and language
areas are injured, a global aphasia results. This is
usually due to a large middle cerebral artery
infarction that affects most of the left hemisphere.
Broca’s and Wernicke’s areas, the insula, the arcuate
fasciculus, dorsolateral frontal areas, the anterior
superior temporal gyrus, the posterior superior
temporal gyrus and the inferior parietal lobule, the
middle temporal gyrus, and underlying temporal
white matter are usually all involved. Somatosensory
and auditory cortices may also be affected. When
certain of the previously mentioned areas are spared,
an atypical pattern of performance may result,
with preservation of certain speech or language
functions.
In general, all aphasic patients will present with
more profound language deficits acutely that, given
time, resolve into a less severe form of aphasia.
Knowledge of the relationship between lesion site
and specific behavioral deficits can assist in more
accurate prognoses. It is also important to note that
although the most dramatic recovery occurs in the
first year, aphasic patients continue to make language
gains far beyond the first 12 months. Age, etiology,
general health, motivation, and other patient vari-
ables are also prognostic indicators.
TREATMENT FOR APHASIA
Any brain-injured patient suspected of having speech
and language deficits should be referred to a speech–
language pathologist for thorough diagnostic testing
and treatment. Research increasingly supports the
efficacy of speech and language therapy for aphasic
adults. In a cooperative study involving 94 aphasic
patients, Wertz et al. concluded that patients who
received treatment in the first year postonset im-
proved significantly more than those who did not.
Basso et al. and Shewan and Kertesz reported similar
findings, supporting the value of treatment. How-
ever, the amount of therapy seems to play a role in
this success. Patients in the Wertz et al. study received
8–10 hr of treatment each week during a 12-week
period, suggesting that intensive therapy is most
beneficial.
Impairments of memory, attention, perception,
or other cognitive functions can also affect the
success of the therapy. If such deficits are suspected,
a neuropsychologist should be consulted for a
thorough evaluation that could assist in possible
neurocognitive rehabilitation. It is also common
for aphasic patients, especially those with more
anterior lesions, to experience mood disorders; these
patients would therefore benefit from a referral
to mental health specialists. Although neurology
consultations occur acutely, follow-up visits to
the neurologist can ensure adequate monitoring
of medications as well as recommendations for

continued physical, occupational, and speech–lan-
guage therapy, as appropriate.
—Nina F. Dronkers and Jennifer Ogar
See also–Agrammatism; Agraphia; Alexia;
Anomia; Broca’s Area; Geschwind, Norman;
Language and Discourse; Language Disorders,
Overview; Language, Overview; Speech
Disorders, Overview; Wernicke’s Area
Further Reading
Benson, D. F., and Ardila, A. (1996). Aphasia: A Clinical
Perspective. Oxford Univ. Press, New York.
Dronkers, N. F. (1996). A new brain region for coordinating
speech articulation. Nature 384, 159–161.
Goodglass, H. (1993). Understanding Aphasia. Academic Press,
San Diego.
Sarno, M. T. (Ed.) (1998). Acquired Aphasia, 3rd ed. Academic
Press, San Diego.
Stemmer, B., and Whitaker, H. A. (Eds.) (1998). Handbook of
Neurolinguistics. Academic Press, San Diego.
Wertz, R. T., Weiss, D. G., Aten, J. L., et al. (1986). Comparison
of clinic, home, and deferred language treatment for aphasia: A
Veterans Administration cooperative study. Arch. Neurol. 43,
653–658.
Apnea
see Sleep Disorders
Apoptosis
see Cell Death
Apraxia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
APRAXIA is defined as an inability to correctly
perform learned skilled movements even though the
patient feels sensation and is strong and coordinated.
Because the primary functions of sensation and
motor control are normal, apraxia is termed one of
the ‘‘higher cortical’’ abnormalities seen in neurology.
Testing for apraxia is carried out in several ways,
such as observing how patients wash their hands, use
eating utensils, wave good-bye, and imitate the
APRAXIA 251
examiner’s movements. Apraxia can be classified as
follows:
1. Ideational apraxia, when there is a failure to
conceive or formulate a series of acts, either
spontaneously or to command. For example,
when writing and sending a letter, the patient
with apraxia may seal the envelope before
inserting the letter.
2. Ideomotor apraxia, when the patient may know
and remember the planned action but cannot
execute it with either hand (e.g., cutting a piece
of paper with scissors).
3. Conduction apraxia, when the patient shows a
greater impairment when imitating movements
than when pantomiming to command.
4. Disassociation apraxia, when the patient cannot
gesture normally to command but can perform
well with imitation and actual tools and objects.
5. Conceptual apraxia, when the patient makes
content and tool selection errors. For example,
when asked to demonstrate the use of a
screwdriver, the patient may use it as if it were a
hammer.
Apraxias may also be classified by the body area
most involved. Facial–oral apraxia is probably the
most common of all apraxias and may be associated
with apraxia of the limbs. Such patients are unable to
articulate or carry out facial movements to command
(lick the lips, blow out a match, etc.). Gait apraxia
represents a loss of integration, at the cortical and
basal ganglionic levels, of the essential elements of
stance and locomotion that were acquired in infancy
and are often lost in old age. Patients assume a posture
of slight flexion, with the feet placed farther apart than
normal. They advance slowly, with small, shuffling,
hesitant steps. Turning is accomplished by a series of
tiny, uncertain steps that are made with one foot.
Finally, they become unable to stand or even to sit.
Apraxia is usually caused by damage of the
dominant frontal and parietal lobes, usually the right
one, and their connections with both cerebral hemi-
spheres (Table 1). Complementary investigations,
such as magnetic resonance imaging or computed
tomography scan of the brain, electroencephalogram
(brain waves), and neuropsychological testing, can
contribute to the etiological diagnosis, such as
strokes, tumor, and degenerative diseases.
Because the presence of apraxic deficits can result
in the loss of independence for many patients,
occupational rehabilitation is usually indicated. In

continued physical, occupational, and speech–lan-
guage therapy, as appropriate.
—Nina F. Dronkers and Jennifer Ogar
See also–Agrammatism; Agraphia; Alexia;
Anomia; Broca’s Area; Geschwind, Norman;
Language and Discourse; Language Disorders,
Overview; Language, Overview; Speech
Disorders, Overview; Wernicke’s Area
Further Reading
Benson, D. F., and Ardila, A. (1996). Aphasia: A Clinical
Perspective. Oxford Univ. Press, New York.
Dronkers, N. F. (1996). A new brain region for coordinating
speech articulation. Nature 384, 159–161.
Goodglass, H. (1993). Understanding Aphasia. Academic Press,
San Diego.
Sarno, M. T. (Ed.) (1998). Acquired Aphasia, 3rd ed. Academic
Press, San Diego.
Stemmer, B., and Whitaker, H. A. (Eds.) (1998). Handbook of
Neurolinguistics. Academic Press, San Diego.
Wertz, R. T., Weiss, D. G., Aten, J. L., et al. (1986). Comparison
of clinic, home, and deferred language treatment for aphasia: A
Veterans Administration cooperative study. Arch. Neurol. 43,
653–658.
Apnea
see Sleep Disorders
Apoptosis
see Cell Death
Apraxia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
APRAXIA is defined as an inability to correctly
perform learned skilled movements even though the
patient feels sensation and is strong and coordinated.
Because the primary functions of sensation and
motor control are normal, apraxia is termed one of
the ‘‘higher cortical’’ abnormalities seen in neurology.
Testing for apraxia is carried out in several ways,
such as observing how patients wash their hands, use
eating utensils, wave good-bye, and imitate the
APRAXIA 251
examiner’s movements. Apraxia can be classified as
follows:
1. Ideational apraxia, when there is a failure to
conceive or formulate a series of acts, either
spontaneously or to command. For example,
when writing and sending a letter, the patient
with apraxia may seal the envelope before
inserting the letter.
2. Ideomotor apraxia, when the patient may know
and remember the planned action but cannot
execute it with either hand (e.g., cutting a piece
of paper with scissors).
3. Conduction apraxia, when the patient shows a
greater impairment when imitating movements
than when pantomiming to command.
4. Disassociation apraxia, when the patient cannot
gesture normally to command but can perform
well with imitation and actual tools and objects.
5. Conceptual apraxia, when the patient makes
content and tool selection errors. For example,
when asked to demonstrate the use of a
screwdriver, the patient may use it as if it were a
hammer.
Apraxias may also be classified by the body area
most involved. Facial–oral apraxia is probably the
most common of all apraxias and may be associated
with apraxia of the limbs. Such patients are unable to
articulate or carry out facial movements to command
(lick the lips, blow out a match, etc.). Gait apraxia
represents a loss of integration, at the cortical and
basal ganglionic levels, of the essential elements of
stance and locomotion that were acquired in infancy
and are often lost in old age. Patients assume a posture
of slight flexion, with the feet placed farther apart than
normal. They advance slowly, with small, shuffling,
hesitant steps. Turning is accomplished by a series of
tiny, uncertain steps that are made with one foot.
Finally, they become unable to stand or even to sit.
Apraxia is usually caused by damage of the
dominant frontal and parietal lobes, usually the right
one, and their connections with both cerebral hemi-
spheres (Table 1). Complementary investigations,
such as magnetic resonance imaging or computed
tomography scan of the brain, electroencephalogram
(brain waves), and neuropsychological testing, can
contribute to the etiological diagnosis, such as
strokes, tumor, and degenerative diseases.
Because the presence of apraxic deficits can result
in the loss of independence for many patients,
occupational rehabilitation is usually indicated. In
252 AQUEDUCT OF SYLVIUS
Table 1 SELECTED ETIOLOGIES ASSOCIATED WITH
DISORDERS OF PRAXIS
Heredodegenerative disorders
Alzheimer’s disease
Pick’s disease
Corticobasal ganglionic degeneration
Progressive supranuclear palsy
Neurovascular disorders
Ischemic/hemorrhagic stroke
Vascular malformations
Neoplastic disorders
Primary neurological tumors (astrocytoma, glioblastoma,
oligodendroglioma, meningioma)
Metastatic and paraneoplastic syndromes (due to spread of
tumor cells or tumor effects not caused by the primary
growth)
Traumatic disorders
Blunt or penetrating central nervous system trauma
addition, apractic patients should avoid participating
in activities in which they may injure themselves or
others. No pharmacological therapy has been shown
to be useful in treating apraxia.
—Esther Cubo and Christopher G. Goetz
See also–Agraphia; Alexia; Alien Limb; Balint’s
Syndrome; Disconnection Syndromes; Gait and
Gait Disorders
Further Reading
Heilman, K. M., Maher, L. M., Greenwald, M. L., et al. (1997).
Conceptual apraxia from lateralized lesions. Neurology 49,
457–464.
Heilman, K. M., Watson, R. T., and Rothi, L. J. G. (1998). Praxis.
In Textbook of Clinical Neurology (C. G. Goetz and E. J.
Pappert, Eds.), pp. 49–55. Saunders, Philadelphia.
Aqueduct of Sylvius
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE AQUEDUCT of Sylvius or cerebral aqueduct,
which connects the third and fourth ventricles, is a
cerebrospinal fluid passageway located in the mid-
brain. In mature humans it measures approximately
1 mm2 in cross-sectional area and slightly more than
1 cm in length. Cerebrospinal fluid (CSF) flows
through this narrow channel with little impedance.
The first descriptions of the aqueduct probably date
back to antiquity. Rufus of Ephesus (98–117 a.d.) as
well as Galen of Pergamon (129–200 a.d.) described
a connection between the cavities of the brain.
Controversies exist regarding to whom the eponym,
aqueduct of Sylvius, belongs. Jacobius Sylvius (Jac-
ques Dubois, 1478–1555) was a French anatomist
and a preceptor of Vesalius. Franciscus de le Boe
Sylvius (1614–1672) was a physician and anatomist.
Although neither originally described the structure of
the aqueduct, they both were great anatomist and
teachers. In 1523, Barengarius Carpensis specifically
identified and described the aqueduct.
Immediately surrounding the aqueduct is the
periaqueductal gray matter, which plays an impor-
tant role in modulating pain. Dorsal to the aqueduct
is the tectal plate of the midbrain and ventral to the
aqueduct is the midbrain tegmentum.
Embryologically, the aqueduct is a remnant of the
mesencephalon’s neural tube. The mesencephalon
develops into the midbrain. The neural tube cranial
to the mesencephalon expands and curls to form the
third and lateral ventricles of the forebrain. The
neural tube caudal to the mesencephalon expands to
form the fourth ventricle of the hindbrain.
The aqueduct does not contain any vessels or
choroid plexus but does have a cluster of specially
formed cells at its junction with the third ventricle
located just below the posterior commissure, called
the subcommissural organ. The exact function of this
organ has yet to be determined, but it is thought to
have a role in the fluid volume balance of the body.
The endothelial cells of the subcommissural organ,
like the rest of the so-called ‘‘periventricular organs,’’
do not have the tight junctions of the blood–brain
barrier.
CSF can flow in both a cranial and caudal
direction through the aqueduct. A tracer injected
into the spinal subarachnoid space preferentially
flows over the convexities of the brain, and only in
old age or in the presence of a communicating
hydrocephalus does it flow up through the aqueduct
into the third and lateral ventricles.
The major clinical problem associated with the
aqueduct is obstruction, with a resultant triventri-
cular hydrocephalus. Triventricular hydrocephalus
refers to dilatation of the third and both lateral
ventricles with a normal appearing fourth ventricle,
and it is the classic imaging appearance for aque-
ductal stenosis. Different types of hydrocephalus
have different images. Both autosomal recessive and
X-linked genetic causes for aqueductal stenosis have
been described. Most forms of congenital aqueductal
stenosis have no known genetic etiology. Bifid and

forked aqueducts have been described in association
with congenital malformations such as spina bifida
aperta. Rarely, a web will be present closing the
aqueduct near the fourth ventricle. In children with
congenital aqueductal stenosis, the aqueduct remains
lined with ependymal cells, whereas in those with an
acquired stenosis due to viral disease or inflamma-
tion the lining has areas of scar or gliosis.
The treatment for aqueductal stenosis depends on
the reversibility of the etiology, the age of the patient,
and the presence of other sites of CSF obstruction. If
the aqueductal stenosis is due to an intracranial mass
lesion and distortion, then alleviation of the mass
effect may result in a reopening of the aqueduct. If
the cause is a focal lesion such as a benign tectal
glioma, then bypassing the aqueduct by means of
perforating the floor of the third ventricle, a third
ventriculostomy, is a very effective treatment. The
success rate of performing a third ventriculostomy is
lower in newborns. Therefore, many infants require
the insertion of a CSF shunt to divert the obstructed
CSF from the ventricles to the peritoneal cavity.
—Gary Magram
See also–Brain Anatomy; Hydrocephalus;
Nervous System, Neuroembryology of
Further Reading
Baker, F. (1990). The two Sylviuses. An historical study. Bull.
Johns Hopkins Hosp. 224, 329–340.
Davson, H., and Segal, M. B. (1996). Physiology of the CSF and
Blood–Brain Barriers. CRC Press, Boca Raton, FL.
Arachnoid Cysts
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THREE membranes surround the brain: the dura
mater, arachnoid membrane, and pia mater. The
dura mater is the outermost layer and adheres to the
inner margin of the skull. The arachnoid membrane
is immediately deep to the dura mater and abuts it
but is not adherent. The innermost layer is the pia
mater. The pia mater is closely applied to the
convoluted surface of the brain and is the only lining
that truly contacts the underlying brain. All three
membranes continue into the spinal canal.
As its name implies, an arachnoid cyst is a cystic
collection within the arachnoid lining of the brain or
ARACHNOID CYSTS 253
spinal canal. Although arachnoid cysts do occur in
the spinal canal, they are distinctly uncommon and
beyond the scope of this entry. True arachnoid cysts
are developmental lesions that are present since
birth. Their exact etiology remains unclear, although
it is postulated that they occur from maldevelopment
of the arachnoid lining early in uterine life. The
abnormal arachnoid allows normal cerebrospinal
fluid (CSF) to accumulate between two thin, almost
transparent layers of arachnoid to create an ara-
chnoid cyst.
Arachnoid cysts occur sporadically and do not run
in families with one notable exception; patients with
autosomal dominant polycystic kidney disease have
an increased frequency of arachnoid cysts, estimated
at 8%. Because many arachnoid cysts are asympto-
matic, their frequency in the general population is
likely underestimated. In the general population,
approximately 1% of nontraumatic intracranial
masses are arachnoid cysts. Although arachnoid
cysts occur in all age groups, they are most
commonly diagnosed in children (75%), especially
when symptomatic. Males are affected three times
more often than females.
In neuroimaging studies, arachnoid cysts appear
as CSF-filled focal, rounded, smoothly marginated
lesions (Figs. 1–3). They are commonly located in
the middle cranial fossa and displace the adjacent
brain. They can cause thinning of the adjacent bone
from chronic CSF pulsation. When normal flow of
CSF is obstructed, the ventricular system enlarges
(hydrocephalus). Differentiating between an ara-
chnoid cyst and other intracranial lesions such as
epidermoid is not difficult with current neuroimaging
techniques.
Small arachnoid cysts tend to be asymptomatic
unless they are near a sensitive area of the brain.
Typically, small cysts are found incidentally on
neuroimaging studies. Large arachnoid cysts can
also be asymptomatic but are more likely to cause
symptoms than are smaller cysts. Symptoms are
varied and relate to the direct mass effect exerted by
the cyst on adjacent structures or to the disruption of
CSF flow. The symptoms attributed to arachnoid
cysts are nonspecific and include headaches, seizures,
visual disturbances, focal neurological deficits, endo-
crine abnormalities, and developmental delay. Ara-
chnoid cysts seldom enlarge over time.
Small, asymptomatic arachnoid cysts are rarely
treated. If they are large or located in a sensitive area,
they may be followed with imaging or treated
electively. In any age group, symptomatic arachnoid
252 AQUEDUCT OF SYLVIUS
Table 1 SELECTED ETIOLOGIES ASSOCIATED WITH
DISORDERS OF PRAXIS
Heredodegenerative disorders
Alzheimer’s disease
Pick’s disease
Corticobasal ganglionic degeneration
Progressive supranuclear palsy
Neurovascular disorders
Ischemic/hemorrhagic stroke
Vascular malformations
Neoplastic disorders
Primary neurological tumors (astrocytoma, glioblastoma,
oligodendroglioma, meningioma)
Metastatic and paraneoplastic syndromes (due to spread of
tumor cells or tumor effects not caused by the primary
growth)
Traumatic disorders
Blunt or penetrating central nervous system trauma
addition, apractic patients should avoid participating
in activities in which they may injure themselves or
others. No pharmacological therapy has been shown
to be useful in treating apraxia.
—Esther Cubo and Christopher G. Goetz
See also–Agraphia; Alexia; Alien Limb; Balint’s
Syndrome; Disconnection Syndromes; Gait and
Gait Disorders
Further Reading
Heilman, K. M., Maher, L. M., Greenwald, M. L., et al. (1997).
Conceptual apraxia from lateralized lesions. Neurology 49,
457–464.
Heilman, K. M., Watson, R. T., and Rothi, L. J. G. (1998). Praxis.
In Textbook of Clinical Neurology (C. G. Goetz and E. J.
Pappert, Eds.), pp. 49–55. Saunders, Philadelphia.
Aqueduct of Sylvius
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE AQUEDUCT of Sylvius or cerebral aqueduct,
which connects the third and fourth ventricles, is a
cerebrospinal fluid passageway located in the mid-
brain. In mature humans it measures approximately
1 mm2 in cross-sectional area and slightly more than
1 cm in length. Cerebrospinal fluid (CSF) flows
through this narrow channel with little impedance.
The first descriptions of the aqueduct probably date
back to antiquity. Rufus of Ephesus (98–117 a.d.) as
well as Galen of Pergamon (129–200 a.d.) described
a connection between the cavities of the brain.
Controversies exist regarding to whom the eponym,
aqueduct of Sylvius, belongs. Jacobius Sylvius (Jac-
ques Dubois, 1478–1555) was a French anatomist
and a preceptor of Vesalius. Franciscus de le Boe
Sylvius (1614–1672) was a physician and anatomist.
Although neither originally described the structure of
the aqueduct, they both were great anatomist and
teachers. In 1523, Barengarius Carpensis specifically
identified and described the aqueduct.
Immediately surrounding the aqueduct is the
periaqueductal gray matter, which plays an impor-
tant role in modulating pain. Dorsal to the aqueduct
is the tectal plate of the midbrain and ventral to the
aqueduct is the midbrain tegmentum.
Embryologically, the aqueduct is a remnant of the
mesencephalon’s neural tube. The mesencephalon
develops into the midbrain. The neural tube cranial
to the mesencephalon expands and curls to form the
third and lateral ventricles of the forebrain. The
neural tube caudal to the mesencephalon expands to
form the fourth ventricle of the hindbrain.
The aqueduct does not contain any vessels or
choroid plexus but does have a cluster of specially
formed cells at its junction with the third ventricle
located just below the posterior commissure, called
the subcommissural organ. The exact function of this
organ has yet to be determined, but it is thought to
have a role in the fluid volume balance of the body.
The endothelial cells of the subcommissural organ,
like the rest of the so-called ‘‘periventricular organs,’’
do not have the tight junctions of the blood–brain
barrier.
CSF can flow in both a cranial and caudal
direction through the aqueduct. A tracer injected
into the spinal subarachnoid space preferentially
flows over the convexities of the brain, and only in
old age or in the presence of a communicating
hydrocephalus does it flow up through the aqueduct
into the third and lateral ventricles.
The major clinical problem associated with the
aqueduct is obstruction, with a resultant triventri-
cular hydrocephalus. Triventricular hydrocephalus
refers to dilatation of the third and both lateral
ventricles with a normal appearing fourth ventricle,
and it is the classic imaging appearance for aque-
ductal stenosis. Different types of hydrocephalus
have different images. Both autosomal recessive and
X-linked genetic causes for aqueductal stenosis have
been described. Most forms of congenital aqueductal
stenosis have no known genetic etiology. Bifid and

forked aqueducts have been described in association
with congenital malformations such as spina bifida
aperta. Rarely, a web will be present closing the
aqueduct near the fourth ventricle. In children with
congenital aqueductal stenosis, the aqueduct remains
lined with ependymal cells, whereas in those with an
acquired stenosis due to viral disease or inflamma-
tion the lining has areas of scar or gliosis.
The treatment for aqueductal stenosis depends on
the reversibility of the etiology, the age of the patient,
and the presence of other sites of CSF obstruction. If
the aqueductal stenosis is due to an intracranial mass
lesion and distortion, then alleviation of the mass
effect may result in a reopening of the aqueduct. If
the cause is a focal lesion such as a benign tectal
glioma, then bypassing the aqueduct by means of
perforating the floor of the third ventricle, a third
ventriculostomy, is a very effective treatment. The
success rate of performing a third ventriculostomy is
lower in newborns. Therefore, many infants require
the insertion of a CSF shunt to divert the obstructed
CSF from the ventricles to the peritoneal cavity.
—Gary Magram
See also–Brain Anatomy; Hydrocephalus;
Nervous System, Neuroembryology of
Further Reading
Baker, F. (1990). The two Sylviuses. An historical study. Bull.
Johns Hopkins Hosp. 224, 329–340.
Davson, H., and Segal, M. B. (1996). Physiology of the CSF and
Blood–Brain Barriers. CRC Press, Boca Raton, FL.
Arachnoid Cysts
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THREE membranes surround the brain: the dura
mater, arachnoid membrane, and pia mater. The
dura mater is the outermost layer and adheres to the
inner margin of the skull. The arachnoid membrane
is immediately deep to the dura mater and abuts it
but is not adherent. The innermost layer is the pia
mater. The pia mater is closely applied to the
convoluted surface of the brain and is the only lining
that truly contacts the underlying brain. All three
membranes continue into the spinal canal.
As its name implies, an arachnoid cyst is a cystic
collection within the arachnoid lining of the brain or
ARACHNOID CYSTS 253
spinal canal. Although arachnoid cysts do occur in
the spinal canal, they are distinctly uncommon and
beyond the scope of this entry. True arachnoid cysts
are developmental lesions that are present since
birth. Their exact etiology remains unclear, although
it is postulated that they occur from maldevelopment
of the arachnoid lining early in uterine life. The
abnormal arachnoid allows normal cerebrospinal
fluid (CSF) to accumulate between two thin, almost
transparent layers of arachnoid to create an ara-
chnoid cyst.
Arachnoid cysts occur sporadically and do not run
in families with one notable exception; patients with
autosomal dominant polycystic kidney disease have
an increased frequency of arachnoid cysts, estimated
at 8%. Because many arachnoid cysts are asympto-
matic, their frequency in the general population is
likely underestimated. In the general population,
approximately 1% of nontraumatic intracranial
masses are arachnoid cysts. Although arachnoid
cysts occur in all age groups, they are most
commonly diagnosed in children (75%), especially
when symptomatic. Males are affected three times
more often than females.
In neuroimaging studies, arachnoid cysts appear
as CSF-filled focal, rounded, smoothly marginated
lesions (Figs. 1–3). They are commonly located in
the middle cranial fossa and displace the adjacent
brain. They can cause thinning of the adjacent bone
from chronic CSF pulsation. When normal flow of
CSF is obstructed, the ventricular system enlarges
(hydrocephalus). Differentiating between an ara-
chnoid cyst and other intracranial lesions such as
epidermoid is not difficult with current neuroimaging
techniques.
Small arachnoid cysts tend to be asymptomatic
unless they are near a sensitive area of the brain.
Typically, small cysts are found incidentally on
neuroimaging studies. Large arachnoid cysts can
also be asymptomatic but are more likely to cause
symptoms than are smaller cysts. Symptoms are
varied and relate to the direct mass effect exerted by
the cyst on adjacent structures or to the disruption of
CSF flow. The symptoms attributed to arachnoid
cysts are nonspecific and include headaches, seizures,
visual disturbances, focal neurological deficits, endo-
crine abnormalities, and developmental delay. Ara-
chnoid cysts seldom enlarge over time.
Small, asymptomatic arachnoid cysts are rarely
treated. If they are large or located in a sensitive area,
they may be followed with imaging or treated
electively. In any age group, symptomatic arachnoid

forked aqueducts have been described in association
with congenital malformations such as spina bifida
aperta. Rarely, a web will be present closing the
aqueduct near the fourth ventricle. In children with
congenital aqueductal stenosis, the aqueduct remains
lined with ependymal cells, whereas in those with an
acquired stenosis due to viral disease or inflamma-
tion the lining has areas of scar or gliosis.
The treatment for aqueductal stenosis depends on
the reversibility of the etiology, the age of the patient,
and the presence of other sites of CSF obstruction. If
the aqueductal stenosis is due to an intracranial mass
lesion and distortion, then alleviation of the mass
effect may result in a reopening of the aqueduct. If
the cause is a focal lesion such as a benign tectal
glioma, then bypassing the aqueduct by means of
perforating the floor of the third ventricle, a third
ventriculostomy, is a very effective treatment. The
success rate of performing a third ventriculostomy is
lower in newborns. Therefore, many infants require
the insertion of a CSF shunt to divert the obstructed
CSF from the ventricles to the peritoneal cavity.
—Gary Magram
See also–Brain Anatomy; Hydrocephalus;
Nervous System, Neuroembryology of
Further Reading
Baker, F. (1990). The two Sylviuses. An historical study. Bull.
Johns Hopkins Hosp. 224, 329–340.
Davson, H., and Segal, M. B. (1996). Physiology of the CSF and
Blood–Brain Barriers. CRC Press, Boca Raton, FL.
Arachnoid Cysts
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THREE membranes surround the brain: the dura
mater, arachnoid membrane, and pia mater. The
dura mater is the outermost layer and adheres to the
inner margin of the skull. The arachnoid membrane
is immediately deep to the dura mater and abuts it
but is not adherent. The innermost layer is the pia
mater. The pia mater is closely applied to the
convoluted surface of the brain and is the only lining
that truly contacts the underlying brain. All three
membranes continue into the spinal canal.
As its name implies, an arachnoid cyst is a cystic
collection within the arachnoid lining of the brain or
ARACHNOID CYSTS 253
spinal canal. Although arachnoid cysts do occur in
the spinal canal, they are distinctly uncommon and
beyond the scope of this entry. True arachnoid cysts
are developmental lesions that are present since
birth. Their exact etiology remains unclear, although
it is postulated that they occur from maldevelopment
of the arachnoid lining early in uterine life. The
abnormal arachnoid allows normal cerebrospinal
fluid (CSF) to accumulate between two thin, almost
transparent layers of arachnoid to create an ara-
chnoid cyst.
Arachnoid cysts occur sporadically and do not run
in families with one notable exception; patients with
autosomal dominant polycystic kidney disease have
an increased frequency of arachnoid cysts, estimated
at 8%. Because many arachnoid cysts are asympto-
matic, their frequency in the general population is
likely underestimated. In the general population,
approximately 1% of nontraumatic intracranial
masses are arachnoid cysts. Although arachnoid
cysts occur in all age groups, they are most
commonly diagnosed in children (75%), especially
when symptomatic. Males are affected three times
more often than females.
In neuroimaging studies, arachnoid cysts appear
as CSF-filled focal, rounded, smoothly marginated
lesions (Figs. 1–3). They are commonly located in
the middle cranial fossa and displace the adjacent
brain. They can cause thinning of the adjacent bone
from chronic CSF pulsation. When normal flow of
CSF is obstructed, the ventricular system enlarges
(hydrocephalus). Differentiating between an ara-
chnoid cyst and other intracranial lesions such as
epidermoid is not difficult with current neuroimaging
techniques.
Small arachnoid cysts tend to be asymptomatic
unless they are near a sensitive area of the brain.
Typically, small cysts are found incidentally on
neuroimaging studies. Large arachnoid cysts can
also be asymptomatic but are more likely to cause
symptoms than are smaller cysts. Symptoms are
varied and relate to the direct mass effect exerted by
the cyst on adjacent structures or to the disruption of
CSF flow. The symptoms attributed to arachnoid
cysts are nonspecific and include headaches, seizures,
visual disturbances, focal neurological deficits, endo-
crine abnormalities, and developmental delay. Ara-
chnoid cysts seldom enlarge over time.
Small, asymptomatic arachnoid cysts are rarely
treated. If they are large or located in a sensitive area,
they may be followed with imaging or treated
electively. In any age group, symptomatic arachnoid
254 ARACHNOID CYSTS
Figure 1
Axial T1-weighted magnetic resonance image showing an oval
mass with the signal intensity of CSF on the patient’s right side.
The mass displaces the right frontal lobe toward the midline. The
differential diagnosis includes arachnoid cyst and epidermoid.
cysts are considered for treatment. Therapy for
arachnoid cysts is based on the principle of decom-
pression. Cysts may be fenestrated so that they
communicate with the normal CSF space around the
Figure 2
Axial T2-weighted magnetic resonance image showing the same
mass as seen in Fig. 1. The high signal intensity of the mass is
identical to the signal intensity of the CSF in the ventricular
system. There is a focal area of increased signal intensity (bright
signal) in the adjacent brain between the mass and the ventricles.
Figure 3
Diffusion-weighted magnetic resonance image showing low signal
intensity (dark) in the cystic mass and the ventricles. This sequence
indicates that the contents of the cyst and ventricles are identical,
confirming that the mass is an arachnoid cyst. On this sequence, an
epidermoid would have a high signal intensity. The focal area of
increased signal intensity in the adjacent brain is ischemia. This
arachnoid cyst was decompressed because of its size, mass effect,
and the potential relationship to the area of ischemia.
brain. They can also be shunted by placing synthetic
tubing under the skin into the abdominal cavity.
Patients with asymptomatic arachnoid cysts can lead
normal lives. Patients who require surgery for
arachnoid cyst also fare extremely well. Rarely does
an arachnoid cyst significantly affect a patient’s life.
—Matthew T. Walker and Shahram Partovi
See also–Arachnoiditis; Dura Mater;
Subarachnoid Hemorrhage (SAH)
Further Reading
Ciricillo, S. F., Cogen, P. H., Harsh, G. R., et al. (1991).
Intracranial arachnoid cysts in children. A comparison of the
effects of fenestration and shunting. J. Neurosurg. 74, 230–235.
Flodmark, O. (1992). Neuroradiology of selected disorders of the
meninges, calvarium, and venous sinuses. Am. J. Neuroradiol.
13, 483–491.
Rengachary, S. S., and Kennedy, J. D. (1996). Intracranial
arachnoid and ependymal cysts. In Neurosurgery (R. H.
Wilkins and S. S. Rengachary, Eds.), 2nd ed., pp. 3709–3728.
McGraw-Hill, New York.
Taveras, J. M. (1996). Brain congenital anomalies. In Neuro-
radiology (J. M. Taveras, Ed.), 3rd ed., pp. 195–201. Williams
& Wilkins, Baltimore.

Arachnoiditis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ARACHNOIDITIS is a nonspecific inflammatory pro-
cess involving the arachnoid membrane, which is one
component of several protective layers of connective
tissue that ensheath the central nervous system. The
dura mater, the outermost layer, is known as the
pachymeninges. The arachnoid and pia mater com-
pose the leptomeninges. The term arachnoid is
derived from the Greek arachne (spider) and ceides
(shape). The arachnoid membrane is an avascular,
diaphanous membrane consisting of elastic connec-
tive tissue covered on both sides by a single layer of
endothelial cells. Its origin is thought to be meso-
dermal, with some contributions from the neuro-
ectoderm. Arachnoiditis is the result of a local
invasion of inflammatory cells, proliferation of
arachnoidal membrane cells, or both. Immune
reaction studies have shown that arachnoidal cells
can initiate and sustain an inflammatory reaction.
INCIDENCE
Arachnoiditis is widespread and its debilitating
effect cannot be overstated. The incidence of radio-
graphic arachnoiditis is higher than that of clini-
cally significant arachnoiditis. The most common
type of arachnoiditis is lumbosacral arachnoiditis.
Approximately 10% of patients with failed back
surgery syndrome have lumbar adhesive arachnoidi-
tis as their primary organic disease. The American
Society of Neuroradiology estimates that approxi-
mately 2% of all patients with a history of
iophendylate myelography have gross evidence of
arachnoiditis.
ETIOLOGY
Arachnoiditis is the result of any injury that causes
an inflammatory response leading to fibrosis in the
delicate arachnoid membrane. Infection, nonsurgical
and surgical trauma, and retained irritants are
important causes. Tuberculosis and syphilis are the
most common infectious agents and were the most
common overall cause before the 1940s. Spinal cord
injuries, intrathecal hemorrhage, and intrathecally
injected agents, such as steroids, anesthetics, and
radiological contrast material, have also been im-
plicated. Since the introduction of water-soluble and
ARACHNOIDITIS 255
newer nonionic contrast agents, the incidence of
postmyelographic arachnoiditis has diminished sig-
nificantly. The clinical syndrome of arachnoiditis is
now most often associated with repeated surgical
trauma. In particular, lumbosacral arachnoiditis is
most often associated with myelography and spinal
surgical procedures. Retained foreign bodies in the
epidural space can also induce arachnoiditis.
CLINICAL MANIFESTATIONS
The symptoms of arachnoiditis are pain and pro-
gressive neurological deficit, and they can mimic
other causes of neural compression. The primary
complaint of patients with lumbosacral arachnoiditis
is lower back and leg pain (usually burning).
Neurological examination may reveal signs of
mechanical tension, weakness, sensory deficits, and
reflex changes. The pain may involve the distribution
of multiple nerve roots. Bowel and bladder dysfunc-
tion may also be present. Most patients describe a
history of spinal surgery, myelography with oil-based
or ionic contrast agents, or both. The latency
between the inciting event and the appearance of
symptoms is variable, but most patients are affected
within the first year. Arachnoiditis may be a
significant cause of failed back syndrome. Advanced
forms may be associated with incapacitating pain,
disability, and even death.
RADIOGRAPHIC CHARACTERISTICS
Classically, myelography has been used to confirm
the diagnosis of arachnoiditis. Findings can range
from a filling defect of a single nerve root to complete
obliteration of the thecal sac. High-resolution
computed tomography demonstrates arachnoiditis
effectively, particularly the calcific variety.
Magnetic resonance imaging (MRI) has replaced
myelography for the definitive diagnosis of arachnoi-
ditis primarily because it is noninvasive and because
arachnoiditis and recurrent disk herniation cannot be
differentiated on myelography. Three common pat-
terns are seen on MRI. First, the nerve roots may be
clumped together centrally—a pattern best demon-
strated on T1-weighted MRI. Second, the nerve roots
may be tethered to the dura, creating the appearance
of an ‘‘empty sac.’’ In the third pattern, pockets of
hyperintensity correspond to loculation of cerebrosp-
inal fluid spaces with increased protein. The collage-
nous adhesions show minimal enhancement.
Minimally invasive techniques such as myeloscopy
256 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
are promising modalities for verifying the diagnosis
of arachnoiditis.
MANAGEMENT
The primary treatment of arachnoiditis is sympto-
matic care and includes physical therapy, medica-
tions, transcutaneous electrical nerve stimulation,
and chronic pain rehabilitation. The outcomes of
microsurgical adhesiolytic procedures have been
modest, and the procedure is reserved for patients
with progressive neurological deficits.
Dorsal column stimulation for pain control has
gained widespread clinical acceptance for patients
with symptoms refractory to conservative manage-
ment. Many centers advocate direct placement of
epidural electrodes under local anesthesia followed
by ambulatory testing. Subsequently, the system is
internalized if appropriate. The mechanism of relief
from dorsal column stimulation is unknown,
although synaptic inhibition is one hypothesis. For
this modality to be efficacious, patients must develop
paresthesias upon stimulation over the painful area.
Long-term success has been reported in more than
50% of patients.
The results of neuroablative procedures such as
dorsal rhizotomy and dorsal root ganglionectomy for
the management of arachnoiditis have been dismal. If
an ablative procedure is to be attempted, pain must
be localized to one or two nerve roots. No long-term
follow-up studies exist; therefore, neuroablative
procedures have largely been abandoned.
CONCLUSION
Arachnoiditis is a debilitating clinicopathological
entity that develops in a significant number of
patients with failed back surgery syndrome. Post-
operative arachnoiditis can be prevented by ensuring
meticulous hemostasis, by handling tissues carefully,
and by avoiding foreign bodies in the epidural space.
The mainstay of treatment for refractory cases is
dorsal column stimulation.
—Vivek Deshmukh and Harold L. Rekate
See also–Arachnoid Cysts; Leptomeninges:
Arachnoid and Pia
Further Reading
Burton, V. (1996). Lumbosacral arachnoiditis. In Neurological
Surgery: A Comprehensive Reference Guide to the Diagnosis
and Management of Neurosurgical Problems (J. R. Youmans,
Ed.), pp. 2483–2491. Saunders, Philadelphia.
Caplan, L. R., Norohna, A. B., and Amico, L. L. (1990).
Syringomyelia and arachnoiditis. J. Neurol. Psychiatry 53,
106–113.
Dolan, R. A. (1993). Spinal adhesive arachnoiditis. Surg. Neurol.
39, 479–484.
Jenik, F., Tekle-Haimanot, R., and Hamory, B. H. (1981). Non-
traumatic adhesive arachnoiditis as a cause of spinal cord
syndromes. Investigation of 507 patients. Paraplegia 19, 140–
154.
Kitagawa, H., Kanamori, M., Tatezaki, S., et al. (1990). Multiple
spinal ossified arachnoiditis. A case report. Spine 15, 1236–
1238.
Kok, A. J., Verhagen, W. I., Bartels, R. H., et al. (2000). Spinal
arachnoiditis following subarachnoid haemorrhage: Report of
two cases and review of the literature. Acta Neurochir. (Wien)
142, 795–798.
Martin, R. J., and Yuan, H. A. (1996). Neurosurgical care of
spinal epidural, subdural, and intramedullary abscesses and
arachnoiditis. Orthop. Clin. North Am. 27, 125–136.
Matsui, H., Tsuji, H., Kanamori, M., et al. (1995). Laminectomy-
induced arachnoradiculitis: A postoperative serial MRI study.
Neuroradiology 37, 660–666.
Park, Y. K., and Tator, C. H. (1998). Prevention of arachnoiditis
and postoperative tethering of the spinal cord with Gore-Tex
surgical membrane: An experimental study with rats. Neuro-
surgery 42, 813–823.
Sharma, A., Goyal, M., Mishra, N. K., et al. (1997). MR imaging
of tubercular spinal arachnoiditis. Am. J. Roentgenol. 168,
807–812.
Arboviruses, Encephalitis
Caused by
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MORE THAN 30 arthropod-borne RNA viruses are
potential causes of human meningitis, encephalitis,
or encephalomyelitis. Most of these viruses are from
one of four viral families: Togaviridae, Bunyaviridae,
Reoviridae, and Flaviviridae. Arboviruses are found
throughout the world; individual species tend to have
geographically and climatically restricted distribu-
tion, as part of a particular ecological subsystem
entailing virus, vectors, and amplifying hosts. The
vectors are largely mosquitoes and ticks.
The capacity of these viruses to cause human
neurological disease is based on a complex set of
factors that determine the ecosystem within which
each virus thrives. Of particular importance are
determinants expressed as cell-surface glycopro-
teins, nucleocapsid proteins, and polymerases that
256 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
are promising modalities for verifying the diagnosis
of arachnoiditis.
MANAGEMENT
The primary treatment of arachnoiditis is sympto-
matic care and includes physical therapy, medica-
tions, transcutaneous electrical nerve stimulation,
and chronic pain rehabilitation. The outcomes of
microsurgical adhesiolytic procedures have been
modest, and the procedure is reserved for patients
with progressive neurological deficits.
Dorsal column stimulation for pain control has
gained widespread clinical acceptance for patients
with symptoms refractory to conservative manage-
ment. Many centers advocate direct placement of
epidural electrodes under local anesthesia followed
by ambulatory testing. Subsequently, the system is
internalized if appropriate. The mechanism of relief
from dorsal column stimulation is unknown,
although synaptic inhibition is one hypothesis. For
this modality to be efficacious, patients must develop
paresthesias upon stimulation over the painful area.
Long-term success has been reported in more than
50% of patients.
The results of neuroablative procedures such as
dorsal rhizotomy and dorsal root ganglionectomy for
the management of arachnoiditis have been dismal. If
an ablative procedure is to be attempted, pain must
be localized to one or two nerve roots. No long-term
follow-up studies exist; therefore, neuroablative
procedures have largely been abandoned.
CONCLUSION
Arachnoiditis is a debilitating clinicopathological
entity that develops in a significant number of
patients with failed back surgery syndrome. Post-
operative arachnoiditis can be prevented by ensuring
meticulous hemostasis, by handling tissues carefully,
and by avoiding foreign bodies in the epidural space.
The mainstay of treatment for refractory cases is
dorsal column stimulation.
—Vivek Deshmukh and Harold L. Rekate
See also–Arachnoid Cysts; Leptomeninges:
Arachnoid and Pia
Further Reading
Burton, V. (1996). Lumbosacral arachnoiditis. In Neurological
Surgery: A Comprehensive Reference Guide to the Diagnosis
and Management of Neurosurgical Problems (J. R. Youmans,
Ed.), pp. 2483–2491. Saunders, Philadelphia.
Caplan, L. R., Norohna, A. B., and Amico, L. L. (1990).
Syringomyelia and arachnoiditis. J. Neurol. Psychiatry 53,
106–113.
Dolan, R. A. (1993). Spinal adhesive arachnoiditis. Surg. Neurol.
39, 479–484.
Jenik, F., Tekle-Haimanot, R., and Hamory, B. H. (1981). Non-
traumatic adhesive arachnoiditis as a cause of spinal cord
syndromes. Investigation of 507 patients. Paraplegia 19, 140–
154.
Kitagawa, H., Kanamori, M., Tatezaki, S., et al. (1990). Multiple
spinal ossified arachnoiditis. A case report. Spine 15, 1236–
1238.
Kok, A. J., Verhagen, W. I., Bartels, R. H., et al. (2000). Spinal
arachnoiditis following subarachnoid haemorrhage: Report of
two cases and review of the literature. Acta Neurochir. (Wien)
142, 795–798.
Martin, R. J., and Yuan, H. A. (1996). Neurosurgical care of
spinal epidural, subdural, and intramedullary abscesses and
arachnoiditis. Orthop. Clin. North Am. 27, 125–136.
Matsui, H., Tsuji, H., Kanamori, M., et al. (1995). Laminectomy-
induced arachnoradiculitis: A postoperative serial MRI study.
Neuroradiology 37, 660–666.
Park, Y. K., and Tator, C. H. (1998). Prevention of arachnoiditis
and postoperative tethering of the spinal cord with Gore-Tex
surgical membrane: An experimental study with rats. Neuro-
surgery 42, 813–823.
Sharma, A., Goyal, M., Mishra, N. K., et al. (1997). MR imaging
of tubercular spinal arachnoiditis. Am. J. Roentgenol. 168,
807–812.
Arboviruses, Encephalitis
Caused by
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MORE THAN 30 arthropod-borne RNA viruses are
potential causes of human meningitis, encephalitis,
or encephalomyelitis. Most of these viruses are from
one of four viral families: Togaviridae, Bunyaviridae,
Reoviridae, and Flaviviridae. Arboviruses are found
throughout the world; individual species tend to have
geographically and climatically restricted distribu-
tion, as part of a particular ecological subsystem
entailing virus, vectors, and amplifying hosts. The
vectors are largely mosquitoes and ticks.
The capacity of these viruses to cause human
neurological disease is based on a complex set of
factors that determine the ecosystem within which
each virus thrives. Of particular importance are
determinants expressed as cell-surface glycopro-
teins, nucleocapsid proteins, and polymerases that

determine the capacity of viral particles to pass
through various host cell membrane barriers, ser-
ological characteristics, and neurovirulence of any
given viral species. Generally, human arboviral
infection occurs after subcutaneous or intravenous
injection of virus by a biting mosquito or tick. Initial
viral replication occurs in skin or muscle, followed
by primary viremia with seeding of reticuloendothe-
lial sites where further replication may take place
and then secondary viremia. Central nervous system
penetration via vascular endothelium, olfactory bulb,
or choroid plexus may occur during either viremia
phase in susceptible individuals.
Pathological changes in brain after infection with
the various arboviruses discussed in this entry are not
distinctive, consisting of leptomeningeal inflamma-
tory infiltration, patchy perivascular lymphocytic
cuffing, scattered neuronophagia, and focal necrosis.
Although arboviruses can be isolated from blood
during the viremic prodrome, cultures of blood or
cerebrospinal fluid (CSF) are usually negative during
the encephalitic phase of these illnesses. Therefore,
diagnosis is usually made on the basis of a fourfold
increase or decrease of serum titers by any of various
immunological techniques. There is cross-reactivity
of varied degree on such testing between many of
these viruses.
There are no specific treatments for any of the
arboviruses considered in this entry. Avoidance of
breeding areas of mosquito vectors during times of
high mosquito prevalence is the best way to avoid
contracting encephalitis. Vaccines for some of these
viruses have been developed, but they are available
only for high-risk laboratory personnel. Natural
infection confers lifelong immunity to a particular
strain or arbovirus.
TOGAVIRUSES
Togaviruses are small, positive-strand RNA envel-
oped viruses. Only one genus of the Togavirus family,
the alphaviruses, contains arboviruses that are
important causes of human encephalitis. Rubella, a
member of genus Rubivirus, is associated with
encephalomyelitis. The range of alphaviruses is
restricted to the Western Hemisphere; all are closely
related, with just six serotypes. The most important
encephalitogenic agents are the eastern equine (EEE),
western equine (WEE), and Venezuela equine (VEE)
viruses. EEE is found mainly on the eastern and Gulf
coasts of the United States, with occasional epi-
demics in the upper Midwest, Caribbean, or the
ARBOVIRUSES, ENCEPHALITIS CAUSED BY 257
northeastern coasts of South America. WEE is found
in the western regions of the United States and
Canada. VEE is found in South and Central America,
with occasional outbreaks in Florida and the Amer-
ican southwest. Alphaviruses are harbored in passer-
ine birds, rodents, and some vertebrates and are
transmitted to humans by mosquitoes. Humans and
horses may contract potentially fatal illnesses from
these viruses when exposed to particular habitats in
which the mosquito vectors thrive. Mosquito control
by the methods of Gorgas and Reed, combined with
vaccination of horses, has reduced the public health
risk from these viruses. Equine epizootics often
precede human epidemics of these forms of encepha-
litis.
Human vulnerability to encephalitis varies de-
pending on relative neuroinvasiveness and neuro-
virulence of the given equine virus. EEE is the most
invasive and neurovirulent virus, with high rates of
encephalitis, mortality, and morbidity. The statistic is
mentioned in the next sentence. EEE is presumed to
penetrate the nervous system in 1 in 23 individuals
who develop viremia. WEE tends to cause encepha-
litis only in individuals younger than 1 year of age,
although it may produce severe disease in such young
patients. VEE seldom causes human encephalitis,
although it may produce a taxing febrile illness.
Human neuropathology of fatal equine encephali-
tides includes multiple punctate hemorrhages, peri-
vascular inflammatory cuffing, cerebrovascular
thromboses, edema, neuronal necrosis, and neuro-
nophagia. With EEE, these sorts of changes may be
found in the cerebral cortex, thalamus, globus
pallidus, and pons as well as the midbrain, basal
ganglia, and cerebellum. With WEE, such changes
may be largely confined to the basal ganglia and
brainstem. VEE pathology is not well-known.
Eastern Equine Encephalitis
EEE was first isolated from horse brain in 1933 and
from human brain during the Massachusetts epi-
demic of 1938. The EEE zoonosis is maintained by
passerine birds and Culiseta melanura mosquitoes in
forested marshes. These mosquitoes feed mainly on
birds; Aedes and Culex mosquitoes account for
transmission of EEE to horses or humans. With
occasional exceptions there are usually fewer than
five cases of human EEE each year in the United
States, with most occurring in mid- to late summer.
Most cases occur in swampy, marshy, or forested
regions of the Atlantic and Gulf coasts, with rare
cases as far west as the Great Lakes region. Attack
258 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
rates are highest in very young children and the
elderly. Infants account for approximately one-third
of all cases. After an incubation period of 5–10 days,
fever, malaise, headache, photophobia, and vomiting
rapidly evolve into meningismus with fulminant
deterioration in consciousness. In many cases, coma
with paralysis has developed by the second or third
day of illness. Initial leukopenia is followed by the
development of leukocytosis. CSF discloses lympho-
cytic pleocytosis (50–100 cells/mm3) and CSF protein
is elevated (100–150 mg/dl). Human cases can be
anticipated on the basis of equine outbreaks in a
given region. Diagnosis is serologically confirmed.
There is no specific treatment for EEE. Supportive
care should include careful ascertainment and treat-
ment of increased intracranial pressure. The fatality
rate for EEE ranges from 20 to 70% across all ages,
but it is 75% for infants and is also high for the
elderly. A majority of survivors manifest significant
neurological injury with intellectual impairment,
personality changes, or spastic paralysis. Permanent
abnormalities of this sort occur as a result of EEE in
70–90% of infants The overall risk for epilepsy is
14–37%. However, some patients experience com-
plete recovery.
Western Equine Encephalitis
The isolation of WEE from equine brain in Califor-
nia in 1930 was the first isolation of an encephalito-
genic arbovirus in the United States. The virus was
recovered from the brain of a child in 1938. WEE is
less neurovirulent for humans than for horses. WEE
is harbored in birds and wild herds of western horses.
The vectors for humans and horses are principally
Culex tarsalis and C. melanura mosquitoes. Most
human and equine cases of WEE occur in the
summer, especially in June and July or slightly later
in Canada. Cases are typically confined to the
western and Midwestern areas of the United States
and Canada and generally occur weeks after a period
of significant rain with warm weather. In most years,
there are fewer than 10 cases in the United States,
although 41 cases occurred in 1987. Horse vaccina-
tion and declining numbers of wild horses have
reduced the frequency of WEE cases. Young boys and
girls are at equal risk, but among older individuals,
men and boys are at greater risk. Although the risk
for encephalitis after WEE viremia is 1:1200 in
adults and 1:60 in children, it is approximately 1:1 in
infants. Infants account for approximately one-third
of WEE cases. In utero infection of the fetus may
occur.
Clinical manifestations are much the same as those
of EEE, although they are somewhat milder overall.
After a 10-day incubation, patients manifest malaise,
fever, and headache, often with nausea, vomiting,
and photophobia. These changes may be followed by
obtundation, extremity weakness, hypo- or hyper-
reflexia, and tone abnormalities alternating between
flaccidity and spasticity. Muscle stretch reflexes may
be increased or decreased. Seizures are common. CSF
shows lymphocytic pleocytosis (fewer than 500 cells/
mm3) and elevated protein concentration. Virus is
occasionally isolated from CSF if cultured early in
the course of illness. Young children and infants are
at greatest risk for severe infections or death, and
among those who recover there is great risk for
epilepsy (focal or generalized convulsive) and other
forms of significant permanent neurological impair-
ment. The case fatality rate is 6–8% for WEE, with
highest rates in elderly patients. Permanent motor
signs or intellectual difficulties are found in approxi-
mately 13% of cases. The overall risk for epilepsy is
4–11%. Several closely antigenically related viruses
may also cause encephalitis resembling WEE or EEE,
including Highlands J, Sinbis, Fort Morgan, Y-62-63,
and Avrorra strains. Highlands J cases may occur
east of the Mississippi River. A live attenuated
vaccine is available for laboratory personnel at risk
for acquisition of WEE.
Venezuelan Equine Encephalitis
VEE virus was first isolated from an equine brain in
1938 and from a human brain in 1952. Birds do not
figure in the ecology of this virus. The transmitting
vector is the mosquito, including Aedes aegyptii,
Psorophora, and Culex (Melanoconion) species.
There are currently six serological subtypes: VEE,
Everglades, Mucambo, Pixuna, Cabassou, and
AG80-663. Less pathogenic enzootic strains are
amplified by rodents or horses. Within an endemic
focus, humans living in damp and swampy forests
have a high frequency of antibodies to these strains
but little recognized disease. Horses play the major
amplifying role in the more virulent epizootic strains
of VEE. Human disease breaks at intervals in
northern South America and Peru. Occasionally,
cases occur in Central and North America. A clinical
equine outbreak usually precedes human epidemics
by 1 or 2 weeks. Rarely, laboratory outbreaks occur
due to aerosolation of virus particles. Estimates of
the rate at which human exposure to VEE results in
clinical manifestations range from 4 to 60%.

Incubation after mosquito bite is 4–6 days. In most
instances, the clinical manifestations of VEE include
fever (100–1051F), malaise, myalgia, headache,
anorexia, and prostration, resembling influenza.
Most complaints resolve in 2–5 days, although
fatigue and malaise often persist for several weeks.
Reticuloendothelial abnormalities rarely complicate
particularly severe cases. Encephalitis is also a rare
complication, encountered more commonly in chil-
dren (4%) than in adults (0.5%). Manifestations of
encephalitis include nuchal rigidity, photophobia,
alteration of consciousness, and seizures. Abnormal-
ities of liver enzymes and CSF pleocytosis with
proteinosis are consistent with VEE. Early in the
course of illness, virus may be cultured from
nasopharyngeal swabs. Otherwise, diagnosis is con-
firmed serologically. Treatment is supportive. Overall
mortality rate for VEE is approximately 0.6%.
Equine vaccination has afforded significant control
of epizootic strains of VEE. A live attenuated vaccine
is available for laboratory personnel at risk for
acquisition of VEE.
BUNYAVIRUSES
This family includes more than 250 RNA viruses
classified into five genera. Of these, Bunyavirus and
Phlebovirus contain viruses of importance as causes
of human meningoencephalitis. Hantaan, a Hanta-
virus, produces severe human disease and may cause
encephalitis, but it is not clearly arthropod trans-
mitted. It remains unclear what role viruses classified
in the remaining two genera, Nairovirus and
Uukuvirus, may play in human disease. The sequence
of viremia, systemic illness, development and man-
ifestation of encephalitis by these viruses is similar to
the manifestations of other arboviruses, as are the
neuropathological features. Generally, the ratio of
clinically unapparent or mild infection to noteworthy
clinical infection is high and recovery from Bunya-
viridial meningoencephalitis is good. Bunyaviruses
have been shown to exhibit tropism for fetal tissues.
Limited evidence suggests that these viruses may
cause congenital brain injury, hydrocephalus, or
arthrogryposis as well as anasarca, oligohydramnios,
or fetal demise.
California Serogroup Viruses
The main agents of human encephalitis in the
Bunyavirus genus are the California serogroup
viruses (CSVs), examples of which have been
identified on five continents. The CSVs have played
ARBOVIRUSES, ENCEPHALITIS CAUSED BY 259
a very important role in the investigation of vector–
virus biology, ecology, epidemiology, and pathogen-
esis of all arboviruses. California, the namesake of
the CSVs, was identified in 1943. Ironically, this
particular virus has been associated with only five
cases of human encephalitis. The most important
human pathogen of the California serogroup is the
LaCrosse virus (LCV), first isolated in 1965. LCV
has maintained a stable ecological niche in ungla-
ciated coulees in the vicinity of the Ohio and upper
Mississippi Rivers since the last ice age. Hardwood
trees with crotches at their base (‘‘tree holes’’) where
several trunks intersect have been the favored
breeding ground of the sylvatic, aggressive Aedes
triseriatus tree-hole mosquitoes, the principal vector.
In the past 50 years, artificial breeding sites
(discarded radial tires and other water-containing
debris) have contributed greatly to the frequency of
these mosquitoes and LaCrosse encephalitis in
endemic regions. Elimination of tires and debris
and filling of tree holes with concrete have appreci-
ably reduced LCV encephalitis incidence. Chipmunks
and ground and tree squirrels are the amplifying
hosts for LCV.
Most LCV infections are mild or subclinical; many
cases are ascribed to flu or summer cold. More than
95% of those who develop LCV encephalitis or
aseptic meningitis are younger than 18 years of age,
with peak risk at 6–9 years of age. Between 60 and
80% of encephalitis cases occur in boys. Exposure to
the woodland mosquito habitat is the greatest risk
factor. Most cases occur between July and September,
with peak incidence in August. Incubation is 7–15
days. Fever, malaise, and headache occur in almost
all cases; disturbance of sensorium ranging from
confusion to coma occurs in 90% of cases. Nausea,
anorexia, and vomiting occur in 70–80%. At least
half of all patients have meningismus, lethargy, or
seizures. Various other neurological abnormalities
(e.g., weakness, choreoathetosis, ataxia, aphasia,
papilledema, and status epilepticus) may develop,
each in a minority of cases. Patients may complain of
sore throat, but other respiratory symptoms are
uncommon, as is diarrhea.
CSF pleocytosis is found in 60–75% of cases,
usually with a lymphocytic predominance. Erythro-
cythemia is found in 25% of cases. CSF glucose
values range from low to high (the only cause for
high CSF glucose is hyperglycemia), CSF protein
is elevated in only 15–30% of cases. Electroence-
phalograms are abnormal in nearly all cases,
typically demonstrating slowing, with epileptogenic
260 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
discharges in nearly one-third of cases. In two-thirds
of cases, there is a left brain emphasis to abnorm-
alities. Pathological changes consistent with viral
encephalitis are found in lethal cases and are
emphasized in the cortex and basal ganglia but to a
lesser extent in white matter; occipital cortex,
brainstem, and spinal cord are largely spared.
Treatment is supportive; it is especially important
to recognize and treat seizures and elevation of
intracranial pressure, either of which may occur in
the first few days of illness. The fatality rate for LCV
is less than 1%. Recovery usually requires days to
weeks, but in some instances it may take many
months. Permanent motor signs or intellectual
disturbances are confirmed in less than 3% of cases.
Epilepsy develops in 13–28% of cases.
Several other CSVs cause encephalitis. Snowshoe
hare virus (SHV) of the boreal/subarctic regions of the
Rocky Mountain states and Canada can be trans-
mitted by any of 15 cold-tolerant mosquito species.
Amplifying hosts include the snowshoe hare and Arctic
ground squirrels. Although it is the most neuroviru-
lent CSV by laboratory standards, the comparative
rarity of SHV encephalitis has been ascribed to low
neuroinvasiveness, remoteness and diminished popu-
lation density of the SHV vector–virus ecosystem, or
the correspondence of peak periods of vector feeding
with the hatch of the blackfly, clouds of which
discourage visits to endemic regions. Boys younger
than 10 years of age are at greatest risk for
encephalitis; sequellae are uncommon. SHV equine
encephalitis has also been documented.
Inkoo–Tahyna virus (ITV) encephalitis has enjoyed
increasing recognition as a public health threat in
central Europe, Scandinavia, and 10 Eurasian time
zones of Russia and the Far East. Aedes mosquitoes
are the vector; mice, voles, and shrews are the
amplifying hosts. Human infections occur from May
to October, peaking in June, with individuals 15–30
years of age at greatest risk. Clinical features include
a respiratory prodrome that may include pneumonia,
toxicosis, fever, shivering, headache, irritability, and
meningismus. Elevated intracranial pressure may
develop. Acute disseminated encephalomyelitis and
chronic neurological diseases have also been linked
with ITV.
First recognized in 1966, Jamestown Canyon virus
(JCV) is the only member of the Melao subtype of
CSVs that is a significant cause of human encepha-
litis. It is prevalent in the northeastern United States
and eastern Canada, especially in the region of the
Great Lakes. Pond-breeding Aedes mosquitoes that
thrive in hilly woodlands are the vector, and the
predominant amplifying host is the white-tail deer.
Most JCV encephalitis occurs in late spring or early
summer in adults. It is a relatively mild illness that is
likely underdiagnosed. Unlike LCV, most encephali-
tis cases occur in individuals older than 30 years of
age and there is a prominent respiratory prodrome.
REOVIRIDAE
Although many different human and veterinary
diseases are produced by viruses of the Reoviridial
family, only the Colorado tick fever virus of the
Orbivirus genus produces human encephalitis. Col-
orado tick bite fever (CTF) was first described in the
19th century, the name was applied by 1930, and the
virus was cultured from human blood in1944. The
tick Dermacentor andersoni was identified as the
vector in 1950. Ground squirrels and chipmunks
serve as amplifying hosts. Wood rats and deer mice
occasionally transmit infection. Multiplication of
CTF virus in bone marrow, an immunologically
privileged site, may protect it from normal host
immunological mechanisms. This may account for
the prolonged phase of viremia and for laboratory
signs of bone marrow dysfunction in infected
individuals. Leukopenia and thrombocytopenia are
distinctive laboratory indications of CTF. Within the
bone marrow, CTF virus may take up residence
within red blood cell precursors. This predilection
may account for hemorrhagic and vasculitic aspects
of CTF.
CTF is acquired at altitudes ranging from 4000 to
10,000 ft in the Rocky Mountains of the United
States and Canada, but mainly in Colorado and
Idaho. In most instances, the onset is between April
and July, although cases have been reported as early
as March and as late as September. The location and
timing associated with cases correspond to the
location and time of feeding activity of the D.
andersoni ticks. Individuals who engage in outdoor
work or recreational activities in the areas of disease
prevalence are most likely to develop CTF, with
young men exhibiting particular risk. Occasionally,
illness develops as a result of blood transfusion.
The incubation period for CTF in humans is 3–6
days. Acute manifestations include fever, chills,
headache, photophobia, nausea, vomiting, aesthenia,
myalgia, weakness, and malaise. These manifesta-
tions persist for 5–10 days and may show a biphasic
course. Aesthenia, malaise, and weakness may per-
sist longer in children than in adults with CTF.

Occasionally, hemorrhagic complications develop.
Neurological findings are not common—found in
only 1–10% of cases. Neurological involvement may
be limited to nuchal rigidity, but in some instances
severe meningoencephalitis develops. Laboratory
manifestations include leukopenia, thrombocytope-
nia, and, if the central nervous system is involved,
CSF abnormalities. CSF pleocytosis is usually less
than 500/mm3; CSF protein elevation may be higher
than 100 mg/dl. Because of residence in red blood
cells and prolonged viremia, virus is often recover-
able from blood cultures. Titer rise, confirming CTF
infection, may require longer than that for many
other viral encephalitides. Treatment of CTF is
supportive. Most individuals infected with CTF
recover without complications or residual abnorm-
alities. CTF is seldom fatal. Tick checks in endemic
areas may prevent illness.
FLAVIVIRUSES
Flaviviridae include nearly 70 small, enveloped,
single-strand RNA viruses, subtypeable on the basis
of E-envelope glycoprotein determinants. Glycopro-
tein E is the determinant of viral virulence. All
Flaviviridae are likely derived from a common
ancestor, possibly 20,000 years ago. Examples are
found on all continents, with continued evolution
and spread with consolidation of ecological niches.
Viral adaptation to methods of environmental
control, human travel, and possibly global climatic
changes has enhanced the threat of these viruses.
Approximately half cause disease in humans, trans-
mitted in most cases (such as with the prototypic
yellow fever virus and other tropical/subtropical/
temperate zone endemics) by mosquito bite. Yellow
fever virus causes a fatal murine encephalitis with
both acute and chronic inflammatory elements to
which humans do not appear to be subject. Close
study of this infectious, inflammatory, and degen-
erative process has challenged the venerable patho-
logical definition of encephalitis formulated many
decades ago by Spatz. Yellow fever virus vaccine may
provoke a severe form of encephalomyelitis in young
children, particularly those younger than 3 years
of age.
The five flaviviruses recognized as causes of human
arthropod-borne encephalitis are Japanese encepha-
litis virus, St. Louis encephalitis virus, Murray Valley
encephalitis virus, tick-borne encephalitis complex,
and West Nile virus. Dengue viruses are of enormous
importance as causes of systemic illness; their role
ARBOVIRUSES, ENCEPHALITIS CAUSED BY 261
has only recently been carefully investigated. The list
of other flaviviridial causes of encephalitis is gradu-
ally becoming even more extensive.
Culex and Aedes mosquitoes are especially promi-
nent tropical and subtropical flavivirus vectors.
Flaviviridae endemic in cooler climates are trans-
mitted by the bite of Ixodes or other ticks. It has
repeatedly been demonstrated that mosquito-borne
arboviral illnesses can be controlled by the elimina-
tion of breeding sites of these various mosquitoes. It
has also been repeatedly demonstrated that with
neglect of this approach—due to indifference, wars,
geopolitical disturbances, and other forces—these
diseases enjoy brisk resurgence. Flaviviridial replica-
tion, dissemination, and neurotropism are subject to
change over time due to genetic shift, genetic drift,
and other factors. Changes in host factors may also
modify susceptibility, and environmental changes
may enhance vector prevalence.
There is evidence for naturally occurring genetic
resistance to flaviviridial disease and for vigorous
induction of immune response to infection. These
features account for the high rates of unapparent to
clinically detectable infection in humans. Genetically
determined resistance may slow the invasion or
replication of virus and spread of infection, permit-
ting more time for secondary immune responses to
develop. Individuals who do manifest disease may
have inadequate natural protection or inadequate
rapidity and degree of evoked immunological reac-
tion to infection. Degree of inadequacy of these
responses or factors assignable to variation in the
infecting virus may determine the degree of severity
of Flaviviridial systemic and central nervous system
manifestations in individuals that do become ill.
The degree of severity may range from barely
apparent to fulminant and fatal. In especially severe
cases, excessive response of the host immune system
may actually mediate the development of disease.
This is quite likely to be the case in the systemic
diseases produced by dengue viruses and may also
play an important role in Japanese B encephalitis.
Both the cellular and the humoral immune responses
of the host may confer protection against reinfec-
tion. This protection may be transient or permanent.
However, marked immune response due to prior
exposure to dengue antigens may be the basis of the
most severe forms of dengue fever. Diagnosis of
flaviviral encephalitides typically rests on the de-
monstration of a fourfold increase or decrease in
serum antibody titers to a given flavivirus, often
determined using the IgM-capture enzyme-linked
262 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
immunosorbent assay (ELISA) technique. In some
instances, it rests upon the recovery or staining of
virus in brain. These viruses are seldom recovered
from cultured blood or CSF.
Japanese B Encephalitis Virus
Worldwide, Japanese B encephalitis (JBE) virus is the
most frequent cause of arboviral encephalitis and the
cause of the greatest amount of arboviral neuro-
logical morbidity and mortality. JBE was first
isolated and identified in 1935. Areas of greatest
endemicity include tropical and subtropical regions
of Japan, eastern Russia, China, India, and virtually
all the rest of Southeast Asia. Four distinct genotypes
are found in Asia. Culex tritaeniorhynchus mosqui-
toes are the usual vector; birds and pigs are
important amplifying intermediary hosts. Human
risk for infection is affected by the cattle:hog ratio in
endemic regions. Where agricultural practice favors
cattle, risk is lower. Cases occur throughout the year
in endemic areas, influenced by vector density, which
reflects both temperature and amount of rainfall.
Vaccination and vector control have reduced the
annual incidence of JBE from approximately 20,000
to approximately 10,000. Greatest control of JBE
has been achieved in Japan and the least in southeast
China and Thailand.
The human incubation period for JBE is 6–16
days; the ratio of clinically nonapparent to apparent
cases is approximately 250:1. The earliest symptoms
of disease are fever and headache. After 2–4 days,
individuals who develop either aseptic meningitis or
encephalitis manifest worsening headache, elevated
fever, and rigors. Abdominal pain, anorexia, nausea,
and vomiting may develop, especially in younger
individuals. Meningismus and alteration of con-
sciousness ensue, sometimes preceded by tremulous-
ness and excitability. Those who develop encephalitis
often have a rapid and fulminant course of neurolo-
gical deterioration that variously includes abnormal
cortical, pyramidal tract, extrapyramidal, brainstem,
or cerebellar signs. Psychosis may develop. Coma
and seizures are more common than in most other
arboviral encephalitides. Seizures are especially
common in children with JBE. Peculiar to JBE are
the assumption in some cases of a mask-like facial
appearance, more extensive bulboparetic findings, or
paralysis of the upper extremities. Peripheral nervous
system dysfunction may develop, including encepha-
lomyeloradiculoneuropathy or Guillain–Barré syn-
drome.
Neuroimaging studies may disclose lesions in
brainstem or basal ganglia, including bilateral
thalamic abnormalities. Pathological studies in fatal
cases demonstrate brain edema, vascular congestion,
and focal hemorrhages that are considerably more
marked than those observed in systemic lupus
erythematosus. In addition to lymphocytic and
microglial inflammation of meninges and brain,
widespread neuronal necrosis with neuronophagia
may be found throughout brain hemispheres, cere-
bellum, and spinal cord.
There is no effective antiviral drug therapy for JBE,
nor has the administration of corticosteroids been
found to provide any benefit. Thus, management is
supportive. Patients destined to recover tend to
manifest improvement after 2–4 days of illness. JBE
is a particularly severe disease, with mortality of 25–
50%, that usually occurs after a brief and fulminant
course of illness. Higher morbidity and mortality are
found in individuals younger than 10 or older than
65 years of age. The development of bulboparetic,
extrapyramidal dysfunction or a central hyperpneic
breathing indicates a graver prognosis. On the other
hand, early appearance of JBE antibodies in CSF is
indicative of a less severe clinical course and
prognosis. Significant neurological disability is found
in most encephalitis survivors, although deficits may
gradually improve during their long convalescence.
Neuropsychiatric dysfunction has been documented
in the majority of encephalitis survivors, especially
children. Typical long-term deficits include emo-
tional lability, incoordination, epilepsy, or weakness.
Prevention is critical in endemic areas, including
vector reduction and vaccination. The available
vaccine has 56–90% efficacy and the risk for
untoward reactions is only 1%.
Murray Valley Encephalitis
The regular occurrence in southeastern Australia of
epidemics of Murray Valley encephalitis (MVE) was
recognized in 1917; the virus was isolated from
human brain in 1951. The tropical Murray Valley of
New South Wales and Victoria are the regions of
highest endemicity; the disease also occurs in tropical
and subtropical western Australia and New Guinea.
Culex annulirostris is the usual vector. The ratio of
unapparent to clinical infection is approximately
750:1. The largest numbers of cases are documented
in periods of greater rainfall, which may also result in
larger regions of endemicity. Although some studies
have suggested that older individuals may be more
susceptible than younger ones, others have suggested

proclivity for more severe disease in children and the
aboriginal population.
The prodromal phase of MVE is marked by febrile
headache, malaise, and myalgia. Such mild findings
may constitute the worst of the ensuing encephalitic
phase, but in other cases the nadir is mild or severe
focal neurological abnormality, convulsions, cerebel-
lar or spinal cord abnormalities, brainstem signs,
coma with respiratory impairment, or death. Re-
spiratory failure or secondary bacterial infections are
among the most important causes of death. As noted
previously, more severe disease may be observed in
children and the Australian aboriginal population.
There is no specific therapy, but with modern
supportive approaches the mortality of MVE has
declined from 60% to approximately 20%. Patients
who become comatose often die; if they do not,
significant neurological impairment can be antici-
pated. Much better recovery can be expected in
noncomatose patients, although epilepsy, abnormal-
ities of speech or intellect, gait disturbance, or
paraplegia may persist. There is no preventive
vaccine. Evidence for increased vector breeding
activity in monitored endemic regions prompts
insecticide applications.
St. Louis Encephalitis Virus
Clinical recognition of St. Louis encephalitis (SLE)
virus occurred in 1932 with the study of an outbreak
in Paris, Illinois. Although the virus was identified
the following year, the Culex mosquito vectors were
not identified until 1947. Although endemic in
certain areas of the United States, epidemic out-
breaks occur in many other areas. Birds serve as
amplifying hosts. Prevalence is greatest in the Ohio
and Mississippi River valleys, Alabama, Texas, and
Florida, but cases occur throughout the United
States, excepting New England and South Carolina,
where cases are quite uncommon or unknown to
occur. LaCrosse virus is the most important endemic
cause, but SLE is the most important epidemic cause
of arboviral encephalitis in the United States. More
than 50,000 cases of SLE have been reported in the
United States since the mid-1950s. In North Amer-
ica, epidemics occur with an approximate 10-year
periodicity. Cases tend to occur in late summer or
early fall. Cases have also been reported in Central
and South America. During epidemics, as much as
6% of the population at risk contracts the infection.
Disease is more common, more severe, and more
often fatal in elderly individuals. Occasionally, SLE
may complicate HIV infection.
ARBOVIRUSES, ENCEPHALITIS CAUSED BY 263
Although some infections are asymptomatic, in
many individuals clinical disease manifests 3 or 4
days after insect bite, with malaise, fever, myalgia,
headache, and nausea that may be accompanied by
vomiting. This syndrome may resolve after 1–4 days
or an epoch of neurological disturbance may ensue.
Neurological illness may be limited to afebrile
headache. However, 70–80% of patients develop
aseptic meningitis (fever, meningismus, and irritabil-
ity). Encephalitis may also develop, manifesting
various types and degrees of neurological abnorm-
ality, including alteration of consciousness, coma
(11–20%), tremor, jitteriness, pyramidal signs
(50%), and brainstem/cranial nerve signs (20–
30%). Approximately 10% of patients display
paresis, ataxia, nystagmus, or convulsions. The
occurrence of convulsions is a poor prognostic sign.
CSF pleocytosis is characteristic—5–100 cells/mm3
with early polymorphonuclear and subsequent lym-
phocytic cell predominance. CSF remains normal,
whereas moderate elevation of CSF protein may be
found. Serological diagnosis is best established with
IgM-capture ELISA.
There is no specific treatment; management is
supportive. If death occurs, it does so within 1 week
of disease onset in 50% and 2 weeks in 80% of fatal
cases. The mortality rate for young adults is
approximately 2%, whereas that for the elderly is
approximately 22%. Pathological changes in fatal
cases share the inflammatory features of JBE but are
much less extensive (leptomeningeal, thalamic, and
substantia nigral) and with less neuronal necrosis. Of
nonfatal cases, approximately two-thirds recover
fairly rapidly, although the majority exhibit memory
loss, irritability, or persistent headache for an
interval. In one-third of cases, these abnormalities
are even more persistent, and disorders of speech,
intellect, and sensorimotor function are also found.
There is no vaccine. Vector control has proven
singularly effective in endemic areas.
West Nile Virus Encephalitis
West Nile virus (WNV) encephalitis has close
antigenic identity to JBE, SLE, and Kunjin viruses,
from which it may be difficult to distinguish by
serological methods. The preferred vectors for this
Old World flavivirus are ornithophilic mosquitoes,
principally Culex pipiens and other Culex species.
Viruses are infected by feeding on viremic birds;
migratory birds are important introductory and
amplifying hosts. Infection with WNV may cause
the death of birds fulfilling these host roles.
264 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
Endemicity is greatest in sub-Saharan Africa, the
Middle East, and India. In the past 40 years,
outbreaks have been documented in southern France,
southern Russia, Belarus, Ukraine, Romania, Cze-
choslovakia, Algeria, and Italy. In 1999, the first
outbreak in North America was documented in New
York City. Recent outbreaks, especially in Romania,
have included a number of serious or even lethal
encephalitic cases in birds, horses, domestic mam-
mals, and humans. Heavy rains and climate warming
may have favored some of these outbreaks, which
were also associated with deaths of migratory birds
and persistence of virus in the local Culex–bird
ecosystems.
Human infections are usually asymptomatic or
may be regarded as summer colds. Clinical cases tend
to occur from mid- to late summer. Onset is marked
by fever, malaise, and headache. Infected individuals
may develop pain in the eyes and muscles, vomiting,
asthenia, hepatitis, pancreatitis, or muscular weak-
ness. Patients with meningitis or encephalitis typi-
cally manifest meningismus and alteration of
consciousness, and they may have extremity tremor,
ataxia, or paralysis. Brainstem signs due to involve-
ment of medulla or cranial nerve roots many be
found. Most severe cases have occurred in elderly
individuals with chronic medical illnesses, although
WNV meningoencephalitis has been diagnosed in
children as young as 1 year of age. The fatality rate
for acute encephalitis may be as high as 15%
compared to less than 2% for WNV meningitis.
Tick-Borne Encephalitis
The first of the various forms of illness caused by the
tick-borne encephalitis (TBE) viruses were recog-
nized at the turn of the 20th century. The TBE virus
complex, like the California Bunyaviruses, consists
of a family of antigenically related viruses with
greater or lesser potential to cause various human
febrile illnesses and encephalitides. These include
Langat and Powassan viruses as well as viruses
causing central European tick-borne encephalitis,
Turkish sheep encephalitis, Louping ill disease, Far
Eastern/Russian spring–summer encephalitis, and
biphasic milk fever. Isolation of a TBE family virus
from the brain of a human who had died from
encephalitis and demonstration of the role of Ixodid
ticks in transmission were achieved in the late 1930s.
Many of these viruses are endemic through a wide
latitudinal and longitudinal range, from western
Europe and Scandinavia to Russia and the Middle
and Far East. They are distributed in stable
ecosystems that involve Ixodid ticks and such
amplifying hosts as rodents, shrews, moles, and
hedgehogs. In the 1960s, it was shown that biphasic
milk fever could also be transmitted by consumption
of unpasteurized goat milk or cheese, and it has been
determined that goats, sheep, and cattle that may
harbor Ixodes ticks can become infected and excrete
virus in milk. The greatest risk for TBE in many
endemic areas is for boys and men engaged in various
outdoor activities. However, in central Europe, the
approximately equal risk for the sexes is ascribed to
exposure during outdoor recreation such as hiking.
Peak risk corresponds with the periods of greatest
activity of adult Northern Hemisphere Ixodes
ticks—May, June, September, and October. Milk-
or cheese-related cases occur less predictably and are
indicated when outbreaks of disease occur in entire
families. Children appear to be at greater risk for
contracting biphasic milk fever. Occasional labora-
tory outbreaks of TBE occur.
Powassan virus is closely related to the TBE
complex of viruses, particularly those producing
Russian spring–summer encephalitis, but it displays
enough antigenic distinction so as not to generate a
reaction to the usual TBE hemagglutination-inhibi-
tion serological tests. Vectors include both Ixodes
and Dermacentor ticks. Intermediate and amplifying
hosts include squirrels, groundhogs, porcupines, and
domestic animals. Human encephalitis due to this
virus is quite rare but may occur in children. Ixodes
ticks are the vectors for the TBE-like virus that causes
Louping ill in sheep. Rarely, this virus produces a
human encephalitis milder than that observed in
many cases of TBE. Other TBE complex viruses that
may rarely play a role in human disease include
Skalica, Karshi, Royal Farm, and Kyasanur Forest
viruses. Negishi and Omsk hemorrhagic fever viruses
show a close antigenic relationship to Louping ill
virus.
Many individuals exposed to TBE viruses remain
nonsymptomatic. Swedish studies have shown sero-
prevalence of 4–22%, despite the fact that the annual
incidence of reported disease is 0–6%. The incuba-
tion period for those who manifest disease is 8–14
days. Onset is often sudden, with febrile headache,
photophobia, nausea, vomiting, and meningismus.
Some cases, however, are fulminant and severe from
the earliest phase of illness, whereas others show
progressive deterioration or a biphasic course.
Seizures, paralysis, and coma are common in severe
forms. Although the range of manifestations of
various TBE illnesses is similar, central European

encephalitis and milk- and cheese-transmitted TBE
tend to have a biphasic course and Far Eastern/
Russian spring–summer encephalitis is usually mono-
phasic. Approximately half of all cases are moderate
or severe, and the overall case fatality rate is
approximately 20%. The monophasic forms tend
to be more severe than the biphasic, with higher
mortality and greater risk for sequella. Children tend
to have more severe disease than adults. Residual
paralysis is found in 30–60% of cases overall,
especially for Far Eastern/Russian spring–summer
encephalitis.
Diagnosis is suspected in endemic areas if there is a
history of tick bite or consumption of unpasteurized
dairy products. However, the history of tick bite is
often missing. It is confirmed by serological studies,
especially with the IgG-capture ELISA method.
There is no specific treatment; care is supportive.
Prevention entails avoidance of or surveillance for
ticks and avoidance of unpasteurized dairy products.
An effective vaccine is available. TBE infection can
readily be prevented with vaccination.
Dengue Viruses: Dengue viruses are of exceeding
importance as a threat to public health throughout
the world, although particularly important endemi-
city is found in India, Southeast Asia, and the
western Pacific, where it has caused more than 3
million hospitalizations and 10,000 deaths in recent
decades and represents a leading cause of morbidity
and mortality for both children and the elderly. This
disease appears to be extending its geographical
boundaries; it is a major problem in Africa and is
found in both tropical and subtropical Americas,
Europe, and Australia. More than 500,000 residents
of tropical areas are hospitalized each year with
dengue fever/dengue shock, 90% of whom are
children. Quite severe acute complications with
potentially grave consequences have only recently
been recognized.
There are four antigenic subcategories of dengue
viruses. Aedes aegypti or albopictus mosquitoes are
the only known vectors. Since A. aegypti is an
aggressive peridomiciliary or ‘‘domestic’’ mosquito,
outbreaks tend to occur in urban areas. Outbreaks
also occur in rural areas, often related to A.
albopictus, a sylvan tree-hole mosquito. Although
outbreaks are more likely to occur several months
after periods of heavy rainfall, they may occur at any
time of the year in regions with tropical climates due
to the year-round persistence of domestic mosqui-
toes. Indoor storage of water is an important risk
ARBOVIRUSES, ENCEPHALITIS CAUSED BY 265
factor. The only known vertebrate reservoirs are
humans and monkeys. The latter do not appear to
participate in the cycle that produces human infec-
tions. In temperate regions the virus may overwinter
in mosquito eggs by diapause.
The attack rate is high. It is estimated that 75% of
acutely infected susceptible individuals will manifest
disease. Most cases of dengue fever occur in
individuals younger than 30 years of age; males are
almost twice as likely to contract dengue fever as
females. Classic presentation of dengue involves
abrupt onset of severe headache, chills, disturbed
sense of taste, lumbar backache, myalgia, high fever
with relative bradycardia and hypotension, conjunc-
tival injection, and severe prostration. In approxi-
mately 10% of cases, marked generalized and local
musculoskeletal pains, particularly likely to occur in
knee and hip joints, account for the dengue synonym
break-bone fever. Fever describes a ‘‘saddleback’’
course in half of all cases, with an initial 2- to 4-day
bout, a day of remission, and another briefer period
of less severe fever. During the first febrile phase a
pink facial rash may be found. During the second, a
generalized red maculopapular rash sparing the face
is found in approximately 40% of cases. Lymphade-
nopathy, edema, cough, hepatomegaly, or splenome-
galy may be found. Fever, rash, and headache
constitute the dengue triad. However, patients with
symptomatic dengue virus infections may be atypi-
cal, manifesting few of the characteristic signs of
infection. Indeed, dengue infection may manifest
merely as an uncomplicated fever or as fever with
hepatomegaly, splenomegaly, edema, or anemia.
Unless severe complications develop, the mortality
for dengue fever is less than 3%.
The severe illnesses with which dengue viruses are
particularly associated are dengue hemorrhagic fever
(DHF) and dengue shock syndrome (DSS). In recent
epidemics, as many as half of all cases have exhibited
some form of hemorrhage and nearly 10% have
shown elements of DSS, which is in essence a
generalized vascular leak syndrome. Bleeding from
gums, nosebleeds, bruising, prolonged bleeding from
injection sites, and both upper and lower gastro-
intestinal tract hemorrhages are evidence of DHF.
These changes are often associated with rapid,
thready pulse, lip and peripheral cyanosis, and cold
and clammy hands with warm trunk. In patients who
exhibit a sudden profound shock, DSS is diagnosed.
It may be preceded by sudden onset of hypotension
and carries a mortality rate of approximately 50%.
These severe syndromes develop some time between
266 ARBOVIRUSES, ENCEPHALITIS CAUSED BY
the second and sixth day of illness and may be
associated with encephalopathy in addition to
lethargy. Features of both DHF and DSS are often
present in a given severely ill patient. As with dengue
fever, DHF tends to occur in individuals younger
than 30 years of age. Children younger than 10 years
of age account for 20–66% or more of cases;
children younger than 1 year of age have the highest
mortality. The development of such hemorrhagic
complications after fever, headache, prostration, and
pain is highly suggestive of infection with either
dengue or the Chikungunya alphavirus.
DHF usually occurs in individuals with acute
dengue type 2 infection after they have previously
experienced a bout of dengue type 1 or acquired anti-
type 1 antibodies transplacentally. It is thus argued
that enhancement of the virulence of infection occurs
because of sensitization to dengue antigens from
prior infection, producing a more exuberant and
inadequately controlled immune response. Thus,
passive immunization to one or a few strains of
dengue virus may actually promote the development
of severe cases. It has also been argued that fast
passages of virus between individuals in an explosive
epidemic may increase viral virulence.
Neurological dysfunction in patients with DHF/
DSS has been ascribed to vasculitis, cerebral edema,
hypoxic–ischemic injury, hyponatremia, liver failure,
renal failure, or other metabolic disturbances. How-
ever, dengue encephalitis has only recently been
characterized in dengue-infected individuals without
these severe complications. Infants and prepubertal
children appear to be more susceptible than older
individuals, and boys are slightly more susceptible
than girls. It occurs in less than 3% of adult classic
cases of dengue fever. It may develop on the second
or third day of the course of classic dengue fever or in
patients who have few if any classic features of
dengue infection except for fever; in endemic areas, it
belongs in the differential of patients presenting with
‘‘viral’’ encephalitis. It may occur in primary or
secondary dengue infections.
The most frequently encountered neurological
manifestations of encephalitis are reduced conscious-
ness (75%), seizures (63%), and pyramidal signs
(37%). Curiously, meningeal signs are present in only
approximately 30% and headache in only approxi-
mately 27% of cases. The risk for persistent
neurological abnormality after dengue encephalitis
is high, perhaps higher in children than adults.
Dengue virus types 2 and 3 appear to be the most
neurovirulent. Virus has been detected or recovered
from brain CSF or brains of some individuals with
dengue encephalitis. Meningoencephalitis may con-
tribute to the nervous system dysfunction of those
who also have DHF/DSS and may, in some instances,
be a manifestation of the immunological response
that appears to account for the pathogenesis of DHF/
DSS.
Other Encephalitogenic Flaviviridae
In Brazil and parts of the Caribbean, the mosquito-
borne Ilheus virus may cause a mild febrile illness that
is occasionally complicated by mild meningoence-
phalitis. There is a close antigenic relationship to
Japanese B encephalitis virus. Rocio virus, antigeni-
cally related to Ilheus virus, was isolated and
identified from brains of patients dying of encepha-
litis during an extensive late summer epidemic in the
coastal region south of São Paulo and the Ribeira
Valley of Brazil in 1975–1977. Case fatality rate was
13%, reflecting in part poor accessibility to hospita-
lization. Young adult males exhibited a predilection.
No additional cases have been reported since 1980.
The Psorophora ferox mosquito may be the vector;
sparrows may be amplifying hosts. Both gray and
white matter injuries may occur. Thalamic inflamma-
tory necrosis is the most consistent finding in lethal
cases. In descending order of frequency, injury to
dentate nucleus, substantia innominata, brainstem,
spinal cord, and basal ganglia may also be found.
Negishi virus shares characteristics with both the
TBE group and JBE. It may rarely be a cause of
human meningoencephalitis. Kunjin virus, antigeni-
cally related to the West Nile group, has been
reported as a cause of encephalitis in tropical
Australia but is encountered there far less frequently
than MVE. The encephalitis may be severe, with
signs referable to cortex, brainstem, cerebellum, and
anterior horn cells. Recovery from acute encephalitis
may be slow. As with MVE, there is only one
genotype of the virus in Australia.
—Robert S. Rust
See also–Encephalitis, Viral; Enteroviruses; Tick
Paralysis
Further Reading
Calisher, C. H. (1994). Medically important arboviruses of the
United States and Canada. Clin. Microbiol. Rev. 7, 89–116.
Leyssen, P., De Clercq, E., and Neyts, J. (2000). Perspectives for
the treatment of infections with flaviviridae. Clin. Microbiol.
Rev. 13, 67–82.

Lundstrom, J. O. (1999). Mosquito-borne viruses in western
Europe: A review. J. Vector Ecol. 24, 1–39.
Rust, R. S., Thompson, W. H., Matthews, C. G., et al. (1999). La
Crosse and other forms of California encephalitis. J. Child
Neurol. 14, 1–14.
Solomon, T., Dung, N. M., Kneen, R., et al. (2000). Japanese
encephalitis. J. Neurol. Neurosurg. Psychiatry 68, 405–415.
Whiteley, R. J. (1997). Arthropod-borne encephalitides. In Infec-
tions of the Central Nervous System (W. M. Scheld, R. J. Whitley,
and D. T. Durack, Eds.). Lippincott–Raven, Philadelphia.
Argyll–Robertson Pupil
see Pupillary Disorders, Efferent
Arm Pain
see Neck and Arm Pain
Arnold–Chiari Malformation
see Chiari Malformation
Arsenic
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
DESPITE its known toxic properties, arsenic remains
in common use in many insecticide sprays for fruits
and vegetables, in disinfectant compounds, and in
chemicals related to paints, prints, and enamels.
Certain homeopathic medications contain potentially
toxic quantities of arsenic, and intoxications in
Africa have followed arsenical therapy of the
infectious disease trypanosomiasis. Significant ar-
senic intoxication still results from accidental and
homicidal ingestion. In almost all cases, arsenic
poisoning follows ingestion of contaminated sub-
stances, although arsenic-containing gases are ra-
pidly absorbed through the respiratory system.
Arsenic is stored in the liver, kidney, intestines,
spleen, lymph nodes, and bones. It is deposited in the
hair within 2 weeks of administration and stays fixed
in this site for years. It also remains within bones for
ARSENIC 267
extended periods. Arsenic is very slowly excreted in
the urine and feces.
Any arsenic compound (inorganic, organic penta-
valent, or organic trivalent) may affect the central
nervous system. Arsenic exerts its toxic effects by
binding to sulfur-containing radicals of enzymes and
inactivating them. Because enzymes concerned with
energy production and oxidative metabolism are
particularly involved, pyruvic acid accumulates in
the blood. Whether toxicity follows oral ingestion,
inhalation of gas, or injection, the neurological
features of acute intoxication are similar. When
arsenic is ingested orally, burning of the buccal
mucosa and severe abdominal pain are prominent.
Following inhalation toxicity, the subject experiences
chills and fever. The acute syndrome is usually
fulminating with a sudden increase in temperature
accompanied by headache, vertigo, nausea and
vomiting, nervousness, and apprehension or a mild
lethargy. Marked excitement may develop, or the
patient may pass into coma. Convulsions are
common. Neurological signs include heightened
tendon reflexes, jerky eye movements (nystagmus),
weakness, neck stiffness suggesting meningitis, and
urinary incontinence. Frequently, the cerebrospinal
fluid is under increased pressure. The pulse and
respirations gradually increase, breathing becomes
difficult and labored, and death may ensue within a
few days after onset of the initial symptoms.
In the subacute or chronic form of arsenic
encephalitis, the onset is more subtle and the course
is prolonged, varying from 16 days to many years.
Patients frequently complain of continuous progres-
sive headaches and marked physical and mental
fatigue. Vertigo, restlessness, mild somnolence, and
focal weakness may be present. Evidence of a
peripheral neuropathy, with decreased ability to feel
touch or pain, weakness of the distal extremities, and
loss of deep tendon reflexes, is characteristic of
chronic intoxication. The patient usually notes severe
burning in the soles. Touch or any pressure, such as
the weight of bed clothes, can cause extreme
discomfort or exacerbation of pain and can interfere
with sleep. Occasionally, paresthesias may be noted
in the face. Muscle tenderness (particularly on calf
pressure) and cramps are common, and increased
sweating is a frequent concomitant sign of arsenic
intoxication. Optic neuritis, manifested by cloudy
vision and field changes, may also be observed. In
severe cases, optic nerve atrophy may be noted. In
addition to a characteristic dermatitis that accom-
panies chronic arsenic intoxication, hepatic, renal,

Lundstrom, J. O. (1999). Mosquito-borne viruses in western
Europe: A review. J. Vector Ecol. 24, 1–39.
Rust, R. S., Thompson, W. H., Matthews, C. G., et al. (1999). La
Crosse and other forms of California encephalitis. J. Child
Neurol. 14, 1–14.
Solomon, T., Dung, N. M., Kneen, R., et al. (2000). Japanese
encephalitis. J. Neurol. Neurosurg. Psychiatry 68, 405–415.
Whiteley, R. J. (1997). Arthropod-borne encephalitides. In Infec-
tions of the Central Nervous System (W. M. Scheld, R. J. Whitley,
and D. T. Durack, Eds.). Lippincott–Raven, Philadelphia.
Argyll–Robertson Pupil
see Pupillary Disorders, Efferent
Arm Pain
see Neck and Arm Pain
Arnold–Chiari Malformation
see Chiari Malformation
Arsenic
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
DESPITE its known toxic properties, arsenic remains
in common use in many insecticide sprays for fruits
and vegetables, in disinfectant compounds, and in
chemicals related to paints, prints, and enamels.
Certain homeopathic medications contain potentially
toxic quantities of arsenic, and intoxications in
Africa have followed arsenical therapy of the
infectious disease trypanosomiasis. Significant ar-
senic intoxication still results from accidental and
homicidal ingestion. In almost all cases, arsenic
poisoning follows ingestion of contaminated sub-
stances, although arsenic-containing gases are ra-
pidly absorbed through the respiratory system.
Arsenic is stored in the liver, kidney, intestines,
spleen, lymph nodes, and bones. It is deposited in the
hair within 2 weeks of administration and stays fixed
in this site for years. It also remains within bones for
ARSENIC 267
extended periods. Arsenic is very slowly excreted in
the urine and feces.
Any arsenic compound (inorganic, organic penta-
valent, or organic trivalent) may affect the central
nervous system. Arsenic exerts its toxic effects by
binding to sulfur-containing radicals of enzymes and
inactivating them. Because enzymes concerned with
energy production and oxidative metabolism are
particularly involved, pyruvic acid accumulates in
the blood. Whether toxicity follows oral ingestion,
inhalation of gas, or injection, the neurological
features of acute intoxication are similar. When
arsenic is ingested orally, burning of the buccal
mucosa and severe abdominal pain are prominent.
Following inhalation toxicity, the subject experiences
chills and fever. The acute syndrome is usually
fulminating with a sudden increase in temperature
accompanied by headache, vertigo, nausea and
vomiting, nervousness, and apprehension or a mild
lethargy. Marked excitement may develop, or the
patient may pass into coma. Convulsions are
common. Neurological signs include heightened
tendon reflexes, jerky eye movements (nystagmus),
weakness, neck stiffness suggesting meningitis, and
urinary incontinence. Frequently, the cerebrospinal
fluid is under increased pressure. The pulse and
respirations gradually increase, breathing becomes
difficult and labored, and death may ensue within a
few days after onset of the initial symptoms.
In the subacute or chronic form of arsenic
encephalitis, the onset is more subtle and the course
is prolonged, varying from 16 days to many years.
Patients frequently complain of continuous progres-
sive headaches and marked physical and mental
fatigue. Vertigo, restlessness, mild somnolence, and
focal weakness may be present. Evidence of a
peripheral neuropathy, with decreased ability to feel
touch or pain, weakness of the distal extremities, and
loss of deep tendon reflexes, is characteristic of
chronic intoxication. The patient usually notes severe
burning in the soles. Touch or any pressure, such as
the weight of bed clothes, can cause extreme
discomfort or exacerbation of pain and can interfere
with sleep. Occasionally, paresthesias may be noted
in the face. Muscle tenderness (particularly on calf
pressure) and cramps are common, and increased
sweating is a frequent concomitant sign of arsenic
intoxication. Optic neuritis, manifested by cloudy
vision and field changes, may also be observed. In
severe cases, optic nerve atrophy may be noted. In
addition to a characteristic dermatitis that accom-
panies chronic arsenic intoxication, hepatic, renal,
268 ARSENIC

For treatment, if intoxication follows oral inges-

Figure 1
With chronic arsenic intoxication, horizontal bands of
discoloration, called Mees’ lines, appear in the fingernails
[reproduced with permission from Chhuttani, P. N., and Chopra,
J. S. (1979). Arsenic poisoning. In Intoxications of the Nervous
System: Handbook of Clinical Neurology (J. P. Vinken, G. W.
Bruyn, M. M. Cohen, and H. L. Klawans, Eds.), Vol. 36, p. 202.
Elsevier, Amsterdam].
tion, gastric lavage with water should be followed by
milk or 1% sodium thiosulfate. 2,3-Dimercapto-1-
propanol (BAL) is given parenterally over several
days, and intravenous fluids are essential to combat
dehydration. Once neuropathy occurs, BAL treat-
ment is considered ineffective or at least only
moderately helpful. Other agents used include 2-3-
dimercaptopropanesulfonate and meso-2,3-dimer-
captosuccinic acid. Morphine or other analgesics
may be necessary for the severe abdominal pain.
When shock occurs, treatment with blood transfu-
sion is indicated, and oxygen administration is
utilized for the resultant hypoxia.
The prognosis in acute severe arsenic encephalitis
is poor, with more than half of the cases being fatal,
usually within 48 hr. When intoxication occurs
during pregnancy, the outlook is particularly poor.
In addition, arsenic has been associated with detri-
mental effects on the developing embryo, including
neural tube defects. Impairment of verbal learning
and memory has been noted following subacute
arsenic exposure. Patients who survive the encepha-

and hematopoietic involvement are common, and

transverse white striae (Mees’ lines) above the lunula
of the nails should in combination suggest arsenic
poisoning (Figs. 1 and 2).
For diagnosis, a renal excretion exceeding 0.1 mg
arsenic in 24 hr is usually considered abnormal.
When concentrations of arsenic are not sufficiently
elevated to allow a diagnosis, mobilization of tissue
arsenic by a therapeutic regimen may increase the
urine concentrations to diagnostic levels. Arsenical
toxicity may occur even when blood and urine
concentrations are normal. Polyneuropathy may
develop shortly after a single ingestion of arsenic-
containing products, but symptoms are often de-
layed for up to 2 weeks after exposure. In cases of
suspected intoxication that might have occurred
weeks before medical evaluation, urinary arsenic
levels cannot be used, and examination of arsenic
levels in the hair may be helpful. The growing ends
of the hair, especially pubic hair, are the most
reliable segments for this purpose. Because arsenic is Figure 2
radiopaque, arsenic exposure can be visualized Skin rash with exfoliation in a patient with severe arsenic
in the gastrointestinal tract during radiological intoxication of long-standing duration [reproduced with
permission from Chhuttani, P. N., and Chopra, J. S. (1979).
examination. Electroencephalographic studies dur-
Arsenic poisoning. In Intoxications of the Nervous System:
ing intoxication may reveal a slow high-voltage Handbook of Clinical Neurology (J. P. Vinken, G. W. Bruyn, M.
activity that becomes less conspicuous as recovery M. Cohen, and H. L. Klawans, Eds.), Vol. 36, p. 202. Elsevier,
occurs. Amsterdam].

lopathy generally exhibit a persistent peripheral
neuropathy.
—Christopher G. Goetz
See also–Environmental Toxins; Intoxication;
Neuropathy, Toxic; Neurotoxicology, Overview;
Tropical Neurology
Further Reading
Bolla-Wilson, K., and Bleecker, M. L. (1987). Neuropsychological
impairment following inorganic arsenic exposure. J. Occup.
Med. 29, 500–503.
Fincher, R. M., and Koerker, R. M. (1987). Long-term survival in
acute arsenic encephalopathy: Follow-up using newer measures
of electrophysiologic parameters. Am. J. Med. 82, 549–552.
Goetz, C. G., and Washburn, K. R. (1999). Metals and
neurotoxicology. In Medical Neurotoxicology (P. G. Blain and
J. B. Harris, Eds.), pp. 181–200. Arnold, London.
Kerr, H. D., and Saryan, L. A. (1986). Arsenic content of homeo-
pathic medicines. J. Toxicol. Clin. Toxicol. 24, 451–459.
Art and the Brain
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ART is a complex behavior and requires the integra-
tion of multiple brain regions. The left hemisphere is
often considered the dominant hemisphere respon-
sible for language and analytic reasoning, whereas
the right hemisphere is considered responsible for
global processing and visuospatial skills. Art making
is more lateralized to the right hemisphere and the
concept of symbolic representation localized to the
left hemisphere. The four different lobes of the brain
also carry out different functions. The frontal lobe is
responsible for organization, the parietal lobe for
visuoconstruction, the temporal lobe for perceptual
abilities and particularly memory, and the occipital
lobe for vision.
BRAIN INJURY EFFECTS ON ART
AND CREATIVITY
Much of the current information on the relationship
of art, creativity, and the brain comes from patients
with degenerative disease and patients with focal brain
injury. Patients with injury to the right hemisphere
experience visual neglect, loss of visuospatial skills,
and a marked deterioration of visual art. Patients
with left brain injury experience a loss of attention to
visual detail and a loss of conceptual/symbolic art but
have a relative sparing of realistic, visual art.
ART AND THE BRAIN 269
RIGHT HEMISPHERE CONTRIBUTIONS
TO ART
The ability to precisely copy internal images, objects,
or drawings is profoundly altered by injury to the
right parietal lobe. Our visual images of the world
are shaped through our right parietal areas. The
ability to perform realistic copies of the internal or
external world is lost with right parietal injury, even
in previously accomplished artists. This loss is due to
a variety of factors relating to spatial cognition.
Neglect of the contralateral visual space will lead to
drawings in which the left half of the space is unused
or only sketchily drawn. One component of this
neglect is that we lose the ability to imagine the left
side of our world when the right parietal lobe is
injured. Similarly, the simple process of copying or
putting together two three-dimensional structures is
impaired. Clearly, right posterior parietal cortex is
required for realistic reproduction. A competent
artist has a profound mastery of these right parietal
lobe functions and can produce onto a canvass both
internal and external images of the world. Great
talent usually goes far beyond simple copying.
LEFT HEMISPHERE CONTRIBUTION TO ART
Less is known regarding the function of the left
hemisphere in the production of art, and it is possible
to suffer a left hemisphere infarct and continue to
produce precise copies of objects or paintings.
However, the left hemisphere contributes to art,
and a few reports suggest that artists who suffer a left
hemisphere stroke lose the ability to produce
symbolic paintings. One of the first accounts of the
effects of left hemisphere brain damage in an artist
was reported by Alajouanine in 1948. He described
how left hemisphere lesions associated with aphasia
affected the creative output of a writer, a musician,
and a painter. Alajouanine observed that in contrast
to the musician and writer, the painter maintained his
artistic ability despite the onset of Wernicke’s
aphasia. Similarly, Gardner reports that artists who
sustain left hemisphere damage may change their
style but maintain their artistic ability. This demon-
strates that despite left hemispheric damage, artists
retain their technical ability but may lose their ability
to represent symbolism.
In healthy individuals, Zaidel and Kasher found
that the left hemisphere was better at recognizing
surrealistic paintings than the right hemisphere,
suggesting that different regions of the brain were

lopathy generally exhibit a persistent peripheral
neuropathy.
—Christopher G. Goetz
See also–Environmental Toxins; Intoxication;
Neuropathy, Toxic; Neurotoxicology, Overview;
Tropical Neurology
Further Reading
Bolla-Wilson, K., and Bleecker, M. L. (1987). Neuropsychological
impairment following inorganic arsenic exposure. J. Occup.
Med. 29, 500–503.
Fincher, R. M., and Koerker, R. M. (1987). Long-term survival in
acute arsenic encephalopathy: Follow-up using newer measures
of electrophysiologic parameters. Am. J. Med. 82, 549–552.
Goetz, C. G., and Washburn, K. R. (1999). Metals and
neurotoxicology. In Medical Neurotoxicology (P. G. Blain and
J. B. Harris, Eds.), pp. 181–200. Arnold, London.
Kerr, H. D., and Saryan, L. A. (1986). Arsenic content of homeo-
pathic medicines. J. Toxicol. Clin. Toxicol. 24, 451–459.
Art and the Brain
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ART is a complex behavior and requires the integra-
tion of multiple brain regions. The left hemisphere is
often considered the dominant hemisphere respon-
sible for language and analytic reasoning, whereas
the right hemisphere is considered responsible for
global processing and visuospatial skills. Art making
is more lateralized to the right hemisphere and the
concept of symbolic representation localized to the
left hemisphere. The four different lobes of the brain
also carry out different functions. The frontal lobe is
responsible for organization, the parietal lobe for
visuoconstruction, the temporal lobe for perceptual
abilities and particularly memory, and the occipital
lobe for vision.
BRAIN INJURY EFFECTS ON ART
AND CREATIVITY
Much of the current information on the relationship
of art, creativity, and the brain comes from patients
with degenerative disease and patients with focal brain
injury. Patients with injury to the right hemisphere
experience visual neglect, loss of visuospatial skills,
and a marked deterioration of visual art. Patients
with left brain injury experience a loss of attention to
visual detail and a loss of conceptual/symbolic art but
have a relative sparing of realistic, visual art.
ART AND THE BRAIN 269
RIGHT HEMISPHERE CONTRIBUTIONS
TO ART
The ability to precisely copy internal images, objects,
or drawings is profoundly altered by injury to the
right parietal lobe. Our visual images of the world
are shaped through our right parietal areas. The
ability to perform realistic copies of the internal or
external world is lost with right parietal injury, even
in previously accomplished artists. This loss is due to
a variety of factors relating to spatial cognition.
Neglect of the contralateral visual space will lead to
drawings in which the left half of the space is unused
or only sketchily drawn. One component of this
neglect is that we lose the ability to imagine the left
side of our world when the right parietal lobe is
injured. Similarly, the simple process of copying or
putting together two three-dimensional structures is
impaired. Clearly, right posterior parietal cortex is
required for realistic reproduction. A competent
artist has a profound mastery of these right parietal
lobe functions and can produce onto a canvass both
internal and external images of the world. Great
talent usually goes far beyond simple copying.
LEFT HEMISPHERE CONTRIBUTION TO ART
Less is known regarding the function of the left
hemisphere in the production of art, and it is possible
to suffer a left hemisphere infarct and continue to
produce precise copies of objects or paintings.
However, the left hemisphere contributes to art,
and a few reports suggest that artists who suffer a left
hemisphere stroke lose the ability to produce
symbolic paintings. One of the first accounts of the
effects of left hemisphere brain damage in an artist
was reported by Alajouanine in 1948. He described
how left hemisphere lesions associated with aphasia
affected the creative output of a writer, a musician,
and a painter. Alajouanine observed that in contrast
to the musician and writer, the painter maintained his
artistic ability despite the onset of Wernicke’s
aphasia. Similarly, Gardner reports that artists who
sustain left hemisphere damage may change their
style but maintain their artistic ability. This demon-
strates that despite left hemispheric damage, artists
retain their technical ability but may lose their ability
to represent symbolism.
In healthy individuals, Zaidel and Kasher found
that the left hemisphere was better at recognizing
surrealistic paintings than the right hemisphere,
suggesting that different regions of the brain were
270 ARTERIAL THROMBOSIS, CEREBRAL
responsible for processing different styles of art.
They suggested that symbolic paintings were more
closely related to language, reflecting similar storage
and retrieval strategies utilized by the left hemi-
sphere. The left hemisphere remains important for
the conceptual and verbal aspects of visual art.
DEGENERATIVE DISEASE AND ART
Two degenerative dementias, Alzheimer’s disease and
frontotemporal dementia, reveal contrasting ways
through which focal brain injury can influence
artistic expression. In Alzheimer’s disease, visuocon-
structive abilities are lost in the early stages of the
illness. Drawings become distorted with diminished
accuracy and spatial perspective. These losses coin-
cide with dysfunction in the right parietal lobe. In
frontotemporal dementia, the ability to copy is
relatively preserved. Even though creativity disap-
pears in most patients with frontotemporal demen-
tia, the ability to draw remains preserved late into
the course of the illness. Furthermore, in one
anatomical subtype of frontotemporal dementia—
patients with left anterior temporal degeneration—
visual creativity remains or develops de novo. The art
is typically realistic and nonsymbolic, but it is
visually appealing and successful. We have hypothe-
sized that both visual perception and visual interest
are enhanced by injury to the left anterior temporal
lobe, which is the brain region responsible for access
to semantic information.
—Tabassum Ahmed and Bruce Miller
See also–Amusia; Aphasia; Degenerative
Disorders; Intelligence; Language and Discourse
Further Reading
Alajouanine, T. (1948). Aphasia and artistic realization. Brain 71,
229–241.
Gardner, H. (1982). Art, Mind and Brain. Basic Books, New York.
Kapur, N. (1996). Paradoxical functional facilitation in brain–
behavior research: A critical review. Brain 119, 1775–1790.
Miller, B. L., Cummings, J. L., Boone, K., et al. (1998). Emergence
of artistic talent in frontotemporal dementia. Neurology 51,
978–981.
Miller, B. L., Boone, K., Cummings, J., et al. (2000). Functional
correlates of musical and visual talent in frontotemporal
dementia. Br. J. Psychiatry 176, 458–463.
Miller, D. (1999). Cave art: An early example of information
processing. MD Comput. 16, 56–59.
Zaidel, D. W., and Kasher, A. (1989). Hemispheric memory
for surrealistic versus realistic paintings. Cortex 25,
617–641.
Arterial Thrombosis, Cerebral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
STROKE is the third leading cause of mortality and
the leading cause of disability in the United States.
There are an estimated 700,000 strokes each year in
the United States. As the population has aged, the
burden of stroke has also increased. Approximately
80% of all strokes are ischemic, and the remaining
20% represent intracerebral hemorrhages and may
be further classified as intraparenchymal hemor-
rhages and subarachnoid hemorrhages.
The term ischemia derives from the Greek word
ischo, which means to keep back. It represents an
anemia due to obstruction of arterial blood flow.
Ischemia in the brain is manifest when delivery of
substrate, principally oxygen and glucose, declines
below the critical thresholds required for sustained
cellular function. Ischemia may be focal, such as
when a single artery is obstructed, or it may be
global, such as in a cardiac arrest in which there
may be decreased blood flow to the entire brain.
There are two basic mechanisms that result in
arterial obstruction: thrombosis and embolism.
Arterial thrombosis, or atherothrombosis, may be
the more common cause of stroke. Cerebral
embolism is discussed elsewhere in this encyclope-
dia; this entry discusses arterial thrombosis as it
relates to the brain.
Thrombotic ischemic stroke results from the
occlusion of a blood vessel that in most circum-
stances has underlying narrowing from atherosclero-
tic disease. Despite a tremendous amount of research
on atherosclerosis, the exact mechanism of its
development is not known. It is clear that the
development of an atherosclerotic plaque involves
an interaction between cholesterol esters, connective
tissue elements within the vessel wall, smooth muscle
cells, endothelial cells, and macrophages.
The earliest sign of atherosclerosis is the appear-
ance of fatty streaks on the endothelial surface of the
blood vessel. These fatty streaks are composed mainly
of lipid-laden macrophages and, to a lesser extent,
lipid-laden smooth muscle cells referred to as foam
cells. In addition, the fatty streaks may also have
extracellular lipid associated with them. Over time,
these fatty streaks stimulate lesions called fibrosis
plaques, usually at branch points in blood vessels.
Endothelial cells typically cover these fibrotic pla-
ques, which consist of the foam cells of macrophage
270 ARTERIAL THROMBOSIS, CEREBRAL
responsible for processing different styles of art.
They suggested that symbolic paintings were more
closely related to language, reflecting similar storage
and retrieval strategies utilized by the left hemi-
sphere. The left hemisphere remains important for
the conceptual and verbal aspects of visual art.
DEGENERATIVE DISEASE AND ART
Two degenerative dementias, Alzheimer’s disease and
frontotemporal dementia, reveal contrasting ways
through which focal brain injury can influence
artistic expression. In Alzheimer’s disease, visuocon-
structive abilities are lost in the early stages of the
illness. Drawings become distorted with diminished
accuracy and spatial perspective. These losses coin-
cide with dysfunction in the right parietal lobe. In
frontotemporal dementia, the ability to copy is
relatively preserved. Even though creativity disap-
pears in most patients with frontotemporal demen-
tia, the ability to draw remains preserved late into
the course of the illness. Furthermore, in one
anatomical subtype of frontotemporal dementia—
patients with left anterior temporal degeneration—
visual creativity remains or develops de novo. The art
is typically realistic and nonsymbolic, but it is
visually appealing and successful. We have hypothe-
sized that both visual perception and visual interest
are enhanced by injury to the left anterior temporal
lobe, which is the brain region responsible for access
to semantic information.
—Tabassum Ahmed and Bruce Miller
See also–Amusia; Aphasia; Degenerative
Disorders; Intelligence; Language and Discourse
Further Reading
Alajouanine, T. (1948). Aphasia and artistic realization. Brain 71,
229–241.
Gardner, H. (1982). Art, Mind and Brain. Basic Books, New York.
Kapur, N. (1996). Paradoxical functional facilitation in brain–
behavior research: A critical review. Brain 119, 1775–1790.
Miller, B. L., Cummings, J. L., Boone, K., et al. (1998). Emergence
of artistic talent in frontotemporal dementia. Neurology 51,
978–981.
Miller, B. L., Boone, K., Cummings, J., et al. (2000). Functional
correlates of musical and visual talent in frontotemporal
dementia. Br. J. Psychiatry 176, 458–463.
Miller, D. (1999). Cave art: An early example of information
processing. MD Comput. 16, 56–59.
Zaidel, D. W., and Kasher, A. (1989). Hemispheric memory
for surrealistic versus realistic paintings. Cortex 25,
617–641.
Arterial Thrombosis, Cerebral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
STROKE is the third leading cause of mortality and
the leading cause of disability in the United States.
There are an estimated 700,000 strokes each year in
the United States. As the population has aged, the
burden of stroke has also increased. Approximately
80% of all strokes are ischemic, and the remaining
20% represent intracerebral hemorrhages and may
be further classified as intraparenchymal hemor-
rhages and subarachnoid hemorrhages.
The term ischemia derives from the Greek word
ischo, which means to keep back. It represents an
anemia due to obstruction of arterial blood flow.
Ischemia in the brain is manifest when delivery of
substrate, principally oxygen and glucose, declines
below the critical thresholds required for sustained
cellular function. Ischemia may be focal, such as
when a single artery is obstructed, or it may be
global, such as in a cardiac arrest in which there
may be decreased blood flow to the entire brain.
There are two basic mechanisms that result in
arterial obstruction: thrombosis and embolism.
Arterial thrombosis, or atherothrombosis, may be
the more common cause of stroke. Cerebral
embolism is discussed elsewhere in this encyclope-
dia; this entry discusses arterial thrombosis as it
relates to the brain.
Thrombotic ischemic stroke results from the
occlusion of a blood vessel that in most circum-
stances has underlying narrowing from atherosclero-
tic disease. Despite a tremendous amount of research
on atherosclerosis, the exact mechanism of its
development is not known. It is clear that the
development of an atherosclerotic plaque involves
an interaction between cholesterol esters, connective
tissue elements within the vessel wall, smooth muscle
cells, endothelial cells, and macrophages.
The earliest sign of atherosclerosis is the appear-
ance of fatty streaks on the endothelial surface of the
blood vessel. These fatty streaks are composed mainly
of lipid-laden macrophages and, to a lesser extent,
lipid-laden smooth muscle cells referred to as foam
cells. In addition, the fatty streaks may also have
extracellular lipid associated with them. Over time,
these fatty streaks stimulate lesions called fibrosis
plaques, usually at branch points in blood vessels.
Endothelial cells typically cover these fibrotic pla-
ques, which consist of the foam cells of macrophage
 ARTERIAL THROMBOSIS, CEREBRAL 271

and smooth muscle cell origin, connective tissue The affected vessels may be extracranial, as in
elements, and a central core of necrotic tissue. extracranial carotid artery disease, which may
Complicated plaques are plaques with similar involve one of the large intracranial blood vessels
consistencies as those just described but with the or one of the smaller penetrating blood vessels in the
addition of hemosiderin, calcium, and areas of brain. Although some of the same mechanisms may
endothelial disruption. Disruption of a plaque may be at play in small vessel strokes (namely thrombotic
result in ulceration, dissection of blood into the or embolic occlusion), other pathophysiological
plaque, and formation of thrombus at the plaque site. mechanisms may also occur. Microatheromas result-
This thrombus may cause in situ obstruction or may ing in a gradual narrowing may be found, and
embolize distally. Risk factors for the development of lipohyalinosis resulting in progressive vascular nar-
atherosclerotic plaques, and subsequent stroke as a rowing and closure has also been described.
result of these plaques, include hypertension, smok- The basic anatomy of the cerebral circulation is
ing, and elevated serum lipids and cholesterol. If the depicted in Fig. 1. Clinical manifestations of ischemic
obstruction caused by plaque rupture and thrombus stroke vary depending on which blood vessel(s) is
formation is sufficient to cause decreases in blood affected. These syndromes can be classified as
flow below thresholds necessary for normal neuronal anterior and posterior circulation syndromes, and
functioning, ischemia will result. they can be further classified as large-vessel and
Normal cerebral blood flow (CBF) is in the range small-vessel syndromes.
of 50–100 ml/100 g of brain weight/min and is In small-vessel stroke (also called lacunar), four
closely related to metabolism, changing in response classic syndromes have been defined: pure motor
to local tissue metabolic demands (i.e., CBF is hemiparesis, pure hemisensory loss, ataxic hemipar-
autoregulated). Decreases in CBF to 18 ml/100 g/ esis, and dysarthria clumsy hand syndrome. These
min result in suppression of electroencephalograph syndromes appear to involve the small penetrating
waveforms, and decreases below 12 ml/100 g/min lenticulostriate vessels in the anterior circulation and
result in the rapid depletion of adenosine tripho- the perforating vessels of the basilar artery and poste-
sphate (ATP). ATP depletion results in failure of the rior cerebral arteries in the posterior circulation.
Na þ /K þ membrane pump that is essential for main- Thrombosis with resulting ischemia in a large-
taining cellular ionic gradients. In addition, the lack vessel territory results in classically recognized
of oxygen and glucose causes the cell using anaerobic
pathways to produce ATP from glucose, and this
results in lactic acidosis. If reperfusion with adequate
amounts of oxygen and glucose does not occur, cell
death will follow.
In cerebral ischemia, the ability of neurons to
survive depends not only on the severity of ischemia
but also on the length of the ischemic period. Current
concepts of cerebral ischemia describe a central
region of severely ischemic tissue that will go on to
cell death, referred to as the ischemic core,
surrounded by a larger area of progressively less
ischemic tissue often referred to as the ischemic
penumbra. The penumbra may be considered a
dynamic volume that may progress to cell death or,
if sufficient blood flow is restored within an
appropriate time frame, may return to a normal
functional state. Thus, the penumbra may be viewed
as the volume of tissue at risk in cerebral ischemia.
Therefore, strategies in the treatment of acute stroke
target the penumbra region to either restore blood
flow or decrease the metabolic demands of the cells
so that existing blood flow may be better matched Figure 1
with metabolic requirements. Vascular supply to the brain.
272 ARTERIAL THROMBOSIS, CEREBRAL
syndromes described in Table 1. The ability to recog-
nize the clinical syndromes associated with large- and
small-vessel thrombosis is essential to developing
strategies to treat ischemic stroke in the acute phase,
and recognizing the risk factors associated with the
development of cerebrovascular disease is helpful in
developing strategies to prevent it.
Treatment of stroke may be consist of prophylac-
tic, or preventative, strategies and therapies for acute
stroke. Of the two strategies, the first is the most
cost-effective.
Prophylactic strategies involve risk factor modifi-
cation: aggressive treatment of hypertension, glucose
control in diabetes, smoking cessation, and aggres-
sive management of elevated serum cholesterol.
Determining whether a patient may have an under-
lying hypercoagulable condition is also important,
especially after a primary vascular event has
occurred. Such disorders include protein C and
protein S deficiency, homocysteinemia, antiphospho-
lipid syndrome, and factor V Leiden deficiencies.
The use of antiplatelet agents has also shown clear
benefit in reducing stroke risk, especially after first
stroke. Normal endothelium does not activate
hemostasis. In addition, blood platelets typically
remain inactive with regard to other platelets and the
vascular endothelium. However, in the setting of
endothelial injury, such as that caused by disruption
of the endothelial lining (as occurs in dissection),
atherosclerosis, or inflammation, the endothelium
may lose much of its ability to resist platelet
activation and thrombus formation.
Once platelets become activated through a series of
complex biochemical events, they begin adhering to
the damaged vessel wall and to each other. In addi-
tion, platelets play an important role in the genera-
tion of thrombin and, consequently, the formation of
Table 1 LARGE-VESSEL STROKE SYMPTOMS
Anterior Posterior
Contralateral weakness Bilateral or shifting weakness
Contralateral sensory deficit Bilateral or shifting sensory
(including extinction) deficit
Dysarthria Ataxia
Aphasia (left hemisphere) Diplopia, nystagmus, or
blindness
Contralateral visual field loss ‘‘Crossed findings’’: ipsilateral
face and contralateral body
Eyes deviated toward the side Eyes deviated away from the
of lesion side of lesion
fibrin. This process can result in obstruction and
ischemia. Therefore, prevention of platelet aggrega-
tion may be beneficial in preventing ischemia.
Aspirin irreversibly affects the enzyme cyclooxy-
genase, thereby preventing platelet activation and
aggregation. It has shown benefit in secondary stroke
prevention and even in improving outcome when
used in the setting of acute stroke. There is contro-
versy regarding the appropriate dose of aspirin, but
most clinicians recommend a dosage of 81 mg/day
for secondary stroke prevention.
Other antiplatelet agents that have shown benefit
in secondary stroke prevention include ticlopidine
and clopidogrel. Both of these agents act by blocking
ADP-mediated platelet activation. Both have shown
benefit in stroke prevention. Clopidogrel has essen-
tially replaced ticlopidine as an antiplatelet agent.
The usual dose is 75 mg/day.
Dipyridamole has a mechanism of action similar to
that of aspirin. Recent studies suggest that the
combination of low-dose aspirin and extended-
release dipyridamole gives benefit in terms of
secondary prevention that is superior to either agent
alone. The usual dose is 50 mg of aspirin and 400 mg
of extended-release dipyridamole.
For acute stroke treatment, reperfusion therapies
and neuroprotective therapies may be employed.
Despite promise in the laboratory, neuroproctec-
tive strategies have yielded disappointing results
clinically.
Since 1995, three treatments have shown benefit
in randomized controlled trials: intravenous recom-
binant tissue plasminogen activator (rt-PA), intra-
arterial pro-urokinase, and ancrod. In each of these
trials drug had to be administered with narrow time
frames (3 hr for rt-PA and ancrod, and 6 hr for pro-
urokinase). Each of these trials used thrombolytic
agents to effect reperfusion of occluded vessels.
However, only intravenous rt-PA has been approved
by the U.S. Food and Drug Administration for
clinical use in the treatment of ischemic stroke. The
other two await further clinical testing.
Tissue plasminogen activator converts plasmino-
gen to plasmin. Plasmin is a protease that is able
to break down fibrin. Both plasminogen and t-PA
bind to the fibrin clot, and activation of t-PA is
stimulated by fibrin. Urokinase and pro-urokinase
function similarly by activating t-PA. Ancrod is a
purified protease from the venom of the Malaysian
pit viper.
In each of these trials, emphasis was placed on
time frames for effective treatment. As a result,

renewed emphasis has been placed on accurately
determining the exact time of onset of symptoms in
patients presenting with acute stroke and expedi-
tiously differentiating between ischemic stroke and
intracerebral hemorrhage so that maximum benefit
can be gained through the use of these agents.
Patients presenting with stroke symptoms should
therefore undergo imaging with computed tomogra-
phy as soon as possible. An urgent evaluation should
be done to exclude seizures, metabolic disturbances,
hyper- or hypoglycemia, and infection as possible
causes of patients’ symptoms. If the onset of
symptoms occurs within an appropriate time frame,
the dose of intravenous rt-PA for acute stroke is 0.9
mg/kg. Ten percent of the total dose is delivered
within the first minute and the remainder over the
course of 1 hr. Pro-urokinase is currently not
approved for use in the United States, but the dose
given in a recent randomized trial demonstrating its
effectiveness was 9 mg given intraarterially over the
course of 2 hr.
Unfortunately, because of the narrow time frames
involved, only a small percentage of patients suffer-
ing acute ischemic stroke may be eligible to receive
treatment. For patients presenting after accepted
time frames for thrombolysis, treatment is designed
to maintain adequate CBF and to prevent further
ischemic damage.
Treatment of elevated blood pressure in the setting
of acute ischemic stroke remains controversial;
however, most recommend against acutely lowering
blood pressure unless it is greatly elevated (systolic
blood pressure in excess of 220 mmHg or a mean
arterial pressure in excess of 130 mmHg). Elevated
blood pressure may be compensatory and therefore
may be helpful in maintaining cerebral perfusion.
The use of anticoagulants in the setting of acute
stroke is controversial. To date, no study has
demonstrated clear benefit of anticoagulation ther-
apy in the setting of acute stroke, although some
advocate its use in certain settings (stroke in
progression, atrial fibrillation, and remitting symp-
toms of ischemia).
In parallel with acute management, an evaluation
should be undertaken to determine the cause of the
thrombosis. This may include the use of magnetic
resonance imagining to evaluate the extent of injury
to the brain and a magnetic resonance angiogram to
evaluate the blood vessels of the brain and neck for
evidence of stenosis or occlusion. Other tests that
may be helpful include carotid duplex evaluation to
search for evidence of internal carotid artery disease
ARTERIAL THROMBOSIS, CEREBRAL 273
and echocardiography, which may be helpful in
identifying ischemia caused by embolism.
Risk factor reduction includes management of dia-
betes and hypertension as noted previously. Secondary
prevention strategies based on the presumed under-
lying stroke mechanism should also be addressed.
—David C. Bonovich
See also–Antiplatelet Therapy; Basilar Artery
Thrombosis; Cerebral Blood Vessels: Arteries;
Cerebral Metabolism and Blood Flow; Cerebral
Venous Thrombosis; Ischemic Cell Death,
Mechanisms
Further Reading
Adams, H. P., Jr. (1994). Guidelines for the management of
patients with acute ischemic stroke: A synopsis. A Special
Writing Group of the Stroke Council, American Heart
Association. Heart Dis. Stroke 3, 407–411.
Adams, H. P., Jr., Brott, T. G., Furlan, A. J., et al. (1996).
Guidelines for thrombolytic therapy for acute stroke: A
supplement to the guidelines for the management of patients
with acute ischemic stroke. A statement for healthcare
professionals from a Special Writing Group of the Stroke
Council, American Heart Association. Circulation 94, 1167–
1174.
Adams, H. P., Jr., Brott, T. G., Furlan, A. J., et al. (1996).
Guidelines for thrombolytic therapy for acute stroke:
A supplement to the guidelines for the management of patients
with acute ischemic stroke. A statement for health-
care professionals from a Special Writing Group of the
Stroke Council, American Heart Association. Stroke 27,
1711–1718.
Bushnell, C. D., and Goldstein, L. B. (2000). Diagnostic testing for
coagulopathies in patients with ischemic stroke. Stroke 31,
3067–3078.
Devuyst, G., and Bogousslavsky, J. (2001). Recent progress in drug
treatment for acute ischemic stroke. Cerebrovasc. Dis. 11,
71–79.
Falk, E., Zhou, J., and Moller, J. (2001). Homocysteine and
atherothrombosis. Lipids 36, S3–S11.
Fisher, C. M. (1982). Lacunar strokes and infarcts: A review.
Neurology 32, 871–876.
Furlan, A., Higashida, R., Wechsler, L., et al. (1999). Intra-arterial
prourokinase for acute ischemic stroke. The PROACT II study:
A randomized controlled trial. Prolyse in Acute Cerebral
Thromboembolism. J. Am. Med. Assoc. 282, 2003–2011.
Sacco, R. L., Owen, J., Mohr, J. P., et al. (1989). Free protein S
deficiency: A possible association with cerebrovascular occlu-
sion. Stroke 20, 1657–1661.
Tell, G. S., Crouse, J. R., and Furberg, C. D. (1988). Relation
between blood lipids, lipoproteins, and cerebrovascular athero-
sclerosis. A review. Stroke 19, 423–430.
Yatsu, F. M., Kasturi, R., Alam, R., et al. (1990). Molecular
biology of atherothrombotic brain infarction. Stroke 21,
131–133.
274 ARTERIOVENOUS FISTULAS
Arteriography
see Angiography
Arteriovenous Fistulas
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL ARTERIOVENOUS FISTULAS (AVFs) are
pathological connections between arteries and veins.
Fistula is Latin for ‘‘pipe’’ or ‘‘tube.’’ The name is
descriptive, indicating the abnormal connection
between an artery and vein without an intervening
capillary bed connection. AVFs are often confused
with the more common arteriovenous malformations
(AVMs), but they differ in several key ways. First,
most fistulas are acquired lesions; therefore, strictly
speaking, they are not malformations. The main
exceptions are vein of Galen malformations and pial
AVFs, which are discussed in more detail later.
Second, these lesions are typically characterized by
direct artery-to-vein connections without the usual
tangle of abnormal vessels (nidus) associated with an
AVM. Although the nidus is absent, there may still be
multiple abnormal connections in an AVF. Third,
unlike AVMs, AVFs seldom exist within the par-
enchyma of the brain. Rather, they are located
superficially to the brain, often within the layers of
the dura.
The majority of cerebral AVFs can be classified as
dural arteriovenous fistulas (DAVFs), vein of Galen
aneurysmal malformations, pial AVFs, or traumatic
AVFs. Traumatic fistulas are not discussed further. The
remaining three categories are described in this entry.
DURAL ARTERIOVENOUS FISTULAS
DAVFs are pathological AVFs that occur within the
dura and are relatively uncommon lesions. Because
they are dural based, their arterial supply may
include any artery with the potential to supply the
dura. The specific arterial supply depends on the
location of the fistula, but branches of the external
carotid artery, particularly the meningeal branches,
are usually prominently involved. Most DAVFs are
closely associated with a dural venous sinus. These
fistulas derive their arterial supply from the menin-
geal arteries and shunt blood to veins within the wall
of the dural sinus or into the sinus. DAVFs are
usually named and classified for the sinus into which
they drain or to which they are most closely related.
The most common locations include the transverse
sinus and the cavernous sinus, but fistulas have been
associated with each of the major dural sinuses (i.e.,
cavernous sinus, transverse sinus, superior sagittal
sinus, superior and inferior petrosal sinuses, straight
sinus, and marginal sinus). In some cases, the
association with a major sinus is not evident.
The etiology of DAVFs is unknown. Most are
idiopathic, but associations with dural sinus stenoses
and occlusions have been reported. It is thought that
a pathological angiogenic response to dural sinus
venous hypertension results in the excessive devel-
opment of otherwise normal preexisting AV connec-
tions within the dura. DAVFs have been observed to
develop after trauma and craniotomies and also
secondary to tumors that impinge on the dural
sinuses. Experimental evidence associates dural sinus
venous hypertension with the formation of DAVFs.
Conversely, the occlusion of dural venous sinuses has
been observed after the development of DAVFs.
DAVFs may be asymptomatic and noted only
incidentally, or they may manifest in a variety of
ways. Common presentations include various com-
binations of pulse synchronous bruits, intracranial
hemorrhage, seizures, and focal neurological deficits.
Certain locations may be associated with more
specific signs and symptoms. The two most common
locations for DAVFs are the transverse sinus and the
cavernous sinus. Figure 1 shows a typical example of
a left transverse sinus DAVF without retrograde
cortical venous drainage. The most common pre-
sentation for fistulas of the transverse sinus is with an
ipsilateral pulse synchronous bruit. If retrograde
venous drainage is present, then additional neurolo-
gical symptoms and signs may occur, as described
previously. The bruit may be very loud and disabling
to the patient because of interference with hearing or
by disrupting concentration and sleep. Patients with
more anteriorly located fistulas (e.g., in the caver-
nous sinus) typically present with a unilateral,
painful, proptotic red eye. Severe proptosis may
result in a mechanical ophthalmoplegia, but ophthal-
moplegia may also occur secondary to ischemic
cranial neuropathy. Intraocular pressures may be
markedly elevated and, if so, vision may be
compromised. Failure to treat fistulas in this setting
may result in permanent visual loss.
DAVFs may be grouped into low- or high-risk
categories, depending on the pattern of their venous

Figure 1
(A) A 43-year-old man presented with a disabling left-sided pulse
synchronous bruit. This angiogram shows a lateral view of the left
internal carotid artery (ICA) with dural branches supplying a left
transverse sinus dural arteriovenous fistula (DAVF). The left
sigmoid sinus is occluded, and the drainage is across the torcula to
the right transverse sinus. There is no retrograde flow to the
cortical veins. An external carotid artery (ECA) injection showed
abundant flow to the fistula from the meningeal arteries. (B)
Lateral skull radiograph shows casts of liquid adhesive occluding
some of the dural feeding arteries to the DAVF and platinum coils
in the left transverse sigmoid sinus. These materials were used to
cure the fistula by endovascular therapy. (C) Lateral left ICA
angiogram 6 months after treatment shows no residual or
recurrent fistula. (D) A later phase than that in C shows
preservation of the ipsilateral vein of Labbé. (E) Lateral left ECA
angiogram shows no residual or recurrent DAVF.
drainage. High-risk DAVFs are characterized by
drainage of the fistula into cortical veins. Figure 2
demonstrates a posterior fossa DAVF. This patient
presented with subarachnoid hemorrhage secondary
to a DAVF with exclusively retrograde cortical
venous drainage. This high-risk venous drainage is
in a retrograde direction relative to the physiological
direction of blood flow and results in cerebral venous
hypertension. Fistula drainage into the adjacent
dural sinus may continue or may be lost if the
ARTERIOVENOUS FISTULAS 275
connection to the sinus occludes or if the dural sinus
becomes occluded. The venous hypertension may be
quite extensive and extend remotely from the site of
the fistula. The effects of venous hypertension on the
involved parenchyma produce the pathophysiologi-
cal state, symptoms, and signs of DAVFs. Intracra-
nial pressures may be elevated as a result of the
venous hypertension. Alternatively, symptoms may
result when arterialized veins rupture, producing
intracranial hemorrhage. The natural history of a
patient with a DAVF demonstrating high-risk venous
drainage is poor. The annual estimated risk of death
or neurological disability is 15%.
Treatment of DAVFs requires interruption of the
pathological artery-to-vein connection by direct
surgery, endovascular techniques, radiosurgery, or a
combination of these methods. Treatment indications
include neurological symptoms, seizures, intracranial
hemorrhage, visual loss, retrograde cortical venous
drainage, or intractable bruit. The bruit can be very
loud and is occasionally reported by the patient’s
spouse. Except for visual loss, neurological symp-
Figure 2
(A) An 80-year-old woman presented with subarachnoid
hemorrhage. This angiogram of the lateral view of her common
carotid artery (CCA) shows a dural arteriovenous fistula (DAVF)
with high-risk retrograde cortical venous drainage in the posterior
fossa. Arterial supply to the fistula is primarily through the
meningeal branches of the middle meningeal artery and the
ascending pharyngeal artery. (B) Lateral skull radiograph shows a
cast of liquid adhesive injected from an arterial catheter placement
that allowed closure of the fistula and draining vein. The patient’s
clinical outcome was excellent. (C) Five-month follow-up
angiogram of the left CCA shows no residual or recurrent DAVF.
276 ARTERIOVENOUS FISTULAS
toms and hemorrhage are rare without retrograde
cortical venous drainage. Even visual loss is usually
related to ocular venous hypertension that results
from retrograde flow in the ophthalmic veins and
produces a syndrome of acute glaucoma and ocular
ischemia.
When possible, endovascular techniques are the
preferred modality of treatment. Unfortunately,
endovascular access is not always possible and a
cure cannot always be achieved. In these cases,
surgical resection may be considered, often with
endovascular embolization as a preoperative adjunct.
Radiosurgery is usually reserved for lesions that
require treatment but that fail endovascular and
surgical therapies.
For DAVFs treated successfully, the prognosis is
excellent. In the absence of severe hemorrhage or
completed stroke as a presentation, major deficits
can recover remarkably once the venous hyperten-
sion is eliminated. Recurrence of DAVFs after
angiographically proven obliteration is very rare.
Recurrence after partial treatment is expected.
Palliative treatments therefore have a relatively
limited role in the treatment of DAVFs.
VEIN OF GALEN MALFORMATIONS
Vein of Galen aneurysmal malformations are rare
congenital lesions that result in arteriovenous shunt-
ing directly into the deep venous system of the
embryonic brain. They are a confusing group of
lesions that can be subclassified according to their
arterial supply. All, however, share the common
feature of a dilated, arterialized deep venous
drainage system. They may be confused with, but
should be considered distinct from, AVMs that
secondarily result in dilation of the deep venous
system. In contrast, vein of Galen aneurysmal
malformations have AV shunting directly into the
deep system.
Embryologically, these fistulas arise before the vein
of Galen forms. Their venous drainage is through the
venous progenitor of the deep venous system, a
structure known as the median vein of the prosence-
phalon. The establishment of this abnormal AV
shunting distorts subsequent development. The
straight sinus frequently fails to develop. In its place,
venous drainage is typically from the fistula to the
dilated median vein of the prosencephalon and then
to the sagittal sinus via a falcine sinus. This deep
venous drainage system may become enormously
dilated, creating the appearance of a giant aneurysm.
The antiquated appellation of vein of Galen aneur-
ysm derives from this appearance. Actually, the
lesion is not an aneurysm, nor is the vein of Galen
involved.
These malformations may become symptomatic
prenatally, at birth, in early childhood, or later in
adult life. Early presentation is usually associated
with high-output cardiac failure. The cardiac failure
results from the exceptionally high volume of blood
shunting from artery to vein. Consequently, these
critically ill newborns often suffer multisystem fail-
ure. When a viable outcome is a reasonable expecta-
tion, initial treatment is directed toward controlling
the heart failure with medical therapies. If these are
inadequate, treatment is directed at the fistula.
Usually, multiple arteries are involved in the fistula
and the initial approach for its elimination is
endovascular embolization. However, in the past,
surgical interventions have been performed. This
situation is very challenging because these infants are
often medically unstable from multisystem organ
failure, and their small size imposes numerous
technical limitations. Immediate cure in such situa-
tions is seldom expected. Treatments are often staged
over months or even years, depending on the
patient’s clinical situation. Once the heart failure is
controlled, the infant should be allowed to recover
and grow before further treatment is attempted.
Fistulas too small to produce heart failure may not
become symptomatic until later in life. Presentation
in early childhood may be as failure to thrive,
developmental delay, or macrocephaly. Later in life,
presentation may be with bruit, visual loss, or
nonspecific neurological symptoms. Presentation
with hemorrhage is rare, and treatment should be
carefully tailored to the clinical situation.
PIAL AFVS
Pial AVFs are most conveniently thought of as
solitary direct connections between a pial artery
and vein. These fistulas can become very large and
result in considerable arteriovenous shunting. There
may be multiple fistulas, or fistulas may be the
dominant feature of an associated small AVM.
Unlike DAVFs, these abnormalities seldom result in
retrograde cortical venous flow and associated
venous hypertension. They may manifest with heart
failure, bruit, headache, neurological symptoms
related to vascular steal from the normal surrounding
brain, or intracranial hemorrhage. Typically, they
become symptomatic during childhood.
 ARTERIOVENOUS MALFORMATIONS, SURGICAL TREATMENT OF
Treatment consists of direct interruption of the
abnormal arteriovenous connection through surgical
exposure or endovascular techniques.
—Cameron G. McDougall
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Endovascular Therapy;
Subarachnoid Hemorrhage (SAH)
Further Reading
American Association of Neurological Surgeons Publications
Committee (1993). Dural Arteriovenous Malformations. Amer-
ican Association of Neurological Surgeons, Park Ridge, IL.
Aminoff, M. J. (1973). Vascular anomalies in the intracranial dura
mater. Brain 96, 601–612.
Awad, I. A., Little, J. R., Akrawi, W. P., et al. (1990). Intracranial
dural arteriovenous malformations: Factors predisposing to an
aggressive neurological course. J. Neurosurg. 72, 839–850.
Kerber, C. W., and Newton, T. H. (1973). The macro- and
microvasculature of the dura mater. Neuroradiology 6, 175–
179.
Lasjaunias, P., and Berenstein, A. (1992). Surgical Neuroangio-
graphy, IV. Endovascular Treatment of Cerebral Lesions.
Springer-Verlag, Berlin.
Lasjaunias, P., Chiu, M., ter Brugge, K., et al. (1986). Neurological
manifestations of intracranial dural arteriovenous malforma-
tions. J. Neurosurg. 64, 724–730.
Lawton, M. T., Jacobowitz, R., and Spetzler, R. F. (1997).
Redefined role of angiogenesis in the pathogenesis of dural
arteriovenous malformations. J. Neurosurg. 87, 267–274.
Malek, A. M., Halbach, V. V., Dowd, C. F., et al. (1998). Diagnosis
and treatment of dural arteriovenous fistulas. Neuroimaging
Clin. North Am. 8, 445–468.
Sundt, T. M., Jr., and Piepgras, D. G. (1983). The surgical
approach to arteriovenous malformations of the lateral and
sigmoid dural sinuses. J. Neurosurg. 59, 32–39.
van Dijk, J. M., ter Brugge, K. G., Willinsky, R. A., et al.
(2002). Clinical course of cranial dural arteriovenous fistulas
with long-term persistent cortical venous reflux. Stroke 33,
1233–1236.
Arteriovenous Malformations
(AVM), Surgical Treatment of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AN ARTERIOVENOUS malformation (AVM) is an
abnormal entanglement of blood vessels in the
central nervous system that has been present since
birth. Ordinarily, arteries and veins are connected by
a bed of capillaries, which is the site where oxygen
277
and nutrients are extracted from the blood by brain
tissue to meet its metabolic needs. However, AVMs
represent a direct connection between arteries and
veins of the brain or spinal cord without an
intervening capillary bed. This direct shunt between
the arterial and venous circulations provides a
relatively low-resistance pathway for blood to pass
through and creates a high-pressure, high flow state
within the AVM. The vascular tissue is also abnormal
and not designed to carry this high flow volume.
AVMs are therefore predisposed to rupture, the
consequences of which can be devastating.
Arteriovenous malformations of the brain and
spinal cord develop early on during the fetal period.
A network of blood vessels begins to form during the
third week of development. During the fourth week,
this primitive vascular meshwork grows and differ-
entiates into vessels that will form arteries, veins, and
capillaries. Although the reasons remain unclear,
rarely there is a failure in complete differentiation
and no capillaries form in a particular region of the
brain or spinal cord. Furthermore, the different
layers that are usually present in small arteries fail
to develop, leaving these vessels more susceptible to
rupture. The result is the persistence of direct
connections between abnormal arteries and veins
and the development of an arteriovenous malforma-
tion. In the adult phase of this condition, one sees a
‘‘Medusa’s head’’ of tangled, enlarged vessels creating
a ‘‘tumor’’ of blood vessels (Figs. 1 and 2).
The natural course of AVMs is variable, and
although somewhat dependent on size and location,
it is difficult to predict exactly how any particular
AVM will develop and behave. An AVM can cause
massive hemorrhage during childhood or remain
silent well into adult life. In general, there is
approximately a 4% chance per year that an AVM
will cause bleeding within the brain. This risk may be
higher during the first year following an initial bleed.
The risk of death for a patient with an AVM is
approximately 1% per year. These percentages may
seem relatively small, but they become cumulative
with time and when considering the outlook for any
patient over the long term, the risk of hemorrhage or
death becomes substantial. It is also highly likely that
there are subgroups of patients that carry a higher
risk of bleeding. We believe that narrowing of
draining veins or small aneurysms within the mass
are two findings that imply higher risk.
Children are diagnosed with an AVM most
commonly after an episode of bleeding, whereas
AVMs in adults are usually diagnosed after a seizure
 ARTERIOVENOUS MALFORMATIONS, SURGICAL TREATMENT OF
Treatment consists of direct interruption of the
abnormal arteriovenous connection through surgical
exposure or endovascular techniques.
—Cameron G. McDougall
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Endovascular Therapy;
Subarachnoid Hemorrhage (SAH)
Further Reading
American Association of Neurological Surgeons Publications
Committee (1993). Dural Arteriovenous Malformations. Amer-
ican Association of Neurological Surgeons, Park Ridge, IL.
Aminoff, M. J. (1973). Vascular anomalies in the intracranial dura
mater. Brain 96, 601–612.
Awad, I. A., Little, J. R., Akrawi, W. P., et al. (1990). Intracranial
dural arteriovenous malformations: Factors predisposing to an
aggressive neurological course. J. Neurosurg. 72, 839–850.
Kerber, C. W., and Newton, T. H. (1973). The macro- and
microvasculature of the dura mater. Neuroradiology 6, 175–
179.
Lasjaunias, P., and Berenstein, A. (1992). Surgical Neuroangio-
graphy, IV. Endovascular Treatment of Cerebral Lesions.
Springer-Verlag, Berlin.
Lasjaunias, P., Chiu, M., ter Brugge, K., et al. (1986). Neurological
manifestations of intracranial dural arteriovenous malforma-
tions. J. Neurosurg. 64, 724–730.
Lawton, M. T., Jacobowitz, R., and Spetzler, R. F. (1997).
Redefined role of angiogenesis in the pathogenesis of dural
arteriovenous malformations. J. Neurosurg. 87, 267–274.
Malek, A. M., Halbach, V. V., Dowd, C. F., et al. (1998). Diagnosis
and treatment of dural arteriovenous fistulas. Neuroimaging
Clin. North Am. 8, 445–468.
Sundt, T. M., Jr., and Piepgras, D. G. (1983). The surgical
approach to arteriovenous malformations of the lateral and
sigmoid dural sinuses. J. Neurosurg. 59, 32–39.
van Dijk, J. M., ter Brugge, K. G., Willinsky, R. A., et al.
(2002). Clinical course of cranial dural arteriovenous fistulas
with long-term persistent cortical venous reflux. Stroke 33,
1233–1236.
Arteriovenous Malformations
(AVM), Surgical Treatment of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AN ARTERIOVENOUS malformation (AVM) is an
abnormal entanglement of blood vessels in the
central nervous system that has been present since
birth. Ordinarily, arteries and veins are connected by
a bed of capillaries, which is the site where oxygen
277
and nutrients are extracted from the blood by brain
tissue to meet its metabolic needs. However, AVMs
represent a direct connection between arteries and
veins of the brain or spinal cord without an
intervening capillary bed. This direct shunt between
the arterial and venous circulations provides a
relatively low-resistance pathway for blood to pass
through and creates a high-pressure, high flow state
within the AVM. The vascular tissue is also abnormal
and not designed to carry this high flow volume.
AVMs are therefore predisposed to rupture, the
consequences of which can be devastating.
Arteriovenous malformations of the brain and
spinal cord develop early on during the fetal period.
A network of blood vessels begins to form during the
third week of development. During the fourth week,
this primitive vascular meshwork grows and differ-
entiates into vessels that will form arteries, veins, and
capillaries. Although the reasons remain unclear,
rarely there is a failure in complete differentiation
and no capillaries form in a particular region of the
brain or spinal cord. Furthermore, the different
layers that are usually present in small arteries fail
to develop, leaving these vessels more susceptible to
rupture. The result is the persistence of direct
connections between abnormal arteries and veins
and the development of an arteriovenous malforma-
tion. In the adult phase of this condition, one sees a
‘‘Medusa’s head’’ of tangled, enlarged vessels creating
a ‘‘tumor’’ of blood vessels (Figs. 1 and 2).
The natural course of AVMs is variable, and
although somewhat dependent on size and location,
it is difficult to predict exactly how any particular
AVM will develop and behave. An AVM can cause
massive hemorrhage during childhood or remain
silent well into adult life. In general, there is
approximately a 4% chance per year that an AVM
will cause bleeding within the brain. This risk may be
higher during the first year following an initial bleed.
The risk of death for a patient with an AVM is
approximately 1% per year. These percentages may
seem relatively small, but they become cumulative
with time and when considering the outlook for any
patient over the long term, the risk of hemorrhage or
death becomes substantial. It is also highly likely that
there are subgroups of patients that carry a higher
risk of bleeding. We believe that narrowing of
draining veins or small aneurysms within the mass
are two findings that imply higher risk.
Children are diagnosed with an AVM most
commonly after an episode of bleeding, whereas
AVMs in adults are usually diagnosed after a seizure
278 ARTERIOVENOUS MALFORMATIONS, SURGICAL TREATMENT OF

lihood of cure. Other features critically important in

the decision analysis include age of patient, surface
representation, proximity to critical brain functions,
characteristics of the mass (angiomatous or wispy
margins), and patient expectations.

EMBOLIZATION
Embolization therapy for AVMs of the brain and
spine has recently emerged as a treatment adjunct to
surgical excision or radiation therapy that occasion-
ally offers complete cure. Rarely, embolization alone
can be curative. Embolization involves plugging
some part or all of the AVM with a glue material
or small platinum coils that block the flow of blood
through the AVM. Sometimes, an AVM can be
completely occluded by embolization. More fre-
quently, however, part of the AVM remains patent
after the procedure, and embolization is undertaken
Figure 1 to reduce the size of the AVM, facilitating definitive
Angiogram of an arteriovenous malformation of the brain. treatment with surgery or radiation. Additional
embolization strategies include the elimination of
associated aneurysms or blocking of deep feeding
or hemorrhage. Occasionally, an AVM is detected in vessels.
a patient with a progressive neurological deficit, such
as increasing numbness or tingling, or partial
paralysis. In these cases, symptoms are possibly
attributable to the steal effect in brain lesions or
venous hypotension in spinal malformations. In the
steal effect, large amounts of blood are diverted
through the low-resistance pathway of the AVM.
This diversion of flow ‘‘steals’’ blood from other
regions of the brain. When blood flow becomes too
low in certain parts of the brain, a patient can begin
to experience symptoms similar to those seen in
stroke or multiple sclerosis. A patient with an AVM
might also begin to experience these neurological
symptoms if the mass of the AVM is large enough to
push on adjacent structures in the brain or spine,
affecting their normal function.
Regardless of how an AVM presents itself, the
question upon discovery is whether to treat it.
Naturally, intervention in any form must carry a
risk far lower than that presented by the untreated
malformation. Today, AVMs are treated by surgical
excision, radiation therapy, or embolization therapy.
Used alone or in conjunction, each modality is
considered based on the risk of the procedure relative
to the risk posed by the untreated AVM. The decision
regarding which therapy is best is a complex one that Figure 2
takes into account location and size of the AVM, Magnetic resonance imaging of the brain showing an
risks associated with each procedure, and the like- arteriovenous malformation.
 ARTERIOVENOUS MALFORMATIONS, SURGICAL TREATMENT OF
Today, most embolization procedures for the
treatment of arteriovenous malformations are per-
formed using a flow-directed microcatheter. This
device is essentially a very small-diameter polymer
tubing that becomes increasingly flexible toward the
tip. The microcatheter is inserted most commonly
through the femoral artery in the thigh, but it can
also be inserted directly into the carotid artery of the
neck. Once inserted, the flow of blood aids in
directing the microcatheter through a succession of
arteries until it reaches vessels that feed the AVM.
The location of the microcatheter is carefully
monitored using intermittent, rapidly acquired x-
ray images. When the microcatheter has reached the
proper position, a polymerizing glue such as n-butyl-
cyanoacrylate is ejected from the tip. This liquid
adhesive quickly solidifies, forming a cast within the
blood vessels of the AVM and stopping the flow of
blood. If all vessels of the AVM can be plugged with
this glue, then no further treatment is needed and
periodic angiographic imaging is performed to
ensure that all vessels remain occluded. More often,
however, the goal of embolization therapy is to
reduce the flow of blood through the AVM to
facilitate either radiosurgery or surgical removal. In
this case, flow reduction using embolization is often
undertaken in multiple sessions over several weeks.
This staged approach is favored because it does not
produce any dramatic changes in blood flow, and it
allows the brain or spine to gradually respond and
adapt to the changes produced by embolization.
Although dependent on the size and location of the
AVM, the risk of serious complications is generally
approximately 5%. This risk includes the possibili-
ties that a microcatheter tip will rupture, spilling glue
into and blocking normal vessels, or that a vessel will
be perforated during the procedure, causing bleed-
ing. Other less life-threatening but serious complica-
tions include swelling in the brain or spine and
seizures.
RADIOSURGERY
Focused radiation was first applied to the treatment
of AVMs of the brain in 1970 and has since become
an important tool in the management of some
cerebral AVMs. This technique, known as radio-
therapy or radiosurgery, utilizes a specialized source
(a gamma knife, proton beam, or linear accelerator)
to carefully aim radiation at the mass of blood vessels
comprising an AVM. Larger AVMs require a higher
dose of radiation for complete obliteration. Unfortu-
279
nately, higher doses of radiation can cause serious
damage to normal brain surrounding the AVM. This
caveat has limited the application of radiosurgery to
AVMs measuring 3 cm or less. In these smaller
AVMs, radiotherapy has been very successful, with
complete cure rates of 80% or even higher for AVMs
smaller than 1 cm.
Just prior to radiotherapy, the patient’s head is
placed in a rigid frame and imaged with magnetic
resonance imaging (MRI), angiography, or both. The
location of the AVM is accurately mapped relative to
the frame, and computer programs are used to
calculate and plan the exact dose of radiation that
will be delivered to the AVM. The patient is then
placed on the treatment bed, and the radiation source
unit (gamma knife, proton beam, or linear accel-
erator) is positioned around the head. A gamma
knife employs a circular array of more than 200
point sources to deliver a single dose of radiation. A
proton beam emits protons over an arc. These
particles lose their energy at a rate that increases
with distance from the source, and they shed most of
their energy just before they stop. In both cases, a
focused dosage of radiation is applied directly to the
AVM, and the patient does not experience any
discomfort during the procedure.
Radiation delivered to blood vessels causes the
layer of cells on the inner surface of the vessel to
proliferate. These cells lose their ability to control
growth and cell division, piling up onto one another
until eventually the entire space within the vessel is
blocked by cells. This will stop the flow of blood
through an AVM, rendering the malformation
harmless. Unfortunately, it may take 1–3 years for
the vessels of an AVM to become completely
occluded. During this time, the risk remains that an
AVM will hemorrhage. Furthermore, a small percen-
tage of AVMs seem to be resistant to radiotherapy
and will never be completely obliterated using this
technique.
There are can be other complications with radio-
therapy. Radiation can damage normal tissue sur-
rounding the AVM, causing neurological symptoms
during a variable amount of time (1–10 years) after
the procedure, although this is rare. Occasionally,
radiosurgery can cause the formation of a cyst within
the brain. Cysts may or may not cause symptoms
depending on their location and size. Fortunately, the
risk of these complications seems to be only
approximately 5%.
Radiosurgery has emerged as an effective treat-
ment option for AVMs less than 3 cm in size. These
280 ARTERIOVENOUS MALFORMATIONS, SURGICAL TREATMENT OF
smaller AVMs are also the malformations treated
most readily by surgical removal. Because radio-
surgery leaves the AVM at risk for hemorrhage for
extended periods of time, surgical excision is often
favored whenever possible. However, some AVMs
are deemed inoperable because of their location deep
within the brain or because of their proximity to
important structures. It is within this subset of
malformations that radiosurgery has been most
extensively applied and has made the greatest
difference in treatment.
MICROSURGERY
Surgical excision has been and continues to be the
cornerstone of definitive treatment for AVMs of the
brain and spine. AVMs are significantly easier to
remove when they are smaller and not situated near
any vital structures. However, successful operations
have been completed on AVMs satisfying neither of
these criteria.
Imaging with MRI and angiography are used to
evaluate whether an AVM is suitable for surgical
resection. Using functional MRI studies, it is possible
to ‘‘see’’ exactly where specific functions of the brain
are located relative to the AVM. We are seeing a
number of patients whose functional brain tissue has
been shifted due to the presence of the AVM, thus
opening up treatment options that historically would
have been considered too dangerous. If it is believed
that the AVM can be reached without significant
injury to the surrounding brain or spinal cord, and
that the malformation can be removed without high
risk of bleeding or other complications, then sur-
gical excision is planned. The neurosurgeon care-
fully studies the location of the AVM and decides on
an approach that will offer the least risk to the
patient.
For cerebral AVMs, a piece of skull is first removed
to expose the underlying brain and AVM. Generally,
the mass of vessels of an AVM form the shape of a
wedge, with the wider base near the surface and the
tip delving deep within the brain. Even AVMs located
predominately on the surface of the brain may
possess hidden vessels or vessels situated deep within
the brain, and since all parts of the AVM must be
removed for the procedure to be successful, the
surgeon must first define the extent of the malforma-
tion. A surgical microscope is used to identify veins
that drain the AVM. Normally, veins appear bluish
as they transport blood from which the oxygen
has been removed in the capillary bed. However,
because there are no capillaries between the arteries
and veins of an AVM, veins draining an AVM are
very noticeable, large red vessels carrying blood
rich in oxygen. These veins can be followed back-
wards to identify the entire tangled mass of the
AVM. The procedure is similar for spinal AVMs. A
section of the bony spine is often removed to
expose the malformation, and the surgeon can then
carefully define the extent of the AVM using draining
veins.
The task is then to separate the cluster of vessels
comprising the AVM from the surrounding tissue and
begin removal. Here, the surgeon must proceed very
gently because rough handling of the brain can cause
unnecessary bleeding or postoperative swelling.
Often, the AVM is resected proceeding from the
surface of the brain inwards. Vessels are ligated, and
bleeding is controlled with coagulation, where
specialized forceps are used to apply pressure to
blood vessels until a blood clot forms. Sometimes,
arteries carrying blood into the AVM can branch and
provide blood to areas distant from the AVM. To
avoid cutting the blood supply to essential areas, the
surgeon painstakingly confirms the course of any
arteries feeding the AVM before removal and
coagulation of diseased branches. Vessels deep within
the brain may also cause difficulties. Bleeding from
these deep arteries may be difficult to control, and
the surgeon must exercise a great deal of patience
and care during coagulation.
Complications related to surgical resection of an
AVM are generally related to postoperative swelling,
hemorrhage, or neurological deficit. Although the
reasons for swelling in the brain or spine after
surgical removal of an AVM remain unclear,
mechanical perturbation of tissue during surgery or
a change in vessel permeability are possible explana-
tions. Fortunately, major swelling occurs in only a
small fraction of patients. Bleeding in the brain after
surgery may be attributed to vessels that were
incompletely coagulated or to vessels rupturing in
part of the AVM that was left behind. This
complication can be extremely grave, and repeat
surgery is often required. frequently, a patient will
awaken with some neurological problem after
surgery for a high-risk AVM. Fortunately, these
deficits usually improve steadily over the ensuing
days, weeks, and months. Usually, the postoperative
deficits are similar to those expected if the AVM
ruptured spontaneously.
—Bernard R. Bendok, Todd Mulderink, Christopher
C. Getch, Timothy Malisch, and H. Hunt Batjer

See also–Angiography; Arteriovenous Fistulas;
Embolization, Therapeutic, Surgical;
Endovascular Therapy; Radiosurgery
Further Reading
Anonymous (1999). Current concepts: Arteriovenous malforma-
tions of the brain in adults. N. Engl. J. Med. 340, 1812–1818.
Batjer, H. H. (Ed.) (1996). Cerebrovascular Disease. Lippincott-
Raven, New York.
Batjer, H. H., and Samson, D. S. (1989). Surgery of arteriovenous
malformations. In Operative Surgery (H. Dudley, D. C. Carter,
and R. C. G. Russel, Eds.), 4th ed., pp. 219–230. Butterworth,
London.
Bendok, B. B., Getch, C., Malisch, T., et al. (2001). Cerebral
vascular malformations. In Neurological Therapeutics:
Principles and Practice. (J. Biller, Ed.) Dunitz Martin Ltd.,
London.
Bendok, B. R., Getch, C. C., Ghandi, R., et al. (2001). Associated
aneurysms. In Intracranial Arteriovenous Malformations (P.
Steig, H. Batjer, and D. Samson, Eds.). Quality Medical, St.
Louis, MO.
Drake, C. G. (1979). Cerebral arteriovenous malformations:
Considerations for and experience with surgical treatment in
166 cases. Clin. Neurosurg. 26, 145–208.
Gandhi, R. T., Bendok, B. R., Schweitzer, J., et al. (2000).
Displacement of hand representation to the contralateral
hemisphere may predict neurologic recovery after AVM
resection from sensorimotor cortex. J. Stroke Cerebrovasc.
Dis. 9, 246–249.
Lewis, A. I., Sathi, S., and Tew, J. M. (1999). Intracranial vascular
malformations. In Principles of Neurosurgery (R. G. Grossman
and C. M. Loftus, Eds.), 2nd ed., pp. 339–351. Lippincott
Williams & Wilkins, Philadelphia.
Ondra, S. L., Troupp, H., George, E. D., et al. (1990). The natural
history of symptomatic arteriovenous malformations of the
brain: A 24-year follow-up assessment. J. Neurosurg. 73, 387–
391.
Purdy, P. D., Batjer, H. H., Kopitnik, T. A., et al. (1994). The team
approach to combined embolization and resection of arterio-
venous malformation. In New Trends in Management of
Cerebrovascular Malformations (A. Pasqualin and R. da Pian,
Eds.), pp. 503–506. Springer-Verlag, New York.
Stieg, P., Batjer, H. H., and Samson, D. S. (2001). Intracranial
Vascular Malformations. Quality Medical, St. Louis, MO.
Arthritis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ARTHRITIS and joint disorders are the most frequently
occurring chronic conditions affecting the U.S.
population. Moreover, the impact of rheumatologi-
cal disorders on both a personal and a social level is
substantial. Approximately 1 of every 5–10 visits to
a primary care provider is for a musculoskeletal
ARTHRITIS 281
disorder. Interestingly, 66% of these patients are
younger than 65 years old. The most common
problems are osteoarthritis, back pain, gout, fibro-
myalgia, and tendonitis/bursitis. Back pain is the
second leading cause of acute disability and is the
number one cause of chronic disability in the general
population. The cost of musculoskeletal disorders in
health care expenditure and lost wages is $149
billion a year. This calls attention to the need for
early diagnosis and appropriate therapy.
The pain associated with arthritis is a uniquely
subjective experience, and there is no clear definition
of what constitutes ‘‘normal’’ for a patient. Current
thinking is that joint and muscle pain is secondary to
the activation of small primary afferent nerve fibers
and is classified as having similarities to those
systems activated in other postinjury states. The
joints are highly innervated structures from which
afferent fibers transmit information about pain and
joint position. The main populations of afferent
fibers are Ad and C, and their receptors respond to
noxious, mechanical, and chemical stimuli. Although
the synovium has been considered largely insensitive,
small-diameter nerve fibers have been identified in
human synovium in pathological studies. Many of
these afferents are poorly activated by even high-
intensity mechanical stimuli but are very sensitive to
local chemical stimuli. For instance, sensitization by
cytokines, potassium, hydrogen ions, or kinins—
products frequently found after joint injury—can
lead to high activity levels in nerve fibers and
subsequent induction of pain. This property has
earned these joint afferents the name silent nocicep-
tors. Skeletal muscle and tendons have similar
innervation and transmission of pain. Thus, the
common organization of the pain associated with
arthritis and musculoskeletal disorders is defined by
two properties: the input, which is mediated largely
by small primary afferents that in the face of injury
and inflammation show a persistent discharge; and
the subsequent development of central sensitization
resulting from this constant activity. Both inflamma-
tory and noninflammatory causes of arthritis are
thought to cause pain by stimulation of these silent
nociceptors.
Treatment of pain in arthritis requires distinguish-
ing inflammatory from noninflammatory arthritic
conditions because the approaches to therapy differ
markedly. For inflammatory disorders, the primary
focus is on reducing inflammation that pari passu
results in amelioration of pain symptoms; for
noninflammatory conditions, therapy is directed at

See also–Angiography; Arteriovenous Fistulas;
Embolization, Therapeutic, Surgical;
Endovascular Therapy; Radiosurgery
Further Reading
Anonymous (1999). Current concepts: Arteriovenous malforma-
tions of the brain in adults. N. Engl. J. Med. 340, 1812–1818.
Batjer, H. H. (Ed.) (1996). Cerebrovascular Disease. Lippincott-
Raven, New York.
Batjer, H. H., and Samson, D. S. (1989). Surgery of arteriovenous
malformations. In Operative Surgery (H. Dudley, D. C. Carter,
and R. C. G. Russel, Eds.), 4th ed., pp. 219–230. Butterworth,
London.
Bendok, B. B., Getch, C., Malisch, T., et al. (2001). Cerebral
vascular malformations. In Neurological Therapeutics:
Principles and Practice. (J. Biller, Ed.) Dunitz Martin Ltd.,
London.
Bendok, B. R., Getch, C. C., Ghandi, R., et al. (2001). Associated
aneurysms. In Intracranial Arteriovenous Malformations (P.
Steig, H. Batjer, and D. Samson, Eds.). Quality Medical, St.
Louis, MO.
Drake, C. G. (1979). Cerebral arteriovenous malformations:
Considerations for and experience with surgical treatment in
166 cases. Clin. Neurosurg. 26, 145–208.
Gandhi, R. T., Bendok, B. R., Schweitzer, J., et al. (2000).
Displacement of hand representation to the contralateral
hemisphere may predict neurologic recovery after AVM
resection from sensorimotor cortex. J. Stroke Cerebrovasc.
Dis. 9, 246–249.
Lewis, A. I., Sathi, S., and Tew, J. M. (1999). Intracranial vascular
malformations. In Principles of Neurosurgery (R. G. Grossman
and C. M. Loftus, Eds.), 2nd ed., pp. 339–351. Lippincott
Williams & Wilkins, Philadelphia.
Ondra, S. L., Troupp, H., George, E. D., et al. (1990). The natural
history of symptomatic arteriovenous malformations of the
brain: A 24-year follow-up assessment. J. Neurosurg. 73, 387–
391.
Purdy, P. D., Batjer, H. H., Kopitnik, T. A., et al. (1994). The team
approach to combined embolization and resection of arterio-
venous malformation. In New Trends in Management of
Cerebrovascular Malformations (A. Pasqualin and R. da Pian,
Eds.), pp. 503–506. Springer-Verlag, New York.
Stieg, P., Batjer, H. H., and Samson, D. S. (2001). Intracranial
Vascular Malformations. Quality Medical, St. Louis, MO.
Arthritis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ARTHRITIS and joint disorders are the most frequently
occurring chronic conditions affecting the U.S.
population. Moreover, the impact of rheumatologi-
cal disorders on both a personal and a social level is
substantial. Approximately 1 of every 5–10 visits to
a primary care provider is for a musculoskeletal
ARTHRITIS 281
disorder. Interestingly, 66% of these patients are
younger than 65 years old. The most common
problems are osteoarthritis, back pain, gout, fibro-
myalgia, and tendonitis/bursitis. Back pain is the
second leading cause of acute disability and is the
number one cause of chronic disability in the general
population. The cost of musculoskeletal disorders in
health care expenditure and lost wages is $149
billion a year. This calls attention to the need for
early diagnosis and appropriate therapy.
The pain associated with arthritis is a uniquely
subjective experience, and there is no clear definition
of what constitutes ‘‘normal’’ for a patient. Current
thinking is that joint and muscle pain is secondary to
the activation of small primary afferent nerve fibers
and is classified as having similarities to those
systems activated in other postinjury states. The
joints are highly innervated structures from which
afferent fibers transmit information about pain and
joint position. The main populations of afferent
fibers are Ad and C, and their receptors respond to
noxious, mechanical, and chemical stimuli. Although
the synovium has been considered largely insensitive,
small-diameter nerve fibers have been identified in
human synovium in pathological studies. Many of
these afferents are poorly activated by even high-
intensity mechanical stimuli but are very sensitive to
local chemical stimuli. For instance, sensitization by
cytokines, potassium, hydrogen ions, or kinins—
products frequently found after joint injury—can
lead to high activity levels in nerve fibers and
subsequent induction of pain. This property has
earned these joint afferents the name silent nocicep-
tors. Skeletal muscle and tendons have similar
innervation and transmission of pain. Thus, the
common organization of the pain associated with
arthritis and musculoskeletal disorders is defined by
two properties: the input, which is mediated largely
by small primary afferents that in the face of injury
and inflammation show a persistent discharge; and
the subsequent development of central sensitization
resulting from this constant activity. Both inflamma-
tory and noninflammatory causes of arthritis are
thought to cause pain by stimulation of these silent
nociceptors.
Treatment of pain in arthritis requires distinguish-
ing inflammatory from noninflammatory arthritic
conditions because the approaches to therapy differ
markedly. For inflammatory disorders, the primary
focus is on reducing inflammation that pari passu
results in amelioration of pain symptoms; for
noninflammatory conditions, therapy is directed at
282 ARTHRITIS
controlling the symptoms (i.e., the perceived pain).
Thus, in the former, the emphasis is on antiinflam-
matory drugs, such as glucocorticoids and more
specific inhibitors of prostaglandin synthesis [non-
steroidal antiinflammatory drugs (NSAIDs)]. In
noninflammatory conditions, therapy often begins
with simple analgesic agents (acetaminophen) and
may later include NSAIDs at analgesic doses or even
centrally acting agents such as opioids.
For the clinician, the approach to distinguishing
inflammatory from noninflammatory arthritic states
requires making the proper diagnosis of the under-
lying condition, relying more on the presentation of
the disorder (history and physical examination) than
any specific laboratory tests. Arthritis encompasses a
wide spectrum of diseases, and often the distribution
of symptoms (monoarticular vs polyarticular and
symmetrical vs nonsymmetrical) helps provide the
physician with a methodical approach to the
accurate diagnosis. By approaching musculoskeletal
pain in this manner, one can begin formulating the
differential diagnosis. This naturally leads to the next
step—determining if the etiology of the joint
symptoms is inflammatory or noninflammatory in
nature.
Of the noninflammatory arthropathies, osteoar-
thritis is the most common. This condition usually
arises without a known cause (primary) but can also
result from joint injury, overuse, or another muscu-
loskeletal disorder (secondary). In osteoarthritis, the
disease process results in cartilage destruction; pain
and stiffness are typically localized to specific joint
structures and can involve the hips, knees, and first
carpometacarpal and interphalangeal joints. Inter-
estingly, there is no known association between the
radiographic appearance of the joint and/or the
extent of cartilage degradation and the symptoms
of patients. Synovial effusions may occur, especially
in the knees, with minimal signs of inflammation.
There is no known treatment for the underlying
disease process; therapy is aimed at controlling the
symptoms, with the mainstay of therapy being
exercise and simple analgesics (e.g., acetaminophen)
initially and then NSAIDS at analgesic doses if
needed. Topical therapies (NSAIDs and capsaicin)
have been employed as well as intraarticular injec-
tion of steroids and hyaluronan preparations. The
use of opioids for the pain of osteoarthritis is
controversial but probably warranted in those
patients who are not candidates for joint replacement
surgery, which is one of the most successful
interventions for this condition.
Gout, the most common type of inflammatory
monoarthritis, results from an inflammatory re-
sponse to the deposition of monosodium urate
crystals and typically involves the first metatarso-
phalangeal joint, ankle, midfoot, or the knee. Later
attacks may be monoarticular or polyarticular and
can even be accompanied by systemic signs such as
fever. The approach to therapy focuses on reduction
of inflammation utilizing several different drugs
(NSAIDs, glucocorticoids, ACTH, and colchicine),
depending on the extent and duration of disease,
comorbidities, and other factors. This treatment
approach also applies to calcium pyrophosphate
disease or pseudogout, which has a similar clinical
presentation.
Septic arthritis presents most commonly as mono-
arthritis, but approximately 20% of adults will have
two or more large joints involved. The pain of septic
arthritis is said to be excruciating, with the slightest
movement causing enormous discomfort. Gonococ-
cal and meningococcal arthritis can frequently
present with a migratory polyarthritis and/or teno-
synovitis. Analysis of the synovial fluid is diagnostic,
but in the case of meningococcal and gonococcal
disease it is often not revealing, so cultures of the
oropharynx and genital areas should also be
obtained. Treatment involves hospitalization and
intravenous antibiotics.
Rheumatoid arthritis (RA) is the most common
form of chronic inflammatory arthritis and is a
symmetrical polyarthritis involving both small and
large joints of the body. In the early stages, pain
reflects the nociceptive effects of local inflammation
caused by release of various cytokines, such as tumor
necrosis factor-a (TNF-a) and interleukins, within
the joint space. Cytokine-driven expression of
metalloproteinases is believed to contribute to the
rapid destruction of affected joints if left untreated.
Therefore, therapy is now initiated early in the
course of disease to prevent the formation of
destructive pannus, which can invade and erode
cartilage, bone, and adjacent structures. Highly
targeted therapies against TNF-a, utilizing soluble
receptor complexes and monoclonal antibodies to
TNF, have been shown to not only reduce the signs
and symptoms (joint swelling and pain) of RA but
also markedly slow the disease process. Thus, in
many patients, pain will respond to disease mod-
ification rather than requiring specific therapy; in
others, NSAIDs and simple analgesics provide addi-
tional control of symptoms that may arise from
previous joint damage or other causes.

Polyarthritis is also a common presentation for
systemic lupus erythematosus (SLE), an autoimmune
inflammatory disorder of unknown etiology. Like
RA, the joint pain accompanying SLE arises from an
inflammatory process and has a very similar joint
distribution involving the hands and feet. However,
in SLE there is often more extensive systemic
involvement than typically seen in RA, and treatment
considerations thus depend on the extent of disease.
In those individuals who have joint pain without
evidence of internal organ involvement, treatment
can be more limited and includes antiinflammatory
drugs such as NSAIDs and hyroxychloroquine, both
of which may be effective in providing pain relief. In
people with more extensive disease, glucocorticoids
and cytotoxic drugs (e.g., cyclophosphamide) may
need to be given to control the disease process.
Ankylosing spondylitis (AS), unlike most other
chronic musculoskeletal disorders, is an inflamma-
tory arthropathy affecting primarily men, often
involves only a few joints, may be asymmetric in
presentation, and most commonly involves the axial
joints, especially the hips, shoulders, and low back.
Treatment focuses on control of inflammation,
although NSAIDs may play a dual role as effective
antiinflammatory and analgesic agents. Other drugs
(sulfasalazine and methotrexate) have been utilized
to control inflammation with some success. Diffuse
nonarticular musculoskeletal pain in patients lacking
objective signs of synovitis, joint enlargement, or
other findings suggestive of structural or inflamma-
tory disease is a common presentation for the general
practitioner and the rheumatologist. Many of these
individuals may have fibromyalgia, a noninflamma-
tory condition seen more frequently in women than
in men. Patients with fibromyalgia complain of pain
localized to specific sites known as trigger points, and
pain may be exacerbated by factors such as poor
sleep, inactivity, and emotional stress. The etiology
of fibromyalgia remains unknown, but evidence
suggests that the pain of fibromyalgia is related to
altered central nervous system processing of noci-
ceptive stimuli (e.g., the pain threshold of fibromyal-
gia patients is two or three times lower than that of
healthy persons). Because there are no diagnostic
tests for this condition, fibromyalgia is ultimately a
diagnosis of exclusion. Treatment of pain with
standard medications such as simple analgesics and
NSAIDs has been shown to be ineffective. Because
there is no evidence for an underlying inflammatory
etiology, more potent antiinflammatory drugs have
not resulted in improvement and should not be used.
ASCENDING RETICULAR ACTIVATING SYSTEM 283
The most successful therapy involves a combination
of exercise and correction of the sleep disorder with
low-dose antidepressants such as amitriptyline.
Patients with rheumatic disease experience pain
that can be intense, persistent, and disabling. This
pain is frequently multifactorial in origin and has
both central and peripheral components. Because of
the array of conditions that can cause musculoske-
letal pain, management of the patient must begin
with a complete clinical assessment that identifies
possible etiologies and measures objective findings
relevant to the subjective complaints. A key element
in the approach to treatment is differentiating
inflammatory from noninflammatory disease. By
applying a comprehensive therapy plan, including
physical therapy, patient education, and appropri-
ately chosen pharmacological therapy, patients with
this prevalent group of painful diseases can achieve
significant benefits.
—Anu Bongu and Thomas J. Schnitzer
See also–Analgesics, Non-Opioid and Other;
Immune System, Overview; Pain, Basic
Neurobiology of; Pain, Overview; Systemic
Lupus Erythematosus (SLE)
Further Reading
Butler, M. J. (1997). Arthritis and musculoskeletal pain. Anesthe-
siol. Clin. North Am. 15, 285–296.
Klippel, J. H. (1997). In Primer on the Rheumatic Diseases (J. H.
Klippel, C. M. Weyand, and R. L. Wortmann, Eds.), 11th ed.
Arthritis Foundation, Atlanta.
Pillemer, S. R., Bradley, L. A., Crofford, L. J., et al. (1997). The
neuroscience and endocrinology of fibromyalgia. Arthritis
Rheum. 40, 1928–1939.
Ascending Reticular
Activating System (ARAS)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
A NODAL POINT in the understanding of conscious-
ness, especially alertness, occurred when Moruzzi
and Magoun produced electroencephalograph arou-
sal by stimulation of the brainstem reticular forma-
tion rostral to the mid-pons. This system, including
its rostral projection, was termed the ascending
reticular activating system (ARAS) (Fig. 1). The
ARAS ascends the brainstem tegmentum, from the

Polyarthritis is also a common presentation for
systemic lupus erythematosus (SLE), an autoimmune
inflammatory disorder of unknown etiology. Like
RA, the joint pain accompanying SLE arises from an
inflammatory process and has a very similar joint
distribution involving the hands and feet. However,
in SLE there is often more extensive systemic
involvement than typically seen in RA, and treatment
considerations thus depend on the extent of disease.
In those individuals who have joint pain without
evidence of internal organ involvement, treatment
can be more limited and includes antiinflammatory
drugs such as NSAIDs and hyroxychloroquine, both
of which may be effective in providing pain relief. In
people with more extensive disease, glucocorticoids
and cytotoxic drugs (e.g., cyclophosphamide) may
need to be given to control the disease process.
Ankylosing spondylitis (AS), unlike most other
chronic musculoskeletal disorders, is an inflamma-
tory arthropathy affecting primarily men, often
involves only a few joints, may be asymmetric in
presentation, and most commonly involves the axial
joints, especially the hips, shoulders, and low back.
Treatment focuses on control of inflammation,
although NSAIDs may play a dual role as effective
antiinflammatory and analgesic agents. Other drugs
(sulfasalazine and methotrexate) have been utilized
to control inflammation with some success. Diffuse
nonarticular musculoskeletal pain in patients lacking
objective signs of synovitis, joint enlargement, or
other findings suggestive of structural or inflamma-
tory disease is a common presentation for the general
practitioner and the rheumatologist. Many of these
individuals may have fibromyalgia, a noninflamma-
tory condition seen more frequently in women than
in men. Patients with fibromyalgia complain of pain
localized to specific sites known as trigger points, and
pain may be exacerbated by factors such as poor
sleep, inactivity, and emotional stress. The etiology
of fibromyalgia remains unknown, but evidence
suggests that the pain of fibromyalgia is related to
altered central nervous system processing of noci-
ceptive stimuli (e.g., the pain threshold of fibromyal-
gia patients is two or three times lower than that of
healthy persons). Because there are no diagnostic
tests for this condition, fibromyalgia is ultimately a
diagnosis of exclusion. Treatment of pain with
standard medications such as simple analgesics and
NSAIDs has been shown to be ineffective. Because
there is no evidence for an underlying inflammatory
etiology, more potent antiinflammatory drugs have
not resulted in improvement and should not be used.
ASCENDING RETICULAR ACTIVATING SYSTEM 283
The most successful therapy involves a combination
of exercise and correction of the sleep disorder with
low-dose antidepressants such as amitriptyline.
Patients with rheumatic disease experience pain
that can be intense, persistent, and disabling. This
pain is frequently multifactorial in origin and has
both central and peripheral components. Because of
the array of conditions that can cause musculoske-
letal pain, management of the patient must begin
with a complete clinical assessment that identifies
possible etiologies and measures objective findings
relevant to the subjective complaints. A key element
in the approach to treatment is differentiating
inflammatory from noninflammatory disease. By
applying a comprehensive therapy plan, including
physical therapy, patient education, and appropri-
ately chosen pharmacological therapy, patients with
this prevalent group of painful diseases can achieve
significant benefits.
—Anu Bongu and Thomas J. Schnitzer
See also–Analgesics, Non-Opioid and Other;
Immune System, Overview; Pain, Basic
Neurobiology of; Pain, Overview; Systemic
Lupus Erythematosus (SLE)
Further Reading
Butler, M. J. (1997). Arthritis and musculoskeletal pain. Anesthe-
siol. Clin. North Am. 15, 285–296.
Klippel, J. H. (1997). In Primer on the Rheumatic Diseases (J. H.
Klippel, C. M. Weyand, and R. L. Wortmann, Eds.), 11th ed.
Arthritis Foundation, Atlanta.
Pillemer, S. R., Bradley, L. A., Crofford, L. J., et al. (1997). The
neuroscience and endocrinology of fibromyalgia. Arthritis
Rheum. 40, 1928–1939.
Ascending Reticular
Activating System (ARAS)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
A NODAL POINT in the understanding of conscious-
ness, especially alertness, occurred when Moruzzi
and Magoun produced electroencephalograph arou-
sal by stimulation of the brainstem reticular forma-
tion rostral to the mid-pons. This system, including
its rostral projection, was termed the ascending
reticular activating system (ARAS) (Fig. 1). The
ARAS ascends the brainstem tegmentum, from the
284 ASPERGER’S SYNDROME
Figure 1
The composite picture of the brain shows several sites at which
functions are localized (grossly oversimplified) as well as those
functions (self-awareness, cognition, and perceptual–motor
integration) that are likely widespread, involving numerous
interconnected cortical and subcortical structures.
mid-pons extending rostrally, through the midline
and intralaminar (formerly called ‘‘nonspecific’’)
nuclei of the thalamus, to the cerebral cortex. The
ARAS was thought to be composed of an undiffer-
entiated collection of neurons in these regions, with
extensive internal connections and projections both
rostrally and caudally. Further studies on the
morphology, connections, and neurochemistry of
separate cell groups in these regions revealed that
they have distinct properties and are components of
the arousal ‘‘system.’’
Discrete regions of the brainstem reticular forma-
tion project to several thalamic nuclei besides the
midline and intralaminar group, and there are
connections to motor and other centers. The
thalamic reticular nucleus performs a key role in
gating reticular activity and allowing feedback to the
brainstem centers that play a role in arousal and
alertness. The reticular thalamic nucleus receives
projections from the brainstem reticular formation
and large regions of the cerebral cortex and projects
mainly to the brainstem reticular formation and the
superior colliculus. With activation or stimulation of
the mesencephalic reticular formation, the reticular
thalamic nucleus is inhibited; this reduces the tonic
inhibition that the reticular nucleus exerts on
thalamic relay nuclei. Sensory information is then
transmitted to the cerebral cortex for further proces-
sing. This gating function should be thought of as a
network of ‘‘neural portals’’ that are capable of
individually or collectively regulating information
flow to the cortex. Thalamic gating is influenced by
feedback from the prefrontal cortex, allowing selec-
tion of certain stimuli and disallowing others from
reaching the cortex for further processing. This is
likely relevant for attention, in which selection of
information is an important component.
In summary, the complex interactions of the
rostral brainstem reticular formation, the thalamus,
other subcortical structures, and the cortex probably
allow for alertness and components of awareness,
including the selection of information for attention
depending on the importance (e.g., danger, needs, or
cognitive values) at the time.
—G. Bryan Young
See also–Alertness; Attention; Awareness;
Consciousness; Self-Awareness
Asperger’s Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN 1944, Hans Asperger, an Austrian physician,
described a group of individuals (older children and
adolescents) whose main disability involved difficul-
ties relating to others and establishing friendships.
His initial cases (all boys) were remarkable in that
although socially quite disabled, they were also quite
verbal and they also pursued special interests (e.g., in
train or bus schedules) with great single-mindedness.
Asperger’s original report noted that the cases often
exhibited motor clumsiness and that the condition
seemed to run in families and was particularly
common in fathers. Although unaware of Kanner’s
earlier description of the syndrome of infantile
autism, Asperger’s original name for the condition
he described (autistischen psychopathen im kindes-
alter or autistic personality disorders in childhood)
also emphasized the central feature of social dis-
ability. An impressive revival of interest in Asperger’s
description followed the rediscovery of his paper by
English-speaking researchers following Wing’s 1981
account.
Asperger’s syndrome (AS) is now defined on the
basis of severe problems in social interaction of the
type seen in autism, but in contrast to autism, early
284 ASPERGER’S SYNDROME
Figure 1
The composite picture of the brain shows several sites at which
functions are localized (grossly oversimplified) as well as those
functions (self-awareness, cognition, and perceptual–motor
integration) that are likely widespread, involving numerous
interconnected cortical and subcortical structures.
mid-pons extending rostrally, through the midline
and intralaminar (formerly called ‘‘nonspecific’’)
nuclei of the thalamus, to the cerebral cortex. The
ARAS was thought to be composed of an undiffer-
entiated collection of neurons in these regions, with
extensive internal connections and projections both
rostrally and caudally. Further studies on the
morphology, connections, and neurochemistry of
separate cell groups in these regions revealed that
they have distinct properties and are components of
the arousal ‘‘system.’’
Discrete regions of the brainstem reticular forma-
tion project to several thalamic nuclei besides the
midline and intralaminar group, and there are
connections to motor and other centers. The
thalamic reticular nucleus performs a key role in
gating reticular activity and allowing feedback to the
brainstem centers that play a role in arousal and
alertness. The reticular thalamic nucleus receives
projections from the brainstem reticular formation
and large regions of the cerebral cortex and projects
mainly to the brainstem reticular formation and the
superior colliculus. With activation or stimulation of
the mesencephalic reticular formation, the reticular
thalamic nucleus is inhibited; this reduces the tonic
inhibition that the reticular nucleus exerts on
thalamic relay nuclei. Sensory information is then
transmitted to the cerebral cortex for further proces-
sing. This gating function should be thought of as a
network of ‘‘neural portals’’ that are capable of
individually or collectively regulating information
flow to the cortex. Thalamic gating is influenced by
feedback from the prefrontal cortex, allowing selec-
tion of certain stimuli and disallowing others from
reaching the cortex for further processing. This is
likely relevant for attention, in which selection of
information is an important component.
In summary, the complex interactions of the
rostral brainstem reticular formation, the thalamus,
other subcortical structures, and the cortex probably
allow for alertness and components of awareness,
including the selection of information for attention
depending on the importance (e.g., danger, needs, or
cognitive values) at the time.
—G. Bryan Young
See also–Alertness; Attention; Awareness;
Consciousness; Self-Awareness
Asperger’s Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN 1944, Hans Asperger, an Austrian physician,
described a group of individuals (older children and
adolescents) whose main disability involved difficul-
ties relating to others and establishing friendships.
His initial cases (all boys) were remarkable in that
although socially quite disabled, they were also quite
verbal and they also pursued special interests (e.g., in
train or bus schedules) with great single-mindedness.
Asperger’s original report noted that the cases often
exhibited motor clumsiness and that the condition
seemed to run in families and was particularly
common in fathers. Although unaware of Kanner’s
earlier description of the syndrome of infantile
autism, Asperger’s original name for the condition
he described (autistischen psychopathen im kindes-
alter or autistic personality disorders in childhood)
also emphasized the central feature of social dis-
ability. An impressive revival of interest in Asperger’s
description followed the rediscovery of his paper by
English-speaking researchers following Wing’s 1981
account.
Asperger’s syndrome (AS) is now defined on the
basis of severe problems in social interaction of the
type seen in autism, but in contrast to autism, early

language skills are preserved and often highly
developed. Although not necessary criteria, special
interests and motor clumsiness are typically ob-
served. Research on the condition has been ham-
pered by differences in nosological approach and a
plethora of terms coined to describe similar condi-
tions (e.g., semantic–pragmatic language disorder,
right hemisphere learning disability, and schizoid
personality disorder).
The validity of AS (e.g., apart from higher
functioning autism) has been addressed in a number
of studies. A relatively frequent finding, and one
consistent with Asperger’s original report, has
been different patterns in IQ profiles: Individuals
with AS typically exhibit much higher verbal than
performance IQ. AS has also been noted to be
differentially associated with the profile of nonverbal
learning disability. Differences from autism also
include the relatively later age of recognition of
the condition, the generally better outcome, and
high rates of social disability in immediate family
members.
The cause of the condition remains unknown.
The particular constellation of difficulties has been
considered as suggestive of difficulties in the right
cerebral cortex. However, structural magnetic reso-
nance imaging (MRI) has yielded inconsistent
results, with some case reports suggestive of such
difficulties. It has been suggested that the nonverbal
learning disability profile, frequently observed in
AS, may reflect right hemisphere white matter
abnormalities. This model is quite relevant to AS
given the observed difficulties in social functioning
and associated neuropsychological deficits. Recent
functional MRI work suggests specific problems
in processing the human face and social informa-
tion. The high rate of social disability in family
members suggests a strong genetic component—even
stronger than that in autism. The delineation of
specific brain mechanisms in AS is an area of active
research.
Treatment of AS is essentially supportive and
symptomatic, with special attention to supporting
the individual’s areas of strength and helping him or
her cope with areas of vulnerability. Given that the
condition is not frequently associated with mental
retardation, eligibility for special services is some-
times problematic and the preservation of language
skills and verbal ability may cause teachers and
others to overlook the severity of the child’s
difficulties in nonverbal tasks. Acquisition of basis
adaptive skills should be encouraged. Specific pro-
ASTERIXIS 285
blem-solving strategies, usually following a verbal
algorithm, may be useful in dealing with recurrent
problem situations (e.g., those that involve more
social interaction or coping with novelty). Supportive
psychotherapy and pharmacological intervention
may be useful. Individuals may be at increased risk
for depression during adolescence and early adult-
hood.
—Fred R. Volkmar and Ami Klin
See also–Autism; Socially Inept Children
Further Reading
Asperger, H. (1944). Die ‘‘autistichen Psychopathen’’ im Kindes-
alter. Arch. Psychiatr. Nervenkrankheiten 117, 76–136.
Klin, A., Sparrow, S., and Volkmar, F. R. (Eds.) (2000). Asperger’s
Syndrome. Guilford, New York.
Wing, L. (1981). Asperger’s syndrome: A clinical account. Psychol.
Med. 11, 115–129.
Asterixis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ASTERIXIS or negative myoclonus is commonly seen
accompanying various metabolic and anoxic distur-
bances. In asterixis, there are brief flappings of the
limbs that are due to transient interruption of the
muscles that maintain posture of those extremities. It
is often bilateral, but unilateral asterixis can be seen
in association with strokes, especially those involving
the thalamus. The diagnosis can be confirmed by
recording the activity of the affected muscles,
showing sudden lapses of activity.
—Esther Cubo and Christopher G. Goetz
See also–Myoclonus
Further Reading
Hiroshi, S. (1998). Myoclonus and startle syndromes. In Parkin-
son’s Disease and Movement Disorders (J. Jankovic and E.
Tolosa, Eds.), pp. 453–466. Williams & Wilkins, Philadelphia.
Astrocytes
see Glia

language skills are preserved and often highly
developed. Although not necessary criteria, special
interests and motor clumsiness are typically ob-
served. Research on the condition has been ham-
pered by differences in nosological approach and a
plethora of terms coined to describe similar condi-
tions (e.g., semantic–pragmatic language disorder,
right hemisphere learning disability, and schizoid
personality disorder).
The validity of AS (e.g., apart from higher
functioning autism) has been addressed in a number
of studies. A relatively frequent finding, and one
consistent with Asperger’s original report, has
been different patterns in IQ profiles: Individuals
with AS typically exhibit much higher verbal than
performance IQ. AS has also been noted to be
differentially associated with the profile of nonverbal
learning disability. Differences from autism also
include the relatively later age of recognition of
the condition, the generally better outcome, and
high rates of social disability in immediate family
members.
The cause of the condition remains unknown.
The particular constellation of difficulties has been
considered as suggestive of difficulties in the right
cerebral cortex. However, structural magnetic reso-
nance imaging (MRI) has yielded inconsistent
results, with some case reports suggestive of such
difficulties. It has been suggested that the nonverbal
learning disability profile, frequently observed in
AS, may reflect right hemisphere white matter
abnormalities. This model is quite relevant to AS
given the observed difficulties in social functioning
and associated neuropsychological deficits. Recent
functional MRI work suggests specific problems
in processing the human face and social informa-
tion. The high rate of social disability in family
members suggests a strong genetic component—even
stronger than that in autism. The delineation of
specific brain mechanisms in AS is an area of active
research.
Treatment of AS is essentially supportive and
symptomatic, with special attention to supporting
the individual’s areas of strength and helping him or
her cope with areas of vulnerability. Given that the
condition is not frequently associated with mental
retardation, eligibility for special services is some-
times problematic and the preservation of language
skills and verbal ability may cause teachers and
others to overlook the severity of the child’s
difficulties in nonverbal tasks. Acquisition of basis
adaptive skills should be encouraged. Specific pro-
ASTERIXIS 285
blem-solving strategies, usually following a verbal
algorithm, may be useful in dealing with recurrent
problem situations (e.g., those that involve more
social interaction or coping with novelty). Supportive
psychotherapy and pharmacological intervention
may be useful. Individuals may be at increased risk
for depression during adolescence and early adult-
hood.
—Fred R. Volkmar and Ami Klin
See also–Autism; Socially Inept Children
Further Reading
Asperger, H. (1944). Die ‘‘autistichen Psychopathen’’ im Kindes-
alter. Arch. Psychiatr. Nervenkrankheiten 117, 76–136.
Klin, A., Sparrow, S., and Volkmar, F. R. (Eds.) (2000). Asperger’s
Syndrome. Guilford, New York.
Wing, L. (1981). Asperger’s syndrome: A clinical account. Psychol.
Med. 11, 115–129.
Asterixis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ASTERIXIS or negative myoclonus is commonly seen
accompanying various metabolic and anoxic distur-
bances. In asterixis, there are brief flappings of the
limbs that are due to transient interruption of the
muscles that maintain posture of those extremities. It
is often bilateral, but unilateral asterixis can be seen
in association with strokes, especially those involving
the thalamus. The diagnosis can be confirmed by
recording the activity of the affected muscles,
showing sudden lapses of activity.
—Esther Cubo and Christopher G. Goetz
See also–Myoclonus
Further Reading
Hiroshi, S. (1998). Myoclonus and startle syndromes. In Parkin-
son’s Disease and Movement Disorders (J. Jankovic and E.
Tolosa, Eds.), pp. 453–466. Williams & Wilkins, Philadelphia.
Astrocytes
see Glia
286 ATAXIA
Astrocytomas
see Glial Tumors
Ataxia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATAXIA is the most characteristic feature of cerebellar
disorders. Cerebellar ataxia is defined as the lack of
accuracy or coordination of movement that cannot
be explained by weakness, altered muscle tone, poor
sensory function, or superimposition of involuntary
movements. Ataxia can affect the entire body or
involve limbs, trunk, speaking and swallowing
muscles, or eye movements preferentially. Gait ataxia
causes poor walking and frequent falls; trunkal
ataxia precludes the patient from sitting or standing
without falling over; limb ataxia causes sloppy and
poorly coordinated movements with frequent drop-
ping of objects; speech ataxia causes slurred and
poorly articulated speech, called dysarthria; and
ocular ataxia, referred to as nystagmus, has numer-
ous variants, most causing a sense of double vision or
jerking eyes.
The two primary categories of cerebellar ataxia are
hereditary and nonhereditary. Hereditary ataxia is
further divided into ataxias with either autosomal
dominant inheritance (meaning that the disorder is
passed on to each generation in the family tree and
each offspring of an affected person carries a 50%
chance of having the condition) or those that are
autosomal recessive (meaning that the disorder can
skip generations, and the risk of disease is less). In the
past several years, a number of genes for hereditary
ataxias have been localized, and their specific
mutations have been characterized. Regarding the
nonhereditary forms of ataxia, some are of unknown
cause, termed primary ataxias, and many are due to
identified disorders that damage the cerebellum or its
inflow/outflow tracts to the spinal cord, brainstem,
or cerebral cortex. These forms of secondary ataxias
include poor coordination due to multiple sclerosis,
cancer, hypothyroidism, and a large number of other
medical conditions.
The classic form of ataxia that is of autosomal
recessive inheritance is Friedreich’s ataxia. It is
caused by a mutation on chromosome 9, where a
coding for the triplet nucleotide sequence, guanine–
adenosine–adenosine, is abnormally expanded. This
condition develops in children between 10 and 15
years of age, with progressive ataxia of their limbs.
They often have scoliosis or a curved spine, poor
ability to perceive touch and vibration, and dimin-
ished or absent deep tendon reflexes. Their limbs lose
mass (atrophy) and they often have abnormal eye
movements. When they are tested with an electro-
myogram, the results suggest a sensory axonal
neuropathy as evidenced by a particular abnormality,
called absent sensory nerve action potentials
(SNAPS). There is no pharmacological treatment
and all patients become dependent on canes, wheel-
chairs, or walking devices. Other autosomal recessive
forms of ataxia include congenital ataxia, ataxia
telangiectasia (a condition associated with abnorm-
alities of blood vessels and vitamin metabolism), and
ataxia in association with isolated vitamin E
deficiency.
There are several forms of autosomal dominant
cerebellar ataxia, and these are divided into families
with signs of pure ataxia, those with signs of
additional spinal cord abnormalities, and those with
disorders affecting the retina of the eye. Most of
these are collectively termed spinocerebellar atro-
phies, and there are numerous subtypes. Genetic
defects have been identified for many but not all.
None is treatable, although some ataxic patients
have reported mild amelioration with drugs such as
amantadine and buspirone. Often, patients with
severe difficulty swallowing need to have feeding
tubes placed into the gastrointestinal tract so that
nutrition can be ensured without undue risk of
aspiration of food into the respiratory system. The
episodic ataxias are unusual because these autoso-
mally dominant conditions can often be treated with
acetazolamide. In these families, patients develop
intermittent ataxia, often in association with chorea
or dystonia. Jerking muscle movements called
myokymia can be present in one form termed type
1. The cellular abnormality appears to relate to an
abnormality in potassium channels in type 1 and to
an abnormality of calcium channels in type 2 disease.
Acetozolamide therapy is most effective for the type
2 disease.
In the nonhereditary cerebellar ataxias, disability
starts during adulthood, after the age of 25. There
may be isolated cerebellar ataxia that is progressive
and disabling or there may additional degeneration
of other areas of the nervous system, including the
basal ganglia, the pyramidal tracts of the spinal cord,
and the areas that control blood pressure, heart rate,

and sexual function. This latter syndrome has many
characteristics of the condition called multiple
system atrophy. However, most patients with adult-
onset ataxia have another well-defined medical or
neurological condition, with the ataxia being one of
many components of the underlying disease. Among
the many causes are strokes, multiple sclerosis,
chronic drug intoxication, hypothyroidism, malab-
sorption, heat stroke, chronic alcoholism, other
toxins, and cancer, either from extension of tumor
into the cerebellar system or as an immunological
effect of the cancer (paraneoplastic syndrome). In the
case of drug exposure, chronic antiepileptic drugs,
such as phenytoin and the psychiatric medication
lithium carbonate, are important to identify because
they are commonly used and when prescribed they
are usually taken chronically. These forms of
secondary ataxia require treatment of the primary
medical or neurological disorder, and in the case of
toxins or drugs, cessation of exposure may improve
the ataxic signs.
—Christopher G. Goetz
See also–Ataxia Telangiectasia; Degenerative
Disorders; Dysequilibrium Syndrome; Episodic
Ataxias; Friedreich’s Ataxia; Gait and Gait
Disorders
Further Reading
Harding, A. (1984). The Hereditary Ataxias. Churchill Living-
stone, Edinburgh, UK.
Klockgether, T. (2003). Ataxias. In Textbook of Clinical Neurol-
ogy (C. G. Goetz, Ed.), pp. 682–699. Saunders, Philadelphia.
Klockgether, T., Schroth, G., and Diener, H. C. (1989). Idiopathic
cerebellar ataxia of late onset: Natural history and MRI
morphology. Neurol. Neurosurg. Psychiatry 52, 8–89.
Müller, U., Graeber, M. B., Haberhausen, G., et al. (1994).
Molecular basis and diagnosis of neurogenetic disorders. J.
Neurol. Sci. 124, 119–140.
Ataxia Telangiectasia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATAXIA TELANGIECTASIA (AT) is a hereditary disorder
characterized by a constellation of signs and symp-
toms associated with progressive cerebellar dysfunc-
tion, conjunctival and cutaneous telangiectasias,
severe immune deficiencies, premature aging, and a
predisposition to cancer. AT occurs equally among
ATAXIA TELANGIECTASIA 287
the sexes and is reported in all races and throughout
the world. The frequency of this disorder ranges
from 1 in 40,000 to 1 in 100,000 births.
Although AT is a multisystem, progressive dis-
order, progressive neurological deterioration is the
hallmark of the syndrome. The early neurological
features of AT are characterized by signs indicative of
a progressive cerebellar degeneration, including
wide-based gait (ataxia) and slurred speech (dysar-
thria). Ataxia becomes apparent shortly after af-
fected children begin to walk. It progresses and
becomes severe enough to warrant the use of a
wheelchair by 10–15 years of age. Other involuntary
movements can be present in older children, includ-
ing jerky movements, stiffness, fixed posturing,
decreased muscle tone, and drooling. Cognitive
impairment is also typical. The neurological exam-
ination is remarkable for abnormal eye movements
as well as sensory and motor system dysfunction.
Nonneurological features vary and include vascular
disorders in the skin, immunological disorders, and
tumoral manifestations. Vasculocutaneous abnorm-
alities (telangiectasias) usually appear later than
ataxia, typically at approximately 3–6 years of age,
in the eyes. These telangiectasias cause the eyes to
look bloodshot and eventually involve the eyelids,
adjoining facial regions, external ears, neck, arms,
and legs.
Patients with AT also demonstrate changes of the
hair and skin, including early graying of the hair and
atrophic, hidebound facial skin. Another prominent
feature of AT is frequent sinopulmonary infections.
These may range from infection of the ears, nose, and
sinuses to chronic bronchitis and recurrent pneumo-
nia. Chronic infections are typically due to common
bacteria; however, they are sometimes poorly re-
sponsive to antibiotic therapy. The predisposition to
infection is due to immunological abnormalities.
Malignant tumors occur in an estimated 10–15% of
patients with AT and are second only to pulmonary
disorders as a cause of death. The most common
tumors include those of Hodgkin’s disease, malignant
lymphomas, reticulum cell sarcoma, and histocyto-
sarcomas. These patients also have retarded physique
growth with bone disorders. Several hormone
abnormalities are also prominent, and poor sexual
development is found consistently. Some studies
report an unusual type of diabetes mellitus that
appears in late adolescence.
The laboratory evaluation of patients with AT
reveals normal results on routine studies of the urine,
blood (except for low white cells count), and spinal

and sexual function. This latter syndrome has many
characteristics of the condition called multiple
system atrophy. However, most patients with adult-
onset ataxia have another well-defined medical or
neurological condition, with the ataxia being one of
many components of the underlying disease. Among
the many causes are strokes, multiple sclerosis,
chronic drug intoxication, hypothyroidism, malab-
sorption, heat stroke, chronic alcoholism, other
toxins, and cancer, either from extension of tumor
into the cerebellar system or as an immunological
effect of the cancer (paraneoplastic syndrome). In the
case of drug exposure, chronic antiepileptic drugs,
such as phenytoin and the psychiatric medication
lithium carbonate, are important to identify because
they are commonly used and when prescribed they
are usually taken chronically. These forms of
secondary ataxia require treatment of the primary
medical or neurological disorder, and in the case of
toxins or drugs, cessation of exposure may improve
the ataxic signs.
—Christopher G. Goetz
See also–Ataxia Telangiectasia; Degenerative
Disorders; Dysequilibrium Syndrome; Episodic
Ataxias; Friedreich’s Ataxia; Gait and Gait
Disorders
Further Reading
Harding, A. (1984). The Hereditary Ataxias. Churchill Living-
stone, Edinburgh, UK.
Klockgether, T. (2003). Ataxias. In Textbook of Clinical Neurol-
ogy (C. G. Goetz, Ed.), pp. 682–699. Saunders, Philadelphia.
Klockgether, T., Schroth, G., and Diener, H. C. (1989). Idiopathic
cerebellar ataxia of late onset: Natural history and MRI
morphology. Neurol. Neurosurg. Psychiatry 52, 8–89.
Müller, U., Graeber, M. B., Haberhausen, G., et al. (1994).
Molecular basis and diagnosis of neurogenetic disorders. J.
Neurol. Sci. 124, 119–140.
Ataxia Telangiectasia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATAXIA TELANGIECTASIA (AT) is a hereditary disorder
characterized by a constellation of signs and symp-
toms associated with progressive cerebellar dysfunc-
tion, conjunctival and cutaneous telangiectasias,
severe immune deficiencies, premature aging, and a
predisposition to cancer. AT occurs equally among
ATAXIA TELANGIECTASIA 287
the sexes and is reported in all races and throughout
the world. The frequency of this disorder ranges
from 1 in 40,000 to 1 in 100,000 births.
Although AT is a multisystem, progressive dis-
order, progressive neurological deterioration is the
hallmark of the syndrome. The early neurological
features of AT are characterized by signs indicative of
a progressive cerebellar degeneration, including
wide-based gait (ataxia) and slurred speech (dysar-
thria). Ataxia becomes apparent shortly after af-
fected children begin to walk. It progresses and
becomes severe enough to warrant the use of a
wheelchair by 10–15 years of age. Other involuntary
movements can be present in older children, includ-
ing jerky movements, stiffness, fixed posturing,
decreased muscle tone, and drooling. Cognitive
impairment is also typical. The neurological exam-
ination is remarkable for abnormal eye movements
as well as sensory and motor system dysfunction.
Nonneurological features vary and include vascular
disorders in the skin, immunological disorders, and
tumoral manifestations. Vasculocutaneous abnorm-
alities (telangiectasias) usually appear later than
ataxia, typically at approximately 3–6 years of age,
in the eyes. These telangiectasias cause the eyes to
look bloodshot and eventually involve the eyelids,
adjoining facial regions, external ears, neck, arms,
and legs.
Patients with AT also demonstrate changes of the
hair and skin, including early graying of the hair and
atrophic, hidebound facial skin. Another prominent
feature of AT is frequent sinopulmonary infections.
These may range from infection of the ears, nose, and
sinuses to chronic bronchitis and recurrent pneumo-
nia. Chronic infections are typically due to common
bacteria; however, they are sometimes poorly re-
sponsive to antibiotic therapy. The predisposition to
infection is due to immunological abnormalities.
Malignant tumors occur in an estimated 10–15% of
patients with AT and are second only to pulmonary
disorders as a cause of death. The most common
tumors include those of Hodgkin’s disease, malignant
lymphomas, reticulum cell sarcoma, and histocyto-
sarcomas. These patients also have retarded physique
growth with bone disorders. Several hormone
abnormalities are also prominent, and poor sexual
development is found consistently. Some studies
report an unusual type of diabetes mellitus that
appears in late adolescence.
The laboratory evaluation of patients with AT
reveals normal results on routine studies of the urine,
blood (except for low white cells count), and spinal
288 ATHETOSIS
fluid. There may be diabetes mellitus. Immunological
disturbances are also helpful in the diagnosis of AT,
including low or absent levels of IgA, IgG-2, and IgE,
but these are not invariable. Computed tomography
and magnetic resonance imaging studies of the head
show cerebellar trophy. Muscle and nerve biopsies
may reveal evidence of denervation atrophy and
axonal degeneration, respectively.
Treatment of patients with AT is supportive and
includes treatment of infections and the use of
sunscreens to retard the cutaneous changes. Early
institution of pulmonary physiotherapy and physical
therapy is important. Prenatal diagnosis is possible
through the measurement of a-fetoprotein levels in
amniotic fluid and chromosomal amniotic cell
testing, documenting an increased spontaneous
chromosomal breakage of amniotic cell DNA.
—Esther Cubo and Christopher G. Goetz
See also–Ataxia; Brain Tumors, Biology; Episodic
Ataxias; Friedreich’s Ataxia; Gait and Gait
Disorders
Further Reading
Murphy, R. C., Berdon, W. E., Ruzal-Shapiro, C., et al. (1999).
Malignancies in pediatric patients with ataxia telangiectasia.
Pediatr. Radiol. 29, 225–230.
Savitsky, K., Bar-Shira, A., Gilad, S., et al. (1995). A single ataxia
telangiectasia gene with a product similar to Pl-3 kinase.
Science 268, 1749–1753.
Sedgwick, R. P., and Boder, E. (1991). Ataxia-telangiectasia. In
Hereditary Neuropathies and Spinocerebellar Atrophies: Hand-
book of Clinical Neurology (J. M. B. V. deJong, Ed.), Vol. 60,
pp. 347–423. Elsevier, Amsterdam.
Athetosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATHETOSIS, a term coined by the celebrated early
American neurologist William A. Hammond, is the
slow, writhing, and continuous worm-like movement
of the limbs or trunk. The neck, face, and tongue can
also be affected. Athetotic patients often show no
abnormal movements at complete rest, but as soon as
they activate a muscle region the body begins to twist
and writhe. The speed of these involuntary move-
ments can sometimes be faster and blend with those
of chorea; in this instance, the term choreoathetosis
is used. Sometimes, athetosis is associated with very
slow contractions producing sustained abnormal
posturing, and in this instance athetosis blends with
dystonia.
Athetosis most commonly occurs as a result of
injury to the brain regions, collectively known as the
basal ganglia. Injury often occurs in the neonatal
period or during infancy, and forms of cerebral palsy
in children are athetotic. In adults, athetosis usually
occurs in patients who have experienced a stroke. As
the weakness resolves, the patient discovers that
movement induces the abnormal twisting movements
rather than normal movement. This syndrome of
posthemiplegic athetosis can be extremely disabling
because the patient cannot perform any meaningful
tasks despite resolution of hemiplegia.
—Christopher G. Goetz
See also–Basal Ganglia; Chorea;
Choreoathetosis; Dystonia
Further Reading
Adams, R. D., and Salam-Adams, M. (1999). Athetosis and
common athetoid syndromes. In Movement Disorders in
Neurology and Neuropsychiatry (A. B. Joseph and R. R.
Young, Eds.), pp. 495–501. Blackwell Science, Oxford.
Fahn, S. (2003). Hypokinesia and hyperkinesia. In Textbook of
Clinical Neurology (C. G. Goetz, Ed.), pp. 267–286. Saunders,
Philadelphia.
Singer, H. S. (1998). Movement disorders in children. In
Parkinson’s Disease and Movement Disorders (J. Jankovic
and E. Tolosa, Eds.), pp. 729–753. Williams & Wilkins,
Baltimore.
Attention
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MOSCOVITCH defined attention as ‘‘a control process
that enables the individual to select, from a number
of alternatives, the task he will perform or the
stimulus he will process, and the cognitive strategy he
will adopt to carry out these operations.’’ As a
prerequisite, the individual must be awake and alert.
In the past few years, some of the neural systems
underlying attention have become better under-
stood. Like memory, attention is not a unitary
cognitive function, and recent cognitive neuroscience
models of attention have linked specific attentional
operations to a network of different anatomical
areas. Studies of brain lesions, electrophysiology,
288 ATHETOSIS
fluid. There may be diabetes mellitus. Immunological
disturbances are also helpful in the diagnosis of AT,
including low or absent levels of IgA, IgG-2, and IgE,
but these are not invariable. Computed tomography
and magnetic resonance imaging studies of the head
show cerebellar trophy. Muscle and nerve biopsies
may reveal evidence of denervation atrophy and
axonal degeneration, respectively.
Treatment of patients with AT is supportive and
includes treatment of infections and the use of
sunscreens to retard the cutaneous changes. Early
institution of pulmonary physiotherapy and physical
therapy is important. Prenatal diagnosis is possible
through the measurement of a-fetoprotein levels in
amniotic fluid and chromosomal amniotic cell
testing, documenting an increased spontaneous
chromosomal breakage of amniotic cell DNA.
—Esther Cubo and Christopher G. Goetz
See also–Ataxia; Brain Tumors, Biology; Episodic
Ataxias; Friedreich’s Ataxia; Gait and Gait
Disorders
Further Reading
Murphy, R. C., Berdon, W. E., Ruzal-Shapiro, C., et al. (1999).
Malignancies in pediatric patients with ataxia telangiectasia.
Pediatr. Radiol. 29, 225–230.
Savitsky, K., Bar-Shira, A., Gilad, S., et al. (1995). A single ataxia
telangiectasia gene with a product similar to Pl-3 kinase.
Science 268, 1749–1753.
Sedgwick, R. P., and Boder, E. (1991). Ataxia-telangiectasia. In
Hereditary Neuropathies and Spinocerebellar Atrophies: Hand-
book of Clinical Neurology (J. M. B. V. deJong, Ed.), Vol. 60,
pp. 347–423. Elsevier, Amsterdam.
Athetosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATHETOSIS, a term coined by the celebrated early
American neurologist William A. Hammond, is the
slow, writhing, and continuous worm-like movement
of the limbs or trunk. The neck, face, and tongue can
also be affected. Athetotic patients often show no
abnormal movements at complete rest, but as soon as
they activate a muscle region the body begins to twist
and writhe. The speed of these involuntary move-
ments can sometimes be faster and blend with those
of chorea; in this instance, the term choreoathetosis
is used. Sometimes, athetosis is associated with very
slow contractions producing sustained abnormal
posturing, and in this instance athetosis blends with
dystonia.
Athetosis most commonly occurs as a result of
injury to the brain regions, collectively known as the
basal ganglia. Injury often occurs in the neonatal
period or during infancy, and forms of cerebral palsy
in children are athetotic. In adults, athetosis usually
occurs in patients who have experienced a stroke. As
the weakness resolves, the patient discovers that
movement induces the abnormal twisting movements
rather than normal movement. This syndrome of
posthemiplegic athetosis can be extremely disabling
because the patient cannot perform any meaningful
tasks despite resolution of hemiplegia.
—Christopher G. Goetz
See also–Basal Ganglia; Chorea;
Choreoathetosis; Dystonia
Further Reading
Adams, R. D., and Salam-Adams, M. (1999). Athetosis and
common athetoid syndromes. In Movement Disorders in
Neurology and Neuropsychiatry (A. B. Joseph and R. R.
Young, Eds.), pp. 495–501. Blackwell Science, Oxford.
Fahn, S. (2003). Hypokinesia and hyperkinesia. In Textbook of
Clinical Neurology (C. G. Goetz, Ed.), pp. 267–286. Saunders,
Philadelphia.
Singer, H. S. (1998). Movement disorders in children. In
Parkinson’s Disease and Movement Disorders (J. Jankovic
and E. Tolosa, Eds.), pp. 729–753. Williams & Wilkins,
Baltimore.
Attention
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MOSCOVITCH defined attention as ‘‘a control process
that enables the individual to select, from a number
of alternatives, the task he will perform or the
stimulus he will process, and the cognitive strategy he
will adopt to carry out these operations.’’ As a
prerequisite, the individual must be awake and alert.
In the past few years, some of the neural systems
underlying attention have become better under-
stood. Like memory, attention is not a unitary
cognitive function, and recent cognitive neuroscience
models of attention have linked specific attentional
operations to a network of different anatomical
areas. Studies of brain lesions, electrophysiology,
288 ATHETOSIS
fluid. There may be diabetes mellitus. Immunological
disturbances are also helpful in the diagnosis of AT,
including low or absent levels of IgA, IgG-2, and IgE,
but these are not invariable. Computed tomography
and magnetic resonance imaging studies of the head
show cerebellar trophy. Muscle and nerve biopsies
may reveal evidence of denervation atrophy and
axonal degeneration, respectively.
Treatment of patients with AT is supportive and
includes treatment of infections and the use of
sunscreens to retard the cutaneous changes. Early
institution of pulmonary physiotherapy and physical
therapy is important. Prenatal diagnosis is possible
through the measurement of a-fetoprotein levels in
amniotic fluid and chromosomal amniotic cell
testing, documenting an increased spontaneous
chromosomal breakage of amniotic cell DNA.
—Esther Cubo and Christopher G. Goetz
See also–Ataxia; Brain Tumors, Biology; Episodic
Ataxias; Friedreich’s Ataxia; Gait and Gait
Disorders
Further Reading
Murphy, R. C., Berdon, W. E., Ruzal-Shapiro, C., et al. (1999).
Malignancies in pediatric patients with ataxia telangiectasia.
Pediatr. Radiol. 29, 225–230.
Savitsky, K., Bar-Shira, A., Gilad, S., et al. (1995). A single ataxia
telangiectasia gene with a product similar to Pl-3 kinase.
Science 268, 1749–1753.
Sedgwick, R. P., and Boder, E. (1991). Ataxia-telangiectasia. In
Hereditary Neuropathies and Spinocerebellar Atrophies: Hand-
book of Clinical Neurology (J. M. B. V. deJong, Ed.), Vol. 60,
pp. 347–423. Elsevier, Amsterdam.
Athetosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATHETOSIS, a term coined by the celebrated early
American neurologist William A. Hammond, is the
slow, writhing, and continuous worm-like movement
of the limbs or trunk. The neck, face, and tongue can
also be affected. Athetotic patients often show no
abnormal movements at complete rest, but as soon as
they activate a muscle region the body begins to twist
and writhe. The speed of these involuntary move-
ments can sometimes be faster and blend with those
of chorea; in this instance, the term choreoathetosis
is used. Sometimes, athetosis is associated with very
slow contractions producing sustained abnormal
posturing, and in this instance athetosis blends with
dystonia.
Athetosis most commonly occurs as a result of
injury to the brain regions, collectively known as the
basal ganglia. Injury often occurs in the neonatal
period or during infancy, and forms of cerebral palsy
in children are athetotic. In adults, athetosis usually
occurs in patients who have experienced a stroke. As
the weakness resolves, the patient discovers that
movement induces the abnormal twisting movements
rather than normal movement. This syndrome of
posthemiplegic athetosis can be extremely disabling
because the patient cannot perform any meaningful
tasks despite resolution of hemiplegia.
—Christopher G. Goetz
See also–Basal Ganglia; Chorea;
Choreoathetosis; Dystonia
Further Reading
Adams, R. D., and Salam-Adams, M. (1999). Athetosis and
common athetoid syndromes. In Movement Disorders in
Neurology and Neuropsychiatry (A. B. Joseph and R. R.
Young, Eds.), pp. 495–501. Blackwell Science, Oxford.
Fahn, S. (2003). Hypokinesia and hyperkinesia. In Textbook of
Clinical Neurology (C. G. Goetz, Ed.), pp. 267–286. Saunders,
Philadelphia.
Singer, H. S. (1998). Movement disorders in children. In
Parkinson’s Disease and Movement Disorders (J. Jankovic
and E. Tolosa, Eds.), pp. 729–753. Williams & Wilkins,
Baltimore.
Attention
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MOSCOVITCH defined attention as ‘‘a control process
that enables the individual to select, from a number
of alternatives, the task he will perform or the
stimulus he will process, and the cognitive strategy he
will adopt to carry out these operations.’’ As a
prerequisite, the individual must be awake and alert.
In the past few years, some of the neural systems
underlying attention have become better under-
stood. Like memory, attention is not a unitary
cognitive function, and recent cognitive neuroscience
models of attention have linked specific attentional
operations to a network of different anatomical
areas. Studies of brain lesions, electrophysiology,

neuroimaging, and mental chronometry have sug-
gested that functionally, attention is a separate and
coherent system involved in the control of mental
processing. It is anatomically separable from other
brain data processing systems. The attentional
system appears to consist of several networks
grouped in relatively distinct anatomical areas that
perform different operations, which can be deli-
neated in cognitive terms.
Posner and Petersen identified at least three
networks that appear to form the attentional system.
First is the vigilance network, which is involved in
the maintenance of the alert state. Second is the
posterior attentional network, which is involved in
orienting to sensory stimuli and has mostly been
studied with regard to visual attention. Third is the
anterior attentional network, which is involved in the
detection of events and has been linked to the choice
in selection for action, voluntary conscious attention,
and the executive control of behavior.
VIGILANCE NETWORK
An important attentional function is the ability to
prepare and to sustain alertness for processing high-
priority signals. The basic brain structure responsible
for arousal is the ascending reticular activating
system. This system originates in the brainstem
reticular formation and extends to the cortex via a
diffuse or nonspecific thalamic projection system. A
group of specialized reticular neurons in the teg-
mental portions of midbrain and upper pons receive
collateral input from most ascending and descending
fiber systems and have the capacity to activate higher
centers. Reticular stimulation alerts a widespread
area of subcortex and cortex on external stimuli. The
reticular activating system maintains constant fluc-
tuating stimulation of higher centers, without which
the cortex cannot function effectively. Any damage
or suppression of this system renders individuals
difficult to arouse or inefficient in performance.
Lesions to reticular formations lead to total disrup-
tion of arousal and to coma. Pressure on the
midbrain from hippocampal or uncal herniation
has been shown to cause a change in the level of
consciousness. Damage to the superior brainstem
reticular system in the thalamus or hypothalamus
produces alteration in arousal as well. Recent
positron emission tomography (PET) studies have
indicated that the midbrain tegmentum and the right
intralaminar region of the thalamus play an im-
portant role in the control of arousal.
ATTENTION 289
Heilman et al. suggest that the ability to develop
and maintain an alert state depends heavily on the
right cerebral hemisphere. This finding is in accor-
dance with clinical observations that patients with
right hemisphere lesions often show signs of neglect.
Several animal and human studies have shown that
right hemisphere lesions can cause difficulties with
alerting. Right hemisphere lesions also impair
performance on vigilance tasks more than do left
hemisphere lesions. Findings from split-brain patient
studies have also suggested that the isolated right
hemisphere is relatively good at maintaining the
vigilant state, whereas the isolated left hemisphere is
not. Cerebral blood flow and metabolic studies
involving vigilance and alerting tasks have shown
the relationship between right hemisphere, alerting,
and vigilance. Cohen et al. reported an area in the
right mid-frontal cortex that was most active during
auditory vigilance tasks, whereas other authors
found the same area activated in both somatosensory
and visual conditions. PET studies show increased
activation of the right lateral prefrontal lobe during
vigilance tasks. These findings indicate that main-
tenance of the alert state may be primarily dependent
on right hemisphere mechanisms.
The neurotransmitter norepinephrine has an
important role in the maintenance of the alert state.
The norepinephrine pathway arises in the locus
coeruleus, and the right frontal area appears to have
an important role in its cortical distribution. Nore-
pinephrine innervation in the visual system of
monkeys is most strongly present in the posterior
parietal lobe, pulvinar, and superior colliculus, which
are all part of the posterior attentional network
discussed next.
POSTERIOR ATTENTIONAL NETWORK
An important aspect of selective attention is orient-
ing to sensory stimuli. When attention is directed
(cued) to a particular sensory feature, stimuli having
this feature are processed more efficiently (i.e., faster
reaction time and lower threshold) than if attention
is not so directed. The posterior attentional network,
which is involved in orienting to sensory stimuli, has
mostly been studied in regard to visual attention.
Orienting of visual attention is not dependent on eye
movements, and visual shifts of attention often
precede eye movements. Therefore, they are often
referred to as covert shifts of attention. Covert
orienting of attention allows a temporary emphasis
outside the fovea, and it appears to be crucial in the
290 ATTENTION
ocular motor system controlling subsequent eye
movements.
Posner and Priesti suggest that three basic compo-
nents are involved when attention is summoned by a
cue: an increase in alertness, initiation of spatially
selective movement of visual attention, and initiation
of two forms of inhibition—cost and inhibition of
return.
The occurrence of a cue produces a nonspatially
specific alerting effect that serves to interrupt the
ongoing performance. It then produces a disengage-
ment of attention, a movement to the cued location,
and subsequent engagement of the target. Cost is a
consequence of orienting attention to the cue. Once
attention is engaged at the cued location, all other
locations will be handled less efficiently than if no
such orienting had occurred, because attention must
first be disengaged from the cued location before it
can be reengaged at other locations. When the
subject’s attention is withdrawn from the cue to
another location, the inhibition of return occurs.
Inhibition of return refers to a reduction in efficiency
of returning attention to an already cued location.
The function of inhibition of return appears to be to
maximize the sampling of novel areas within the
visual field.
Single-cell recordings in monkeys and studies of
patients with restricted neurological lesions, as well
as normal subjects, have been used to support each of
the previously mentioned functions. Single-cell re-
cordings in monkey brains identified three brain
areas that were enhanced (i.e., they had a greater
discharge rate) when the monkey selectively attended
to a specific location or visual stimulus: the posterior
parietal lobe, the lateral pulvinar nucleus of the
posterolateral thalamus, and the superior colliculus.
Similar enhancement effects in the parietal cortex of
normal humans have been observed in PET studies.
Damage to each of these areas appears to produce a
different type of deficit in the ability to covertly
orient attention.
Damage to the posterior parietal lobe has the
greatest impact on the ability to disengage attention
from a focal point and to shift it to a target located
in a direction opposite the site of the lesion.
Furthermore, damage to the right posterior parietal
lobe appears to have a greater overall effect than
damage to the left parietal lobe. In a PET study by
Corbetta, right superior parietal cortex was acti-
vated when attention was shifted to either the left or
the right visual field. On the other hand, left parietal
cortex was activated only during shifts to the right
visual field. One hypothesis for this asymmetry is
that the right parietal lobe is dominant for spatial
attention and controls attention to both sides of
space. The second view is that the ability to
disengage is handled by both hemispheres, but
maintenance of the alert state is handled primarily
by the right hemisphere.
Patients with midbrain lesions, which include the
superior colliculus and surrounding area, show
deficit in moving attention to target location. Their
ability to shift attention is slowed whether or not
their attention is first engaged elsewhere. In addition,
these patients do not show an inhibition of return to
a previously attended location, which is character-
istic of normal subjects and patients with other
cortical lesions.
Patients with thalamic lesions, and monkeys with
chemical injections into the lateral pulvinar, show a
deficit in engaging attention to a target contralateral
to the lesion These patients have very long reaction
times for both correctly and incorrectly cued targets
contralateral to the lesion. This finding contrasts
with the results found in patients with parietal
lesions, whose responses are nearly normal once
their attention is correctly cued to the target location.
These findings support the role of thalamic areas in
the control of the attentional ‘‘spotlight.’’ The
thalamus appears to be an area most likely to be
involved in the search of a complex visual field for
targets. This concept is further supported by the
study of LaBerge and Buchsbaum in which normal
subjects, required to filter out irrelevancies, showed
selective metabolic increase in the pulvinar contral-
ateral to the filtering field.
These findings support the idea that different
anatomical areas carry specific cognitive operations.
The covert shifts of visual attention to a spatial
location seem to involve the following brain circui-
try: the parietal lobe, the midbrain, and the lateral
pulvinar thalamic nucleus. The parietal lobe first
disengages attention from its present focus. Informa-
tion is then sent to the midbrain to move attention to
the area of the target. Then, the lateral pulvinar is
involved in engaging the target. The known anatomy
and close physiological connection of the three areas
would suggest that they have a functional relation-
ship.
Cholinergic pathways in the basal forebrain
appear to have an important role in spatial attention.
Monkeys with basal forebrain lesions have signifi-
cantly increased reaction times when disengaging
their attention toward the location of the target. In

humans and primates, nicotine, which increases
neurotransmission at nicotinic cholinergic receptors,
affects the reaction time in precisely opposite
fashion: It decreases overall reaction time and
facilitates disengagement of attention.
ANTERIOR ATTENTIONAL NETWORK
Posner and Petersen suggest that another attentional
network appears to be involved in the detection of
events. This network involves areas of the mid-
prefrontal cortex (including anterior cingulate gyrus
and the superior supplementary motor area).
Cognitive studies of attention have shown that
detecting a target produces widespread interference
with most other cognitive operations. People can
monitor many input channels at once with little or no
interference; however, if a stimulus on any channel is
detected, the likelihood of detection on another
channel is restricted. PET studies showed that the
anterior cingulate was active during tasks requiring
subjects to detect different visual target stimuli
(color, motion, form, or word semantics). The
anterior cingulate was also much more active during
conflict blocks of Stroop tasks than during noncon-
flict blocks.
It has been known for some time that words can
have relatively automatic input to their semantic
associations. However, when an individual attends to
one meaning of the word, activation of other
meanings is suppressed. Similar to the enhancement
by the posterior attentional network when a visual
location is attended, attending to one semantic
category retards the speed at which words in other
categories are detected.
These enhancements appear to be caused by the
interaction between the anterior cingulate and the
lateral prefrontal areas. The left prefrontal cortical
region appears to be active in semantic association
tasks and in tasks requiring subjects to think about
the meaning of words. When subjects were asked to
visually monitor a list of words for animal names,
both the semantic area of the left dorsolateral
prefrontal cortex and the anterior cingulate were
activated. Since left prefrontal activation was un-
affected by the number of targets, a predominant
involvement of this area in the semantic processing
function was suggested. The activation of the
anterior cingulate increased with the number of
targets, strongly suggesting its role in target selection.
Subsequent studies have shown that the anterior
cingulate area appears to be active during many
ATTENTION 291
attentional tasks, whether or not they involve
language.
Posner and Rorthbart argue that the anterior
attentional network is more closely related to
awareness and control than is the posterior atten-
tional network. They suggest that attention in the
sense of orienting (posterior network) can be
disassociated from awareness and detection (anterior
network). Studies of blindsight provide evidence that
a crude form of orienting can take place without
visual awareness of the target.
Bilateral lesions of the anterior cingulate can cause
akinetic mutism, which involves complete loss of
spontaneous behavior in all domains, with some
preservation of ability to maintain an alert state and
to orient. Unilateral lesions of anterior cingulate and
supplementary motor area can produce a symptom
complex called the alien hand. These patients regard
the hand contralateral to the lesion as not being
controlled by them. This deficit is similar to the
neglect that can be found in patients with lesions of
posterior attentional network. Neglect patients with
severe lesions of the posterior parietal lobe may deny
that a hand or an arm belongs to them. In contrast,
patients with anterior lesions know that it is their
arm or hand but believe that somebody else is
controlling it.
These and other findings suggest that the anterior
and posterior networks share much in common.
However, the anterior network appears to be more
related to feelings of control and volition, whereas
the posterior network appears to be more related to
location in space.
RELATIONSHIP BETWEEN POSTERIOR AND
ANTERIOR NETWORKS
Goldman-Rakic describes strong connections be-
tween areas of lateral and medial frontal cortex
and the posterior parietal lobe. Alternate columns in
the anterior cingulate are connected to the dorso-
lateral prefrontal cortex (involved in semantic
processing in humans) and to the posterior parietal
cortex (posterior attentional network). This anato-
mical organization provides a possible base for
relating different aspects of attention.
Several investigators have approached the problem
of whether attention is a single unified system, or
whether it consists of separate independent systems,
by investigating whether attention in the semantic
domain (anterior attentional network) affects the
ability to orient toward visual location (posterior
292 ATTENTIONAL MECHANISMS
attentional network). These studies have found
independence between the two systems, the degree
of which appears to depend on the amount of mental
activity required by the primary task.
When required to monitor a stream of auditory
information for sound while simultaneously per-
forming a visual orienting task, parietal patients were
bilaterally slowed in their ability to orient toward the
visual cue. The effect of language task was bilateral
rather than mainly on the side contralateral to the
lesion. This suggests that language tasks may affect
some but not all of the mechanisms involved in the
visual orienting of attention. In another study,
normal subjects performed the visual orienting task
while shadowing an auditory message. The effects of
the language task were most pronounced for the
right visual field cues, suggesting a common later-
alized left hemisphere system. These findings are
consistent with close anatomical links of anterior
cingulate with both posterior parietal and lateral
frontal lobe. Posner and Petersen suggest that there
may be a hierarchy of the attentional system in which
the anterior attentional network may be the control
system that affects both language and spatial
functions and controls the posterior visuospatial
attentional network.
CONCLUSION
Although some of the neural systems underlying
attention have become better understood, the anat-
omy and function of attention, particularly of the
anterior network, require further study. Many
disorders are thought to involve deficits of attention,
including neglect syndrome, attention-deficit disor-
der, schizophrenia, Alzheimer’s disease, and closed-
head injury. The specification of attention in terms of
function and anatomy might help determine the
underlying bases for these disorders.
—Tatjana Novakovic-Agopian
See also–Alertness; Attentional Mechanisms;
Attention-Deficit/Hyperactivity Disorder
(ADHD); Awareness; Concentration; Executive
Function; Memory, Overview
Further Reading
Cohen, R. M., Semple, W. E., Gross, M., et al. (1988). Functional
localization of sustained attention. Neuropsychiatry Neuropsy-
chol. Behav. Neurol., 1, 3–20.
Corbetta, M., Meizin, F. M., Shulman, G. L., et al. (1993). A
PET study of visuospatial attention. J. Neurosci. 13, 1202–
1226.
Goldman-Rakic, P. S. (1988). Topography of cognition: Parallel
distributed networks in primate association cortex. Annu. Rev.
Neurosci. 11, 137–156.
Heilman, K. M., Watson, R. T., and Valenstein, E. (1985). Neglect
and related disorders. In Clinical Neuropsychology (K. M.
Heilman and E. Valenstein, Eds.), pp. 243–293. Oxford Univ.
Press, New York.
Kinomura, S., Larsson, J., Gulyas, B., et al. (1996). Activation by
attention in human reticular formation and thalamic intrala-
minar nuclei. Science 271, 612–615.
LaBerge, D., and Buchsbaum, M. S. (1990). Positron emission
tomographic measurements of pulvinar activity during an
attention task. J. Neurosci. 10, 613–619.
Pardo, J. V., Pardo, P. J., Janer, K. W., et al. (1990). The anterior
cingulate cortex mediates processing selection in the Stroop
attentional conflict paradigm. Proc. Natl. Acad. Sci. USA 87,
256–259.
Petersen, S. E., Fox, P. T., Posner, M. I., et al. (1988). Positron
emission tomographic studies of the cortical anatomy of single
word processing. Nature 331, 585–589.
Posner, M. I., and Petersen, S. E. (1990). The attention system of
the human brain. Annu. Rev. Neurosci. 13, 25–42.
Posner, M. I., and Priesti, D. (1987). Selective attention and
cognitive control. Trends Neurosci. 10, 12–17.
Posner, M. I., and Rorthbart, M. K. (1992). Attentional mechan-
isms and conscious experience. In The Neuropsychology of
Consciousness (D. Milner and M. Rugg, Eds.), pp. 91–111.
Academic Press, London.
Posner, M. I., Petersen, S. E., Fox, P. T., et al. (1988). Localization
of cognitive functions in the human brain. Science 240, 1627–
1631.
Attentional Mechanisms
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
WHAT is attention? ‘‘Everyone knows what attention
is. It is the taking possession of the mind in clear and
vivid form of one out of what seem several
simultaneous objects or trains of thought.’’
William James defined attention 100 years ago,
and the previous quote still illustrates several
important aspects of the field. Attention is heavily
tied with subjective experience. Moreover, James’
effort to deal with both attention to objects and
attention to ‘‘trains of thought’’ is important for a
grasp of current approaches to sensory orienting and
executive control. However, attention in the sense of
orienting to sensory objects can be involuntary and
can occur unconsciously, so attention is not, as the
quote from James implies, precisely the same as being
aware.

generalization to related tasks and to everyday life
activities is often limited.
Functional imaging seems to provide an impor-
tant tool for evaluating therapeutic methods.
Imaging provides an opportunity to see whether
and exactly how the therapy influences specific
circuits. This provides an intermediate level of
analysis between the therapy and actual behavior
that may allow a better opportunity to evaluate the
effects of various forms of therapy and improve
their design.
SUMMARY
The advent of neuroimaging of the human brain has
allowed attention to be viewed as an organ system
with its own specific anatomy. This approach makes
possible detailed examination of the cellular, synap-
tic, and genetic bases of normal attentional net-
works. It serves to link attention to the study of brain
states that change with the level of arousal from
wake to deep sleep and with development from
infancy to adulthood. This approach provides a basis
for considering the many pathologies of attention
due to insults to the adult brain or developmental
difficulties.
—Jin Fan, Amir Raz, and Michael I. Posner
See also–Alertness; Attention; Attention-Deficit/
Hyperactivity Disorder (ADHD); Dreaming;
Hypnotics; Sleep, Overview; Wakefulness
Further Reading
Desimone, R., and Duncan, J. (1995). Neural mechanisms of
selective attention. Annu. Rev. Neurosci. 18, 193–222.
Mack, A., and Rock, I. (1998). Inattentional Blindness. MIT Press,
Cambridge, MA.
Marrocco, R. T., and Davidson, M. C. (1998). Neurochemistry of
attention. In The Attentive Brain (R. Parasuraman, Ed.). MIT
Press, Cambridge, MA.
Posner, M. I., and DiGirolamo, G. J. (2000). Cognitive
neuroscience: Origins and prospects. Psychol. Bull. 126, 873–
889.
Posner, M. I., and Petersen, S. E. (1990). The attention system of
the human brain. Annu. Rev. Neurosci. 13, 25–42.
Posner, M. I., and Raichle, M. E. (1994). Images of Mind.
Scientific American Library, New York.
Robertson, I. H., and Murre, J. M. J. (1999). Rehabilitation of
brain damage: Brain plasticity and principles of guided
recovery. Pyschol. Bull. 125, 544–575.
Ruff, H. A., and Rothbart, M. K. (1996). Attention in Early
Development: Themes and Variations. Oxford Univ. Press, New
York.
Toga, A. W., and Mazziotta, J. C. (Eds.) (1996). Brain Mapping:
The Methods. Academic Press, New York.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER 299
Attention-Deficit/
Hyperactivity Disorder (ADHD)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)
is a syndrome of childhood constituting developmen-
tally inappropriate, impairing, and cross-situational
manifestations of inattention/disorganization, impul-
sivity, and motoric overactivity that cannot be better
accounted for by known neurological disease or
injury or by environmental trauma or deprivation.
Since the advent of compulsory education in the 19th
century, certain children’s noteworthy problems of
focusing attention and refraining from extraneous
and disorganized motor behavior have become
salient to society. During much of the 20th century,
such appellations as minimal brain damage, minimal
brain dysfunction, and hyperkinesis or hyperactivity
were invoked as diagnostic terms to describe such
deficits and problems. In 1980, the terminology
shifted to attention deficit disorder, consistent with
research pointing to problems in sustained attention
and maintenance of arousal as the underlying
deficits. The current nosological term, ADHD, as
used in the American Psychiatric Association’s
Diagnostic and Statistical Manual of Mental Dis-
orders, fourth edition, reflects the belief that diffi-
culties in both attentional processing and
hyperactive/impulsive behavior characterize most
individuals who meet criteria for this diagnostic
category. Research on the genetics, neurobiological
underpinnings, and psychosocial correlates of
ADHD has mushroomed in the past two decades.
ADHD received much attention in the latter
part of the 20th century as scientific, clinical, and
public awareness of this condition surged and as
prescription rates for psychotropic medications
(particularly stimulants) steadily increased. On one
side are critics who contend that ADHD is a
convenient psychiatric label used by society (i) to
‘‘medicalize’’ children’s restlessness and inattention,
which might be better explained by dysfunctional
families, faulty schools, or societal pressures for
academic success, and (ii) to legitimize pharma-
cological treatment for such problems. On the other
side are scientists and clinicians who assert that
ADHD is a real condition, with diagnostic validity
and underlying neurobiological reality, for which
300 ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
successful treatments (both pharmacological and
behavioral/psychological) are available. Indeed, a
National Institutes of Health Consensus Develop-
ment Conference, held during the late 1990s and
focusing on the diagnosis and treatment of ADHD,
concluded that the condition is a real, persistent
syndrome that is substantially impairing but one for
which thorough evaluation practices are needed to
ensure accurate diagnosis.
SUBTYPES, IMPAIRMENTS,
AND COMORBIDITIES
The constituent symptoms of ADHD are classified as
inattentive/disorganized vs hyperactive/impulsive be-
havior patterns. Most referred cases show above-
threshold levels of both symptom clusters, constitut-
ing the combined type. These individuals are usually
salient to teachers and caregivers because of their
high rates of disruptive behavior. In contrast,
persons with high levels of inattention (but not
hyperactivity/impulsivity), designated the inattentive
type, display a lack of disruptive behavior and a
sluggish cognitive tempo. Thus, ADHD is a hetero-
geneous condition. In the future, more precise
subtypes (or even distinct disorders) are likely to
emerge on the basis of neurobiologically sophisti-
cated research.
Regardless of subtype, individuals with ADHD
show clear impairment in academic achievement,
interactions with family members, and peer relations.
Severe inattention and impulse control problems do
not bode well for classroom performance or forma-
tion of harmonious friendships. In addition, rates of
accidental injury are well above norms, particularly
for individuals with hyperactivity/impulsivity. Over-
all, ADHD impedes the attainment of competencies
in key developmental domains.
Only rarely does ADHD exist in isolation from
other psychiatric conditions. One-third of those with
the diagnosis suffer from anxiety disorders, and one-
half or more have oppositional defiant disorder or
conduct disorder. This latter subgroup is at particu-
larly high risk for substance abuse and delinquency.
Indeed, the association of ADHD with common risk
factors for antisocial behavior (low socioeconomic
status, discordant family interactions, and poor
verbal skills) tends to fuel an early onset and virulent
course of such antisocial activities. Furthermore,
ADHD may coexist with specific learning disorders
(e.g., reading disability) or with neurological dis-
orders such as Tourette’s syndrome.
ASSESSMENT AND DIAGNOSIS
As for much of psychiatry, no conclusive biological
test is available to confirm the diagnosis of ADHD.
Furthermore, the core symptoms are ubiquitous,
particularly in young children. Thus, evaluation of
ADHD requires documentation of the presence of
developmentally extreme levels of the constituent
behavior patterns. Obtaining information from
parents and teachers is necessary because cross-
situational manifestations are required to meet
diagnostic criteria and children with ADHD are
notorious under-reporters of their own symptoma-
tology. A thorough history, a family evaluation, and
a medical examination are required to rule out
neurological disease, sensory impairment, and such
psychosocial influences as extreme family discord
and child abuse. The practice of diagnosing ADHD
within a brief office visit is not a valid diagnostic
strategy.
PREVALENCE AND DEVELOPMENTAL
COURSE
ADHD afflicts 3–7% of young persons. Among the
combined type, the male:female ratio is approxi-
mately 3:1 or 4:1; in the inattentive type, the sex
ratio may be closer to 2:1. Although it was formerly
believed that ADHD remitted with the onset of
puberty, well-controlled prospective studies confirm
that the overwhelming majority of childhood cases
persist until at least late adolescence, even though
motoric overactivity per se tends to decrease with
age. The absence of specific diagnostic criteria for
adult manifestations of ADHD makes ascertainment
of the prevalence into adulthood problematic, but
ADHD clearly presents risks for lifelong adjustment
problems. ADHD has been found to exist across
diverse socioeconomic strata as well as throughout
non-Western, nonindustrialized nations.
RISK AND ETIOLOGICAL FACTORS
The heritability of the symptom dimensions under-
lying ADHD is quite strong, with a reported range
from 0.6 to 0.9. Thus, ADHD appears to be more
heritable than unipolar depression or schizophrenia
and nearly as heritable as bipolar mood disorder.
Recent molecular genetic work has featured suscept-
ibility genes involved in dopamine neurotransmis-
sion, specifically the gene coding for the fourth
subtype of dopamine receptors (DR4R) and the gene

coding for the dopamine transporter (DAT1). Such
risk factors as low birth weight and maternal tobacco
use or use of alcohol or illicit substances may also
predispose to ADHD. Although no direct evidence
exists to implicate faulty parenting as a primary cause
of ADHD, overly permissive, overly harsh, and/or
inconsistent parenting may exacerbate temperamen-
tal traits (high activity level and intensity) related to
ADHD, and such parenting is clearly implicated in
the development of aggressive and antisocial beha-
vior that frequently accompanies ADHD.
NEUROBIOLOGICAL UNDERPINNINGS
At the level of neuroanatomy, small but reliable
differences between ADHD and control samples have
been found for total brain volume and, more speci-
fically, for the caudate, corpus callosum, and right
frontal regions. With regard to brain activity, positron
emission tomography and functional magnetic reso-
nance imaging investigations have implicated pre-
frontal, premotor, and frontal–striatal circuits in the
pathophysiology of ADHD. Dopamine is the neuro-
transmitter system most heavily implicated in extant
research, although interconnections with other neu-
rotransmitter systems are clearly operative.
The core mechanism responsible for ADHD
symtomatology is a point of contention. Competing
theories implicate deficits in sustained attention,
faulty inhibitory control, problems in frontally
mediated executive functions (e.g., planning, work-
ing memory, and set shifting), erratic response to
rewards, problems in regulating arousal, and moti-
vational deficits. Among these, deficits in response
inhibition and executive functions have generated the
most research in recent years. A continuing challenge
is the specification of underlying mechanisms and
processes responsible for the varied and impairing
symptomatology displayed in persons with ADHD.
PREVENTION AND INTERVENTION
Currently, prevention of ADHD is practically im-
possible because key risk and etiological factors are
either not amenable to influence (e.g., susceptibility
genes) or have proven difficult to address (e.g., low
birth weight). Only two classes of treatment have
shown consistent empirical support regarding inter-
vention for ADHD: stimulant medications and
behavioral treatment modalities that feature parent
and teacher management training to promote more
consistent environmental cues and rewards. Other
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER 301
approaches, such as dietary interventions or neuro-
feedback, must be considered preliminary because
they lack consistent empirical support.
Once believed to exert a paradoxical response on
individuals with ADHD, stimulants enhance dopa-
minergic transmission and positively influence atten-
tional capacities and inhibitory control across
persons with and without ADHD. Therefore, a
positive response to these medications does not
confirm a diagnosis of ADHD. The benefits of these
agents for the core symptomatology and associated
impairments have been repeatedly shown in carefully
controlled investigations. Positive response rates are
between 70 and 90%. Side effects are usually
transitory and manageable with dose adjustment.
Although stimulants clearly effect symptom control,
their benefits disappear when medication treatment
is terminated. Careful monitoring of stimulant
treatment appears to markedly increase the like-
lihood of clinical benefit.
Behavioral treatments require effort on the part of
parents and teachers to establish consistent, regular
incentives for specified target behavioral, academic,
and social goals for children and adolescents with
ADHD. The benefits of these treatments are estab-
lished, but the effects of behavioral intervention are
typically smaller than those of medications, their use
may be limited in families lacking socioeconomic
resources, and the contingencies must remain in
place for benefits to be maintained. The greatest
likelihood of normalization of symptoms occurs
when well-delivered medications and comprehensive
behavioral programs are used in combination. At the
level of service delivery, however, it appears that only
a minority of children diagnosed with ADHD receive
optimal medication or behavioral treatment. In
addition, concern regarding possible overdiagnosis
and inappropriately high rates of medication treat-
ment in recent years must be balanced with the
realization that ADHD is underdiagnosed and not
treated at all in many sectors of the community.
Public awareness of the reality of ADHD, as well as
enforcement of appropriate standards for accurate
evaluation and careful treatment monitoring related
to ADHD, is crucial.
CONCLUSION
Although the subject of considerable controversy in
recent years, ADHD is a valid psychiatric syndrome
marked by developmentally extreme, cross-situa-
tional, and impairing symptoms in the areas of
302 AUDITORY SYSTEM, CENTRAL
inattention/disorganization and hyperactivity/impul-
sivity. It is highly familial and yields marked
dysfunction in key domains required for develop-
mental competence. In addition, it is a lifelong
condition in many if not most cases. Careful
diagnostic assessment is required to distinguish
ADHD from medical and psychosocial conditions
that mimic its symptoms and to appraise comorbid
diagnoses that may require separate treatment.
Neural substrates include dopaminergic tracts in
frontal–striatal regions that are responsible for
executive functions and regulation of motor output.
Inconsistent and erratic family socialization may
exacerbate the child’s temperamental proclivities.
Effective treatment strategies include pharmacologi-
cal intervention (mainly stimulant medication) and
behavioral consultation with parents and teachers to
aid the development of self-control. Combining these
approaches yields the strongest likelihood of normal-
ization of functioning, but both strategies appear to
require long-lasting application if benefits are to be
maintained. Further specification of precise neuro-
biological underpinnings, validated subtypes, and
more efficacious treatment strategies are contingent
on renewed research efforts into this prevalent and
impairing disorder of childhood onset.
—Stephen P. Hinshaw
See also–Attention; Attentional Mechanisms;
Dyslexia, Developmental; Hyperactivity; Impulse
Control Disorders; Learning Disabilities
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed. American Psychiatric
Press, Washington, DC.
Barkley, R. A. (1997). ADHD and the Nature of Self-Control.
Guilford, New York.
DeGrandpre, R. J., and Hinshaw, S. P. (2000). ADHD: Serious
psychiatric problem or all-American cop out? Cerebrum 2, 12–
38.
Greenhill, L. L., and Osman, B. O. (Eds.) (2000). Ritalin: Theory
and Practice, 2nd ed. Liebert, Larchmont, NY.
Hinshaw, S. P. (1994). Attention Deficits and Hyperactivity in
Children. Sage, Thousand Oaks, CA.
Hinshaw, S. P., Klein, R., and Abikoff, H. B. (2002). ADHD:
Nonpharmacologic treatments and their combination with
medication. In A Guide to Treatments That Work (P. E. Nathan
and J. Gorman, Eds.), 2nd ed. Oxford Univ. Press, New York.
Jensen, P. S., Martin, D., and Cantwell, D. P. (1997). Comorbidity
in ADHD: Implications for research, practice, and DSM-V.
J. Am. Acad. Child Adolesc. Psychiatry 36, 1065–1079.
Mannuzza, S., and Klein, R. (1999). Adolescent and adult
outcomes in attention deficit hyperactivity disorder. In Hand-
book of Disruptive Behavior Disorders (H. C. Quay and A. E.
Hogan, Eds.), pp. 279–294. Guilford, New York.
MTA Cooperative Group (1999). Fourteen-month randomized
clinical trial of treatment strategies for attention deficit
hyperactivity disorder. Moderators and mediators of treatment
response for children with attention deficit hyperactivity
disorder. Arch. Gen. Psychiatry 56, 1073–1096.
National Institutes of Health Consensus Development Statement
(1999). Diagnosis and treatment of attention-deficit-hyperac-
tivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 39, 182–
188.
Tannock, R. (1998). Attention deficit hyperactivity disorder:
Advances in cognitive, neurobiological, and genetic research.
J. Child Psychol. Psychiatry 35, 65–99.
Atypical Facial Pain
see Facial Pain
Auditory System, Central
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MAMMALIAN central auditory system processes
and analyzes sounds that have been transformed by
the ear from airborne complex waves into patterned
neural signals. Research during the 20th century
confirmed that the ear acts like a fast Fourier
transformer by decomposing sounds into fundamen-
tal frequency components of different phases and
amplitudes. The central system does more than just
decode the physical features of sounds encoded by
the ear; it also extracts the biologically most
important features of sounds for the listener.
ASCENDING AUDITORY PATHWAYS
The ascending auditory pathways extend from the
cochlear nucleus complex in the lateral medulla to
the auditory cortex (Fig. 1). Information from the
cochlea is transmitted by spiral ganglion neurons,
whose central axons travel in the auditory nerve
(part of cranial nerve VIII) to terminate in the
cochlear nucleus. Between the cochlear nucleus and
the cortex, there are five other major auditory centers
or nuclei that sequentially receive, process, and
transmit auditory information to higher centers.
These include the superior olivary complex in the
292 ATTENTIONAL MECHANISMS
attentional network). These studies have found
independence between the two systems, the degree
of which appears to depend on the amount of mental
activity required by the primary task.
When required to monitor a stream of auditory
information for sound while simultaneously per-
forming a visual orienting task, parietal patients were
bilaterally slowed in their ability to orient toward the
visual cue. The effect of language task was bilateral
rather than mainly on the side contralateral to the
lesion. This suggests that language tasks may affect
some but not all of the mechanisms involved in the
visual orienting of attention. In another study,
normal subjects performed the visual orienting task
while shadowing an auditory message. The effects of
the language task were most pronounced for the
right visual field cues, suggesting a common later-
alized left hemisphere system. These findings are
consistent with close anatomical links of anterior
cingulate with both posterior parietal and lateral
frontal lobe. Posner and Petersen suggest that there
may be a hierarchy of the attentional system in which
the anterior attentional network may be the control
system that affects both language and spatial
functions and controls the posterior visuospatial
attentional network.
CONCLUSION
Although some of the neural systems underlying
attention have become better understood, the anat-
omy and function of attention, particularly of the
anterior network, require further study. Many
disorders are thought to involve deficits of attention,
including neglect syndrome, attention-deficit disor-
der, schizophrenia, Alzheimer’s disease, and closed-
head injury. The specification of attention in terms of
function and anatomy might help determine the
underlying bases for these disorders.
—Tatjana Novakovic-Agopian
See also–Alertness; Attentional Mechanisms;
Attention-Deficit/Hyperactivity Disorder
(ADHD); Awareness; Concentration; Executive
Function; Memory, Overview
Further Reading
Cohen, R. M., Semple, W. E., Gross, M., et al. (1988). Functional
localization of sustained attention. Neuropsychiatry Neuropsy-
chol. Behav. Neurol., 1, 3–20.
Corbetta, M., Meizin, F. M., Shulman, G. L., et al. (1993). A
PET study of visuospatial attention. J. Neurosci. 13, 1202–
1226.
Goldman-Rakic, P. S. (1988). Topography of cognition: Parallel
distributed networks in primate association cortex. Annu. Rev.
Neurosci. 11, 137–156.
Heilman, K. M., Watson, R. T., and Valenstein, E. (1985). Neglect
and related disorders. In Clinical Neuropsychology (K. M.
Heilman and E. Valenstein, Eds.), pp. 243–293. Oxford Univ.
Press, New York.
Kinomura, S., Larsson, J., Gulyas, B., et al. (1996). Activation by
attention in human reticular formation and thalamic intrala-
minar nuclei. Science 271, 612–615.
LaBerge, D., and Buchsbaum, M. S. (1990). Positron emission
tomographic measurements of pulvinar activity during an
attention task. J. Neurosci. 10, 613–619.
Pardo, J. V., Pardo, P. J., Janer, K. W., et al. (1990). The anterior
cingulate cortex mediates processing selection in the Stroop
attentional conflict paradigm. Proc. Natl. Acad. Sci. USA 87,
256–259.
Petersen, S. E., Fox, P. T., Posner, M. I., et al. (1988). Positron
emission tomographic studies of the cortical anatomy of single
word processing. Nature 331, 585–589.
Posner, M. I., and Petersen, S. E. (1990). The attention system of
the human brain. Annu. Rev. Neurosci. 13, 25–42.
Posner, M. I., and Priesti, D. (1987). Selective attention and
cognitive control. Trends Neurosci. 10, 12–17.
Posner, M. I., and Rorthbart, M. K. (1992). Attentional mechan-
isms and conscious experience. In The Neuropsychology of
Consciousness (D. Milner and M. Rugg, Eds.), pp. 91–111.
Academic Press, London.
Posner, M. I., Petersen, S. E., Fox, P. T., et al. (1988). Localization
of cognitive functions in the human brain. Science 240, 1627–
1631.
Attentional Mechanisms
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
WHAT is attention? ‘‘Everyone knows what attention
is. It is the taking possession of the mind in clear and
vivid form of one out of what seem several
simultaneous objects or trains of thought.’’
William James defined attention 100 years ago,
and the previous quote still illustrates several
important aspects of the field. Attention is heavily
tied with subjective experience. Moreover, James’
effort to deal with both attention to objects and
attention to ‘‘trains of thought’’ is important for a
grasp of current approaches to sensory orienting and
executive control. However, attention in the sense of
orienting to sensory objects can be involuntary and
can occur unconsciously, so attention is not, as the
quote from James implies, precisely the same as being
aware.

It is appropriate for neurologists to think about
attention as an organ system not unlike the familiar
ones of respiration and circulation. Like them,
attention has a distinct anatomy that carries out
basic psychological functions and that can be
influenced by specific brain injuries and states. It is
important to ask what are the operations of attention
and then to examine how the brain incorporates
these operations. This entry covers three major
operations: (i) achieving and maintaining the alert
state, (ii) orienting to sensory objects, and
(iii) selecting among conflicting actions. These
operations are discussed using specific terms to better
understand how attention can be affected by brain
state and injury.
METHODS OF STUDY
The study of attention has greatly expanded as new
methods have become available. In the 1940s and
1950s, reflex models that had existed since antiquity
were supplemented by recognition of complex
central states involved with arousal, such as the
reticular activating system. Lesions of this area could
produce a permanent loss of alertness. In the 1950s,
functional models of information flow in the nervous
system were developed in conjunction with interest
in computer simulation of cognitive processes. In the
1970s, studies using microelectrodes with alert
monkeys showed that the firing rate of cells in
particular brain areas was enhanced when the
monkey attended to a stimulus within the cells’
receptive field. In the 1980s and 1990s, human
neuroimaging studies allowed examination of the
whole brain during tasks involving attention. These
newer methods also improved the utility of more
traditional cognitive, lesion, and electrophysiological
studies. The ability to trace anatomical changes over
time has provided methods for validating and
improving pharmacological and other forms of
therapy.
ATTENTIONAL NETWORKS
Attention can be viewed as a system of anatomical
areas that consists of three more specialized net-
works. These networks carry out the functions of
alerting, orienting, and executive control. We exam-
ine first the functional anatomy of these networks
from human imaging and lesion studies and then
some of the cellular mechanisms involved from
animal studies (Fig. 1).
ATTENTIONAL MECHANISMS 293
Figure 1
Functional anatomy of the attentional networks. The pulvinar,
superior colliculus, superior parietal lobe, and frontal eye fields are
often found active in studies of the orienting network. The anterior
cingulate gyrus is an important part of the executive network.
Right frontal and parietal areas are active when people maintain
the alert state. (See color plate section.)
Functional Anatomy
Alerting involves a change in the internal state in
preparation for perceiving a stimulus. For example,
following presentation of a warning signal there are a
variety of changes in heart rate and brain electrical
activity that serve to inhibit competing activity. The
alert state is critical for optimal performance in tasks
involving higher cognitive functions. Neuroimaging
studies have shown activity in the frontal and
parietal regions, particularly of the right hemisphere,
when people are required to achieve and maintain
the alert state for even a brief period of time. Lesions
of these areas will reduce the ability to maintain
alertness. Right frontal lesions have been shown to
impair the ability to voluntarily sustain attention,
producing more errors over time than are found for
left frontal patients in tasks involving continuous
performance. Right parietal patients show deficits in
maintaining the alert state and difficulties in orient-
ing attention that together produce a profound
neglect in the visual field opposite the lesion.
The orienting network involves the selection of
information from sensory input. Orienting can be
reflexive, such as when a sudden target event directs
attention to its location, or it can be more voluntary,
such as when a person searches the visual field
looking for some target. Orienting often involves
294 ATTENTIONAL MECHANISMS
head and/or eye movements toward the target. This
is overt orienting. However, it is possible to increase
the priority for processing the target by orienting
attention covertly without a change in posture or eye
movements. In experimental studies, orienting has
been manipulated by presenting a cue indicating
where a person should attend. When a valid cue
occurs, the target appears in the location indicated by
the cue. Invalid cues indicate a location to which
attention should be oriented but the target is
subsequently presented elsewhere. There is usually
only a small benefit from knowing the correct
location of the target, but if one orients to the wrong
location there is a much larger cost in the efficiency
of processing the target. These findings reflect the
high efficiency with which a cue (e.g., a luminance
change of motion) can direct attention to a target,
particularly if the person is not engaged in processing
at another location. In a crowded field, large changes
can be made outside the focus of attention, and if
luminance and motion cues are suppressed, the
person will simply not be aware of even gross
changes.
It is important to distinguish between those brain
areas that are influenced by acts of orienting (sites)
and those that are the sources of the orienting
network. Orienting has been shown to increase
neuronal activity in most sensory systems. For
example, in the visual system orienting can influence
primary visual cortex or a variety of extrastriate
visual areas, where the computations related to the
target are performed. Orienting to target motion
influences area MT/V5, whereas orienting to target
color will influence area V4. This principle of
activation of brain areas also extends to higher level
visual input; for example, attention to faces modifies
activity in the face-sensitive area of the fusiform
gyrus.
The orienting network that is the source of these
changes has been shown to involve several cortical
areas, including parts of the superior and inferior
parietal lobe, frontal eye fields, and such subcortical
areas as the superior colliculus of the midbrain and
the pulvinar and reticular nucleus of the thalamus.
These areas are thought to carry out different mental
operations involved in the act of orienting. For
example, studies using event-related magnetic reso-
nance imaging have indicated that the superior
parietal lobe is involved in voluntary shifts of
attention required in reorienting covertly to a new
location. The temporal–parietal junction is active
when a target occurs at a novel location (i.e., other
than the one cued). The pulvinar seems to be related
more to connecting the orienting network to sensory
areas that contain information about the target
features, such as color, motion, or form. The exact
functions of many of these areas are under active
investigation.
Stroke patients with damage to the temporopar-
ietal junction may neglect locations in the field
opposite the lesion. If their attention is oriented to
the stimulus on the side of the lesion, these patients
show a delay in reacting to events on the side
opposite the lesion. The temporoparietal junction
appears to be associated with the disengagement
from a cue to respond to a target in the opposite side.
In clinical studies, the right parietal lobe was more
likely to lead to neglect, possibly because of the
asymmetrical organization of the orienting network
and also because damage to the right hemisphere has
greater influence on the alerting network. Patients
with bilateral lesions of the parietal lobes show
deficits in dealing with two objects simultaneously.
The two parietal lobes seem to be coordinated
through the corpus callosum since lesions of this
structure allow simultaneous search of both visual
fields, suggesting that orienting of the two hemi-
spheres is now disconnected.
Results of studies examining reversible lesions in
healthy volunteers are often congruent with deficits
seen in clinical populations. These transient lesions
are achieved by applying a brief transcranial
magnetic stimulation (TMS) to the scalp areas
overlaying the relevant cortical location. Application
of TMS pulses to the parietal cortex has shown that
visual extinction (i.e., impaired detection of contral-
ateral stimulus during bilateral presentation) can be
produced in normal subjects, similar to the clinical
manifestation seen in neglect patients.
Executive control of attention involves more
complex mental operations in monitoring and resol-
ving conflict between computations occurring in
different brain areas. Executive control is needed
most in situations that involve planning or decision
making, error detection, novel or not well-learned
responses, conditions judged to be difficult or
dangerous, and in overcoming habitual actions.
Functional magnetic resonance imaging (fMRI)
studies have been conducted using either the Stroop
task or variants of it. The Stroop task involves
responding to the ink color (e.g., red) used to print a
word when the letters spell a competing color name
(e.g., ‘‘blue’’). In another frequently used conflict
task, a person is required to respond to a central

stimulus (e.g., an arrow pointing left) when it is
surrounded by flankers that either point in the same
direction (congruent) or in the opposite direction
(incongruent). Neuroimaging studies show that these
conflict tasks activate midline frontal areas (anterior
cingulate), lateral prefrontal cortex, and basal gang-
lia. These experimental tasks provide a means of
fractionating the functional contributions of areas
within the executive attention network. One event-
related fMRI study showed that lateral areas were
responsive to cues indicating whether the task would
involve naming the word or the ink color. The cue
did not activate the cingulate. When the task
involved naming the ink color, the cingulate was
more active on incongruent than congruent trials.
This result could reflect the general finding that
lateral areas are involved in representing specific
information over time (working memory), whereas
medial areas are more related to the detection of
conflict.
Large lesions of the anterior cingulate produce
deficits of voluntary behavior. Patients with akinetic
mutism can orient to external stimuli and follow
people with their eyes, but other voluntary activity is
not initiated. Nonetheless, patients often recover
from lesions of the anterior cingulate, suggesting that
other areas may also mediate executive attention.
Lesions of the medial frontal area may produce more
permanent loss of future planning and appropriate
social behavior. Early childhood damage in this area
can produce permanent deficits in decision-making
tasks that require responses based on future plan-
ning. Patients with traumatic brain injury that
involves frontal areas frequently show specific
deficits in executive attention and working memory.
Transmitters
Pharmacological studies of alert monkeys have
related each of the networks with specific chemical
neuromodulators. Alerting is thought to involve the
cortical distribution of the brain’s norepinephrine
(NE) system arising in the locus coeruleus of the
midbrain. Drugs such as clonidine and guanfacine
that act to block NE reduce or eliminate the normal
effect of warning signals on performance. These
drugs do not influence the efficiency of orienting,
however.
Cholinergic systems arising in the basal forebrain
play an important role in orienting. Lesions of the
basal forebrain in monkeys interfere with reorienting
attention. However, it does not appear that the site of
this effect is the basal forebrain. Instead, it appears to
ATTENTIONAL MECHANISMS 295
involve the parietal lobe. Injections of scopolamine
directly into the lateral parietal area of monkeys, a
brain area containing cells that are influenced by cues
about spatial location, have been shown to have a
major effect on the ability to shift attention to a
target. Systemic injections of scopolamine have a
smaller effect on covert orienting of attention than
do local injections in the parietal area. Cholinergic
drugs do not affect the ability of a warning signal to
improve performance; thus, there appears to be
double dissociation that relates NE to the alerting
network and acetylcholine to the orienting network.
Patients with Alzheimer’s disease are known to
have a strong degeneration of the basal forebrain
cholinergic system (nucleus basalis). In accordance
with this finding, early in the disease patients show a
reduction in brain activity in the superior parietal
lobe and a correlated difficulty in orienting of
attention. In fact, orienting difficulties are often one
of the earliest signs of the disorder. Recently, normal
persons who had one or two copies of the e4 allele of
the apolipoprotein E gene were shown to have
increased difficulty in orienting attention and in
adjusting the spatial scale of attention, but they had
no difficulty in maintaining the alert state.
The anterior cingulate and lateral frontal cortex
are target areas of the ventral tegmental dopamine
system. The association of the anterior cingulate with
high-level attentional control may seem rather odd
because this is clearly a phylogenetically old area of
the brain. However, there are reports of large
projection cells that are unique to layer 5 of the
anterior cingulate and that seem to have evolved
recently because they are found only in humans and
higher primates. Moreover, these cells also undergo
late development, in accordance with the finding that
executive control systems develop strongly during
later childhood.
All of the dopamine receptors are expressed in
layer 5 of the cingulate. Several replicated human
genetic studies have demonstrated an association of
one of the dopamine receptor genes D4 (DRD4)
located on chromosome 11p15.5 and an attentional
disorder common in childhood (attention-deficit/
hyperactivity disorder; ADHD). Approximately 50%
of ADHD cases have a seven-repeat allele, whereas
only approximately 20% of ethnically matched
control subjects have a seven-repeat allele. However,
a direct comparison of children with ADHD who
either have or do not have the seven-repeat allele
suggests that attentional abnormalities are more
common in those children without the allele. It
296 ATTENTIONAL MECHANISMS
appears likely that there are multiple pathways to
ADHD, some that involve attentional networks and
others that may involve behavioral but not atten-
tional deficits. Adult subjects who suffer from
ADHD have been studied in conflict tasks. Although
they perform only slightly worse than normal
persons, they appear to activate an entirely different
network of brain areas than do normal persons.
Whereas normals activate the anterior cingulate, the
ADHD adults seem to rely on the anterior insula,
which is usually associated with responses in more
routine tasks not involving conflict.
ATTENTIONAL STATES
Alert State
Diurnal reductions in attention normally occur
during the hours of maximum sleepiness, 2:00–7:00
am, when body temperature is at a nadir, and
enhanced performance is usually seen in the evening
when body temperature peaks. During sleep, volun-
tary attention is often considered to be markedly
attenuated or absent. However, there is evidence that
certain attentional as well as preattentional mechan-
isms remain intact. Dreaming is usually divorced
from a sense of controlled awareness, but purported
accounts of lucid dreaming (i.e., dreaming while
knowing that one is dreaming) suggest that some
control mechanisms may be available during sleep.
Other common anecdotes include the incorporation
of ambient sound into the dream content as well as
the idea of sensitivity to one’s own name or child’s
cry.
One way to investigate information processing in
sleep involves recordings of electrical signals from
the brain (electroencephalograph, EEG). By aver-
aging the brain’s event related potentials (ERPs) to
stimuli, it is possible to examine the processing
capability of the sleeping brain.
One component frequently examined is the mis-
match negativity (MMN). The MMN is an electro-
physiological manifestation of involuntary
preattentive processing in response to auditory odd-
ball stimuli. In a typical MMN paradigm, a
‘‘deviant’’ auditory stimulus is sporadically distrib-
uted within a sequence of ‘‘standard’’ auditory
stimuli. The MMN is evident in the difference
waveform resulting from the subtraction of the
ERP elicited by the standard stimulus from that
elicited by the novel auditory stimuli (the deviants).
The difference waveform, occurring even without
attention, normally peaks between 100 and 250 msec
from the onset of the deviant event (depending on the
dimension of deviance and its magnitude). The
MMN is presumably associated with a mechanism
that compares the current auditory input to the
memory traces formed by previous auditory inputs
and signals the occurrence of a mismatch.
In adults, MMN tends to decline during drowsi-
ness; whether it persists into adult human sleep is still
debated. However, other EEG components do reflect
the brain’s reaction to novelty. Although in the
developed brain active midbrain inhibition blocks
cortical activity, there is reason to believe that the
sleeping infant brain is not as capable of blocking
and inhibiting information efficiently. Indeed, MMN
is obtainable from newborns and young infants.
Another special cognitive state sometimes con-
fused with sleep is hypnosis. Hypnosis has been used
clinically for hundreds of years and is primarily a
phenomenon involving attentive receptive concentra-
tion. Clinicians practicing hypnosis suggest that
when one is in a hypnotic state, attentional and
perceptual changes may occur that would not have
occurred had one been in a more usual state of
awareness. In a responsive subject, hypnotic percep-
tual alteration is accompanied by reproducible
changes in brain action. For example, the activity
of the anterior cingulate to painful stimuli can be
modulated by hypnotic suggestion. Most children are
highly hypnotizable and are more easily induced
into the hypnotic state. The overall data on
hypnotism support the claim that it is a psychological
state with distinct neural correlates and not just a
consequence of role-playing or social compliance.
Neuroimaging data suggest that hypnosis can mod-
ulate visual system responses to colored stimuli.
There is also preliminary evidence that hypnosis can
change the semantic interference from a word when
subjects are required to respond to its ink color
(Stroop effect).
Individual Differences
Normal individuals differ in the efficiency of each of
the attentional networks. One way of exploring these
differences is by use of an Attention Network Test
(ANT) designed to evaluate alerting, orienting, and
executive attention. This test can be performed by
children, adults, and animals because it does not rely
on language. Efficiency of the alerting network is
examined by changes in reaction time (RT) resulting
from a warning signal. Efficiency of orienting is
examined by changes in RT that accompany cues

indicating where the target will occur. The efficiency
of the executive network is examined by requiring
the subject to respond by pressing a key indicating
the direction of a central arrow surrounded by
congruent, incongruent, or neutral flankers. A study
of 40 normal adult subjects showed that the ANT
produces reliable single-subject estimates of alerting,
orienting, and executive function and also that the
efficiency of these three networks is uncorrelated.
This procedure may prove to be convenient and
useful in evaluating attentional abnormalities asso-
ciated with cases of brain injury, stroke, schizophre-
nia, and attention-deficit disorder, and may provide a
useful repeated measure in studies designed to
improve attention in patients and developmental
populations.
Self-report scales have also been used to study
individual differences in attentional components.
One higher level factor called effortful control
involves the ability to voluntarily shift and focus
attention and inhibit non-attended information.
Effortful control as reported by the subject seems
to relate most closely to the executive attention
network. Twin studies have suggested that the
difference between people in effortful control is
highly heritable. People high in effortful control also
report themselves as relatively low in negative
emotion. This is one source of evidence supporting
the idea that executive attention is important for
control of both cognition and emotion.
Development
Dramatic changes occur in the brain during the early
life of the person. In the first few years of life, there is
a great increase in synaptic density, which becomes
much higher than adult levels and is pruned back
later in development. These cellular changes are
accompanied by changes in the attentional control
networks discussed previously.
During the first year of life, there is a strong
development of the orienting network. The abilities
to control fixation, to disengage for a visual stimulus,
and to move attention in anticipation of a new event
all undergo rapid development. These events appear
to relate to maturation of basal ganglia and parietal
networks during this period.
Later, there is a dramatic development of the
ability to control conflict, which appears to involve
the executive attention network. Tasks that involve
conflict between stimulus elements in inhibiting
predominant responses undergo strong development
between 2 and 4 years of age. These changes affect
ATTENTIONAL MECHANISMS 297
the child’s everyday life activity, as is evident to
caregivers. One way to demonstrate this is to ask
parents to report on their children’s temperament by
using behaviorally anchored-based questions. For
example, the parents are asked such questions as: (i)
When engaged in play with his or her favorite toy,
how often did your child play for 5 minutes during
the last 2 weeks? and (ii) When told ‘‘no,’’ how often
did your child stop the activity quickly? The scales
can then be combined into a factor called effortful
control. This score measures individual differences in
the ability of children to regulate their behavior as
observed by the parents.
Children who respond to conflict tasks with high
accuracy also receive higher ratings from parents in
effortful control. These children also show better
ability to delay gratification in tasks designed to
probe this ability. They also show higher empathy for
others and are less likely to cheat when given the
opportunity to do so. These results suggest that
toddlers are acquiring a brain system that serves to
regulate their behavior in important ways in their
everyday lives.
Pathology
The executive attention network is particularly
vulnerable to the effects of both frontal lesions and
various forms of mental illness. This vulnerability
results in a neuropsychological condition called
dysexecutive syndrome, in which behavior is often
unregulated and includes inappropriate responses.
Performance on tests involving the ability to make
decisions guided by long-term consequences and the
ability to inhibit inappropriate responses are im-
paired following closed head injury, stroke, or
degenerative disorders of frontal structures.
Schizophrenics exhibit difficulty in controlling
their thoughts and behaviors consistent with the
dysexecutive syndrome. Neuroimaging data indicate
that the neural abnormality in schizophrenia starts in
the left globus pallidus and gradually produces a
dysregulation of both the anterior cingulate and the
dorsolateral prefrontal cortex. There is a vast body
of research suggesting that these structures are
involved in the control processes of executive
attention. Indeed, when healthy volunteers engage
in a verbal auditory shadowing task known to
challenge executive attention capacities, an orienting
abnormality is evident that is similar to one observed
in schizophrenic patients. In acute schizophrenia, a
marked loss of frontotemporal language is found.
These factors make it plausible that poor regulation
298 ATTENTIONAL MECHANISMS
of executive attention mechanisms is an important
part of schizophrenia. At autopsy, the brains of
schizophrenics appear to contain very specific ab-
normalities of the cingulate, consonant with the
importance of this region in the disorder. It is
important to keep in mind that executive attention
may be involved in the initiation of attentional shifts,
and thus impairment of executive attention could
influence parietal regions, resulting in orienting
deficits.
REHABILITATION
Because attention is very vulnerable to effects of
brain damage, is closely related to issues of volition,
and can influence many other cognitive processes, it
should be an important candidate for therapy. Three
kinds of therapy have been applied to attentional
networks: pharmacological, removing competition,
and practice. There has been relatively little effort,
however, to ascertain the effectiveness and mechan-
ism of each of these therapies.
Pharmacology
As described previously, each of the three networks
has strong connections to a particular neurochemical
modulator. For example, lesions and pharmacologi-
cal studies suggest that orienting of attention appears
to be influenced by the brain cholinergic system.
There are reports that nicotine, whether adminis-
tered by smoking or directly, can improve attention.
The close relation between smoking and schizophre-
nia has sometimes been considered to be a form of
self-medication. Stimulant drugs such as methylphe-
nidate that influence both norepinephrine and
dopamine transmission have been shown to be
successful in reducing the symptoms of attention
deficit disorder.
Competition
Brain injuries often result in imbalances between the
two hemispheres because they produce lesions in one
hemisphere. One striking example occurs in neglect
of the spatial world discussed previously. As a
consequence of the lesion, perception of a stimulus
on the side opposite the lesion is impaired, but
perception of a stimulus on the side of the lesion may
be enhanced above normal levels. Evidence for this
supranormal sensitivity to stimuli on the side of the
lesion comes from studies in which neglect patients
outperformed control subjects in the detection of an
ipsilesional stimulus.
The idea of hemispheric competition has been
applied to rehabilitation studies, with the notion that
inhibitory competition from undamaged circuits may
impede recovery of function. In one study, patients
with neglect of the left side of space due to right
parietal lesions had a patch placed over the right eye.
Patching improved performance, presumably by
increasing the influence of information in the
neglected field on the right superior colliculus.
Although the procedure did reduce neglect, recovery
was incomplete, was short lived, and did not
generalize to other tasks.
In other rehabilitation studies, patients with right
parietal lesions ameliorated their neglect by moving
their left hand in the left hemispace. The benefit
lasted several weeks after training and generalized to
everyday function. It is important to note that
bilateral activation abolished the benefit, suggesting
that competition from the healthy hemisphere had
detrimental effects on the rehabilitation of the
lesioned hemisphere. The mechanism by which using
a contralesional limb ameliorates neglect remains
unknown.
Practice
It is now known that rehabilitation of the damaged
brain can foster reconnection of damaged neural
circuits. Animal models have suggested that specific
practice may be important in fostering changes in the
damaged area. Neuroimaging studies suggest several
possible mechanisms, such as strong activation of
tissue surrounding the damage, involvement of the
same brain area in the opposite hemisphere, or the
use of circuitry not previously involved in the task.
Reports of each of these changes and of the role of
experience have supported the use of therapies that
involve practice in performing the damaged function.
A number of therapeutic methods involve practice
with attention. These have often been used in cases of
traumatic brain injury, in which the patients may be
quite young and face debilitating damage to atten-
tional networks. For example, attention process
therapy involves practice with auditory tapes and
includes exercises designed to aid alertness, improve
orienting, and allow better selection of relevant
information. Other methods may be much more
general—for example, providing knowledge about
the brain or training in the management of memory
or keeping goals in mind while carrying out a
practical task. There is evidence that these improve
the specific function practiced, but the extent of

generalization to related tasks and to everyday life
activities is often limited.
Functional imaging seems to provide an impor-
tant tool for evaluating therapeutic methods.
Imaging provides an opportunity to see whether
and exactly how the therapy influences specific
circuits. This provides an intermediate level of
analysis between the therapy and actual behavior
that may allow a better opportunity to evaluate the
effects of various forms of therapy and improve
their design.
SUMMARY
The advent of neuroimaging of the human brain has
allowed attention to be viewed as an organ system
with its own specific anatomy. This approach makes
possible detailed examination of the cellular, synap-
tic, and genetic bases of normal attentional net-
works. It serves to link attention to the study of brain
states that change with the level of arousal from
wake to deep sleep and with development from
infancy to adulthood. This approach provides a basis
for considering the many pathologies of attention
due to insults to the adult brain or developmental
difficulties.
—Jin Fan, Amir Raz, and Michael I. Posner
See also–Alertness; Attention; Attention-Deficit/
Hyperactivity Disorder (ADHD); Dreaming;
Hypnotics; Sleep, Overview; Wakefulness
Further Reading
Desimone, R., and Duncan, J. (1995). Neural mechanisms of
selective attention. Annu. Rev. Neurosci. 18, 193–222.
Mack, A., and Rock, I. (1998). Inattentional Blindness. MIT Press,
Cambridge, MA.
Marrocco, R. T., and Davidson, M. C. (1998). Neurochemistry of
attention. In The Attentive Brain (R. Parasuraman, Ed.). MIT
Press, Cambridge, MA.
Posner, M. I., and DiGirolamo, G. J. (2000). Cognitive
neuroscience: Origins and prospects. Psychol. Bull. 126, 873–
889.
Posner, M. I., and Petersen, S. E. (1990). The attention system of
the human brain. Annu. Rev. Neurosci. 13, 25–42.
Posner, M. I., and Raichle, M. E. (1994). Images of Mind.
Scientific American Library, New York.
Robertson, I. H., and Murre, J. M. J. (1999). Rehabilitation of
brain damage: Brain plasticity and principles of guided
recovery. Pyschol. Bull. 125, 544–575.
Ruff, H. A., and Rothbart, M. K. (1996). Attention in Early
Development: Themes and Variations. Oxford Univ. Press, New
York.
Toga, A. W., and Mazziotta, J. C. (Eds.) (1996). Brain Mapping:
The Methods. Academic Press, New York.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER 299
Attention-Deficit/
Hyperactivity Disorder (ADHD)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)
is a syndrome of childhood constituting developmen-
tally inappropriate, impairing, and cross-situational
manifestations of inattention/disorganization, impul-
sivity, and motoric overactivity that cannot be better
accounted for by known neurological disease or
injury or by environmental trauma or deprivation.
Since the advent of compulsory education in the 19th
century, certain children’s noteworthy problems of
focusing attention and refraining from extraneous
and disorganized motor behavior have become
salient to society. During much of the 20th century,
such appellations as minimal brain damage, minimal
brain dysfunction, and hyperkinesis or hyperactivity
were invoked as diagnostic terms to describe such
deficits and problems. In 1980, the terminology
shifted to attention deficit disorder, consistent with
research pointing to problems in sustained attention
and maintenance of arousal as the underlying
deficits. The current nosological term, ADHD, as
used in the American Psychiatric Association’s
Diagnostic and Statistical Manual of Mental Dis-
orders, fourth edition, reflects the belief that diffi-
culties in both attentional processing and
hyperactive/impulsive behavior characterize most
individuals who meet criteria for this diagnostic
category. Research on the genetics, neurobiological
underpinnings, and psychosocial correlates of
ADHD has mushroomed in the past two decades.
ADHD received much attention in the latter
part of the 20th century as scientific, clinical, and
public awareness of this condition surged and as
prescription rates for psychotropic medications
(particularly stimulants) steadily increased. On one
side are critics who contend that ADHD is a
convenient psychiatric label used by society (i) to
‘‘medicalize’’ children’s restlessness and inattention,
which might be better explained by dysfunctional
families, faulty schools, or societal pressures for
academic success, and (ii) to legitimize pharma-
cological treatment for such problems. On the other
side are scientists and clinicians who assert that
ADHD is a real condition, with diagnostic validity
and underlying neurobiological reality, for which
302 AUDITORY SYSTEM, CENTRAL
inattention/disorganization and hyperactivity/impul-
sivity. It is highly familial and yields marked
dysfunction in key domains required for develop-
mental competence. In addition, it is a lifelong
condition in many if not most cases. Careful
diagnostic assessment is required to distinguish
ADHD from medical and psychosocial conditions
that mimic its symptoms and to appraise comorbid
diagnoses that may require separate treatment.
Neural substrates include dopaminergic tracts in
frontal–striatal regions that are responsible for
executive functions and regulation of motor output.
Inconsistent and erratic family socialization may
exacerbate the child’s temperamental proclivities.
Effective treatment strategies include pharmacologi-
cal intervention (mainly stimulant medication) and
behavioral consultation with parents and teachers to
aid the development of self-control. Combining these
approaches yields the strongest likelihood of normal-
ization of functioning, but both strategies appear to
require long-lasting application if benefits are to be
maintained. Further specification of precise neuro-
biological underpinnings, validated subtypes, and
more efficacious treatment strategies are contingent
on renewed research efforts into this prevalent and
impairing disorder of childhood onset.
—Stephen P. Hinshaw
See also–Attention; Attentional Mechanisms;
Dyslexia, Developmental; Hyperactivity; Impulse
Control Disorders; Learning Disabilities
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed. American Psychiatric
Press, Washington, DC.
Barkley, R. A. (1997). ADHD and the Nature of Self-Control.
Guilford, New York.
DeGrandpre, R. J., and Hinshaw, S. P. (2000). ADHD: Serious
psychiatric problem or all-American cop out? Cerebrum 2, 12–
38.
Greenhill, L. L., and Osman, B. O. (Eds.) (2000). Ritalin: Theory
and Practice, 2nd ed. Liebert, Larchmont, NY.
Hinshaw, S. P. (1994). Attention Deficits and Hyperactivity in
Children. Sage, Thousand Oaks, CA.
Hinshaw, S. P., Klein, R., and Abikoff, H. B. (2002). ADHD:
Nonpharmacologic treatments and their combination with
medication. In A Guide to Treatments That Work (P. E. Nathan
and J. Gorman, Eds.), 2nd ed. Oxford Univ. Press, New York.
Jensen, P. S., Martin, D., and Cantwell, D. P. (1997). Comorbidity
in ADHD: Implications for research, practice, and DSM-V.
J. Am. Acad. Child Adolesc. Psychiatry 36, 1065–1079.
Mannuzza, S., and Klein, R. (1999). Adolescent and adult
outcomes in attention deficit hyperactivity disorder. In Hand-
book of Disruptive Behavior Disorders (H. C. Quay and A. E.
Hogan, Eds.), pp. 279–294. Guilford, New York.
MTA Cooperative Group (1999). Fourteen-month randomized
clinical trial of treatment strategies for attention deficit
hyperactivity disorder. Moderators and mediators of treatment
response for children with attention deficit hyperactivity
disorder. Arch. Gen. Psychiatry 56, 1073–1096.
National Institutes of Health Consensus Development Statement
(1999). Diagnosis and treatment of attention-deficit-hyperac-
tivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 39, 182–
188.
Tannock, R. (1998). Attention deficit hyperactivity disorder:
Advances in cognitive, neurobiological, and genetic research.
J. Child Psychol. Psychiatry 35, 65–99.
Atypical Facial Pain
see Facial Pain
Auditory System, Central
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MAMMALIAN central auditory system processes
and analyzes sounds that have been transformed by
the ear from airborne complex waves into patterned
neural signals. Research during the 20th century
confirmed that the ear acts like a fast Fourier
transformer by decomposing sounds into fundamen-
tal frequency components of different phases and
amplitudes. The central system does more than just
decode the physical features of sounds encoded by
the ear; it also extracts the biologically most
important features of sounds for the listener.
ASCENDING AUDITORY PATHWAYS
The ascending auditory pathways extend from the
cochlear nucleus complex in the lateral medulla to
the auditory cortex (Fig. 1). Information from the
cochlea is transmitted by spiral ganglion neurons,
whose central axons travel in the auditory nerve
(part of cranial nerve VIII) to terminate in the
cochlear nucleus. Between the cochlear nucleus and
the cortex, there are five other major auditory centers
or nuclei that sequentially receive, process, and
transmit auditory information to higher centers.
These include the superior olivary complex in the

Figure 1
Schematic of ascending central auditory system pathways. The
cochlear nucleus (CN) receives input from the ipsilateral cochlea
and projects primarily to the contralateral side of the brain.
Smaller ipsilateral and commissural projections establish binaural
input to nuclei above the CN. Binaural connections important for
sound localization occur in the superior olivary complex (SOC).
All auditory information ascends through the brainstem in parallel
pathways to the inferior colliculus (IC) before transmission via the
medial geniculate body to auditory cortex. For these higher
auditory centers, lemniscal pathways connect core regions with
high tonotopicity, whereas nonlemniscal pathways connect belt
regions (shaded) with more diffuse tonotopicity.
medulla (the pons in humans), the nuclei of the
lateral lemniscus in the pons, the inferior colliculus in
the midbrain, and the medial geniculate body in the
thalamus. The predominant projection from each
cochlear nucleus is to contralateral brainstem nuclei,
but a smaller projection remains ipsilateral. Conse-
quently, higher auditory centers contain mostly
binaural cells that receive input from both ears.
Ordered patterns of divergence and convergence in
the ascending pathways further ensure the transmis-
sion of auditory information from both cochleae to
the auditory centers above the cochlear nucleus.
Postsynaptic cochlear nucleus neurons project di-
rectly or indirectly to higher brainstem auditory
AUDITORY SYSTEM, CENTRAL 303
centers via three pathways—the ventral, the dorsal,
and the intermediate acoustic striae—establishing
multiple channels of auditory information flow.
Ascending axons from the superior olivary complex
merge with both crossed and uncrossed axons from
the cochlear nuclei to form the lateral lemniscus, the
major pathway to the inferior colliculus. Consider-
able auditory information is also relayed across the
midline at the level of the nuclei of the lateral
lemniscus via Probst’s commissure and in the
midbrain via the commissure of the inferior collicu-
lus. Thus, there is extensive bilateral representation
of both cochleae in the auditory brainstem nuclei.
Consequently, unilateral lesions of the auditory
pathways produce a unilateral deafness only if they
are located within or peripheral to the cochlear
nuclei.
A representation of the ipsilateral cochlea is
established in each cochlear nucleus by the ordered
pattern of termination of auditory nerve fibers in
each of the three subdivisions of the nucleus (Fig. 2).
After entering the nucleus, the fibers bifurcate to send
an ascending branch to the anteroventral subdivision
and a descending branch that goes first to the
Figure 2
Schematic of the cochlear nucleus complex. After entering the
nucleus, afferent nerve fibers branch and then terminate in an
orderly pattern in each of the three subdivisions to establish a
functional representation of the cochlea. High-frequency fibers
from the base of the cochlea branch more medially than do low-
frequency fibers from the apex. The tonotopic axis in the nucleus is
thus oriented perpendicular to the course of the fibers, with low
frequencies represented more laterally. Tonotopic organization is
found at all levels of the auditory neuraxis. AVCN, anteroventral
cochlear nucleus; DCN, dorsal cochlear nucleus; PVCN,
posteroventral cochlear nucleus.
304 AUDITORY SYSTEM, CENTRAL
posteroventral and then to the dorsal subdivision.
Fibers carrying low-frequency information from the
apex of the cochlea bifurcate soon after entering the
cochlear nucleus, whereas fibers carrying high-
frequency information from the base of the cochlea
bifurcate more dorsomedial in the nucleus. Conse-
quently, postsynaptic neurons with the same char-
acteristic frequency (i.e., the frequency to which they
respond best) form ‘‘isofrequency’’ sheets or laminae
within each subdivision that are oriented perpendi-
cular to the tonotopic axis. The cochleotopic
topographical distribution of auditory nerve termi-
nation thus imparts a functional tonotopic organiza-
tion in the cochlear nucleus. Tonotopy is a general
organizational principle maintained at all levels of
the central auditory pathway.
Auditory nuclei in the ascending pathways do
more than relay auditory information from the
cochlear nucleus to the cortex; they also perform a
sequential integration and transformation of audi-
tory signals being conveyed in multiple parallel
channels. The processing that occurs at one level is
not simply passed on unmodified to neurons in
higher centers but is modified at multiple sites. The
patterns of divergence and convergence throughout
the ascending system provide a basis for this
hierarchical and parallel processing. The transforma-
tion of auditory signals at each nucleus in the
ascending pathways, however, is complex and poorly
understood. Consequently, it has been difficult to
assign a unique role in auditory processing to a
particular nucleus. An exception is the nuclei in the
superior olivary complex (SOC) that play an
important role in sound localization.
The SOC consists of two large nuclei, the medial
superior olive (MSO) and lateral superior olive
(LSO), surrounded by a number of smaller perioli-
vary nuclei. Many ventral acoustic stria fibers cross
in the trapezoid body to innervate the contralateral
SOC; a smaller number terminate in the ipsilateral
SOC. The first binaural cells are found in the SOC.
The bilateral input to cells in the SOC is of particular
importance because it conveys differences in the
input from each ear that can be used as cues for
binaural sound localization. Interaural time differ-
ences (ITDs) occur because sound reaches the ear
closest to the source first. Interaural level differences
(ILDs) result when the head forms a ‘‘sound
shadow,’’ reducing the intensity of the sound at the
ear farther from the source. Both ITDs and ILDs are
good cues for sound localization because they vary
with sound source azimuth. Thus, MSO neurons
process ITDs and LSO neurons process ILDs to
determine the azimuthal position of sound sources.
Because of the physical properties of sound, however,
ITDs are useful for sounds at frequencies lower than
approximately 2 kHz and ILDs are significantly large
only at high frequencies. Predictably, the tonotopic
organization of the MSO is biased toward neurons
with low characteristic frequencies, and the LSO is
biased toward neurons of high characteristic fre-
quency.
The auditory pathways from the midbrain to the
cortex can be classified by degree of tonotopic
organization. The inferior colliculus, medial genicu-
late body, and auditory cortex can be categorized as
‘‘core’’ and ‘‘belt’’ subdivisions that have clear and
less obvious tonotopic organization, respectively
(Fig. 1). The highly tonotopic ‘‘lemniscal’’ pathways
connect the core subdivisions, which include the
central nucleus of the inferior colliculus, the ventral
division of the medial geniculate body, and primary
auditory cortex (corresponding to Brodmann areas
41 and 42 on Heschl’s gyri in the superior temporal
lobe). The ‘‘nonlemniscal’’ pathways connect the belt
regions: the pericentral nuclei and tegmentum of the
inferior colliculus, the dorsal and medial divisions of
the medial geniculate body, and auditory cortical
areas that include some primary fields as well as
neighboring nonprimary ‘‘association’’ areas. The
core subdivisions are believed to process specific
auditory information with high fidelity, whereas the
belt regions process more diffuse auditory informa-
tion as well as some nonauditory sensory informa-
tion. In both types of pathways, the projections are
primarily ipsilateral from the inferior colliculus to
the medial geniculate body via the brachium of the
inferior colliculus and exclusively ipsilateral from the
medial geniculate body to cortex via the auditory
radiations.
Certain aspects of the organization of the auditory
cortex deserve mention. First, cortical fields are
connected with each other and their counterparts in
the opposite hemisphere by highly ordered cortico-
cortical connections. Second, cortical neurons are
arranged in columns that extend, perpendicular to
the pial surface, through all six cortical layers.
Neurons within a column have similar response
properties, such as characteristic frequencies and
binaural response interactions. The distribution of
cells and columns along lines of similar frequency
creates a tonotopic map within the cortex that
reflects the topographical arrangement of the audi-
tory projections from the cochlea. In contrast, the
 AUDITORY SYSTEM, PERIPHERAL 305

binaural cortical map is a computational one based
on the spatial and temporal interactions resulting
from stimulation of both ears. For binaural cells, the
input from one ear is dominant and produces an
excitatory response. The response to the opposite ear
can be either excitatory and facilitate the dominant
ear response (summation interaction) or inhibitory
and suppressive of the dominant ear response
(suppressive interaction). Alternating binaural sum-
mation and suppression columns are often organized
along an axis that is more or less perpendicular to the
tonotopic axis in primary auditory cortex. A final
point relates to pathological lesions of the cortex.
Because there is extensive representation of each ear
in both hemispheres, unilateral lesions of the
auditory cortex do not significantly disrupt the
perception of sound frequency. However, unilateral
lesions do affect the ability to localize sounds that lie
in the contralateral hemifield, reflecting the predo-
minantly crossed ascending pathways.
Overview; Vestibulocochlear Nerve (Cranial
Nerve VIII); Visual System, Central
Further Reading
Brown, M. C. (1999). Audition. In Fundamental Neuroscience (M.
J. Zigmond, et al., Eds.), pp. 791–820. Academic Press, San
Diego.
Hudspeth, A. J. (2000). Hearing. In Principles of Neural Science
(E. R. Kandell, J. H. Schwartz, and T. M. Jessell, Eds.), pp. 590–
613. McGraw-Hill, New York.
Rouiller, E. M. (1997). Functional organization of the auditory
pathways. In The Central Auditory System (G. Ehret and R.
Romand, Eds.), pp. 3–96. Oxford Univ. Press, New York.
Webster, D. B. (1992). An overview of mammalian auditory
pathways with an emphasis on humans. In The Mammalian
Auditory Pathway: Neuroanatomy (D. B. Webster, A. N. Popper,
and R. R. Fay, Eds.), pp. 1–22. Springer-Verlag, New York.
Auditory System, Peripheral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

DESCENDING AUDITORY PATHWAYS

THE PERIPHERAL auditory system consists of the
The auditory system also has extensive descending,
external ear, the middle ear, the inner ear or cochlea,
efferent connections that probably interact with the
and the auditory nerve (Fig. 1). Together, they act to
ascending pathways at many levels to provide
collect, filter, and amplify sound, converting it into
complex feedback circuits. For example, the auditory
patterns of neural impulses that are transmitted to the
cortex has recurrent connections with both the
brain for further processing. The auditory system is
medial geniculate and the inferior colliculus, and
the inferior colliculus has connections with the SOC
and the dorsal cochlear nucleus. The SOC has a role
in two efferent reflexes that alter function in the
ear. In the stapedial reflex, a group of periolivary
neurons project to facial nucleus motoneurons
that innervate the stapedial muscle via the facial
nerve to decrease transmissions in the middle ear.
Another group of periolivary neurons project via the
efferent olivocochlear bundle to terminate on outer
hair cells and afferent nerve fibers to increase
thresholds in the cochlea. Although both reflexes
are believed to play a role in protecting the ear from
damage by intense sound, the olivocochlear reflex is
believed to also have an antimasking function to
allow increased responses to particular sounds.
Future research is necessary to determine how the
recurrent systems at all levels alter the processing of
auditory information.
—Ronald K. de Venecia and Steven D. Rauch

See also–Auditory System, Peripheral; Hearing Figure 1

Loss; Neuroophthalmology; Sensory System, Cross section of the human external, middle, and inner ears.
 AUDITORY SYSTEM, PERIPHERAL 305

binaural cortical map is a computational one based
on the spatial and temporal interactions resulting
from stimulation of both ears. For binaural cells, the
input from one ear is dominant and produces an
excitatory response. The response to the opposite ear
can be either excitatory and facilitate the dominant
ear response (summation interaction) or inhibitory
and suppressive of the dominant ear response
(suppressive interaction). Alternating binaural sum-
mation and suppression columns are often organized
along an axis that is more or less perpendicular to the
tonotopic axis in primary auditory cortex. A final
point relates to pathological lesions of the cortex.
Because there is extensive representation of each ear
in both hemispheres, unilateral lesions of the
auditory cortex do not significantly disrupt the
perception of sound frequency. However, unilateral
lesions do affect the ability to localize sounds that lie
in the contralateral hemifield, reflecting the predo-
minantly crossed ascending pathways.
Overview; Vestibulocochlear Nerve (Cranial
Nerve VIII); Visual System, Central
Further Reading
Brown, M. C. (1999). Audition. In Fundamental Neuroscience (M.
J. Zigmond, et al., Eds.), pp. 791–820. Academic Press, San
Diego.
Hudspeth, A. J. (2000). Hearing. In Principles of Neural Science
(E. R. Kandell, J. H. Schwartz, and T. M. Jessell, Eds.), pp. 590–
613. McGraw-Hill, New York.
Rouiller, E. M. (1997). Functional organization of the auditory
pathways. In The Central Auditory System (G. Ehret and R.
Romand, Eds.), pp. 3–96. Oxford Univ. Press, New York.
Webster, D. B. (1992). An overview of mammalian auditory
pathways with an emphasis on humans. In The Mammalian
Auditory Pathway: Neuroanatomy (D. B. Webster, A. N. Popper,
and R. R. Fay, Eds.), pp. 1–22. Springer-Verlag, New York.
Auditory System, Peripheral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

DESCENDING AUDITORY PATHWAYS

THE PERIPHERAL auditory system consists of the
The auditory system also has extensive descending,
external ear, the middle ear, the inner ear or cochlea,
efferent connections that probably interact with the
and the auditory nerve (Fig. 1). Together, they act to
ascending pathways at many levels to provide
collect, filter, and amplify sound, converting it into
complex feedback circuits. For example, the auditory
patterns of neural impulses that are transmitted to the
cortex has recurrent connections with both the
brain for further processing. The auditory system is
medial geniculate and the inferior colliculus, and
the inferior colliculus has connections with the SOC
and the dorsal cochlear nucleus. The SOC has a role
in two efferent reflexes that alter function in the
ear. In the stapedial reflex, a group of periolivary
neurons project to facial nucleus motoneurons
that innervate the stapedial muscle via the facial
nerve to decrease transmissions in the middle ear.
Another group of periolivary neurons project via the
efferent olivocochlear bundle to terminate on outer
hair cells and afferent nerve fibers to increase
thresholds in the cochlea. Although both reflexes
are believed to play a role in protecting the ear from
damage by intense sound, the olivocochlear reflex is
believed to also have an antimasking function to
allow increased responses to particular sounds.
Future research is necessary to determine how the
recurrent systems at all levels alter the processing of
auditory information.
—Ronald K. de Venecia and Steven D. Rauch

See also–Auditory System, Peripheral; Hearing Figure 1

Loss; Neuroophthalmology; Sensory System, Cross section of the human external, middle, and inner ears.
306 AUDITORY SYSTEM, PERIPHERAL
extraordinarily sensitive and operates over wide
frequency and intensity ranges. The human ear can
sense sound pressures as low as 0.0002 dyn/cm2
(B0.0000001 lb/in.2), accurately encodes loudness
over a 1 million:1 range of physical sound intensities
(corresponding to 120 dB of sound pressure), and
processes musical pitch over a 1000:1 range of
frequencies. The frequency range sensed by adult
humans with normal hearing is nominally 20–
20,000 Hz, but prepubescent children can usually
hear even higher frequencies and adults older than 40
typically experience a progressive loss of the ability to
hear high frequencies, termed presbycusis. The effects
of presbycusis and other forms of hearing loss become
significant when sensitivity is affected in the 500- to
2000-Hz frequency range, where the bulk of acoustic
information about human speech resides. Audiology
is the science of clinical hearing and speech testing
and the prescription and fitting of hearing aids.
EXTERNAL EAR
The external ear is composed of the pinna and the
external auditory meatus. Its principal functions are
to collect and funnel sound to the tympanic
membrane (eardrum) and to provide cues about the
location of wideband sound sources in the vertical
plane. With regard to the latter, the unique convolu-
tions of a person’s pinna, combined with reflections
off the upper body, filter sound such that energy is
enhanced or attenuated at different frequencies when
a sound source is located above, behind, below, or in
front of the head. These head-related transfer
functions are specific to each individual.
MIDDLE EAR
Principal structures of the mammalian middle ear are
the tympanic membrane, three ossicles [the malleus
(hammer), incus (anvil), and stapes (stirrup)], and
two muscles (the stapedius and the tensor tympani).
The middle ear is normally air filled and is lined by
secretory cells that form mucus. Air pressure across
the tympanic membrane is equalized by the eu-
stachian tube, which connects the middle ear to the
throat and permits fluid drainage in older children
and adults. Deficits in sound transmission through
the external and middle ears lead to conductive
hearing loss. This is differentiated from sensorineural
hearing loss, which refers to defects in biochemical,
receptor cell, or neural function.
The middle ear transmits eardrum vibrations to
the cochlea, filtering and amplifying sound pressure
along the way. It also prevents the cochlea from
being overstimulated via muscle contractions known
as the acoustic reflex. The middle ear is often referred
to as a transformer or impedance-matching device
that minimizes the loss that occurs when energy is
transmitted from one medium to another with a
different density. The two media in this case are air
and the cochlear fluid, which has the density of salt
water. Without a middle ear, 99% of sound energy
would be reflected off the air–fluid interface, and
sound reaching the inner ear would undergo a 40-dB
intensity loss. The middle ear reduces this loss to
nearly zero by passively amplifying sound pressure.
Pressure amplification through the middle ear stems
from several factors, the most significant of which is
a gain of B26 dB that occurs when sound energy is
collected over a relatively large surface (the eardrum)
and applied to a much smaller surface (the stapes
footplate). Other factors include a 2- or 3-dB
amplification that arises from the lever arrangement
of the malleus and incus and a B6-dB amplification
afforded by the specific way the eardrum vibrates.
The external and middle ears also filter the
frequency content of incoming sound. Middle
frequencies (1000–2000 Hz) are essentially unfil-
tered, but transmitted energy at low (o1000 Hz) fre-
quencies is reduced at a rate of B12 dB per doubling
of frequency (i.e., per octave) and high frequencies
(44000 Hz) are attenuated at a rate of B6 dB/
octave. Filtering at low frequencies occurs because at
a constant sound pressure the eardrum must move
proportionately more, thereby compressing the air
behind it and producing a resistive force, and also
because the eardrum and middle ear ligaments are
elastic, progressively absorbing more energy as
frequency decreases. Filtering at frequencies
44000 Hz arises from energy absorption by the
incudostapedial joint, which is the flexible connec-
tion between the incus and the stapes. The joint
possesses limited stiffness and progressively fails to
transmit energy across it as frequency increases. A
third component of middle ear filtering stems from
the acoustic resonant properties of the external ear
canal, which has the physical characteristics of a 1.5-
in. tube that is closed at one end. This arrangement
produces B10-dB pressure amplification in the
2000- to 4000-Hz frequency range. The shape of
the composite middle ear filter function matches
the shape of the human sensitivity curve nearly
perfectly.
The acoustic reflex constitutes the protective
function of the middle ear. It attenuates sound

transmission into the inner ear as a result of tensor
tympani and stapedius muscle contraction, thereby
reducing the ability of loud sounds to damage
cochlear structures. The tensor tympani connects to
the long process of the malleus and, upon contrac-
tion, pulls the eardrum inward and decreases the area
over which sound energy may be collected. It is
innervated by the trigeminal or fifth cranial nerve
and does not contract in response to sound in
humans; however, it often contracts immediately
prior to vocalizing. The stapedius is connected to the
stapes. It contracts in response to loud sound,
distorting and stiffening the incudostapedial joint.
The stapedius is innervated by neurons originating in
the motor nucleus of the facial or seventh cranial
nerve, and its responses to sound are the result of a
brainstem reflex arc with a path length of at least
four neurons, three of which are auditory. The
acoustic reflex operates at intensities 460 dB sound
pressure level (or 0.0002 dyn/cm2), and it progres-
sively increases in strength as intensity increases. It
has a maximum attenuative effect of B40 dB;
however, it takes 10–40 msec to develop fully and
only attenuates frequencies o2000 Hz.
Normal vs abnormal middle ear function can be
tested clinically by impedance tympanometry, which
involves measuring the tendency of the eardrum to
impede (reflect) sound as static pressure in the ear
canal is systematically altered in the presence of a
low-frequency tone. Normal middle ear function is
associated with an impedance minimum at atmo-
spheric pressure. Abnormal function, due to the
presence of fluid in the middle ear, partial immobi-
lization of the ossicles, etc., produces a minimum at a
different pressure or no minimum at all. Multi-
frequency tympanometry and wideband reflectance
are recently developed improvements on standard
impedance tympanometry that provide information
about middle ear function at several frequencies
rather than at one. The presence of and threshold for
the acoustic reflex are tested clinically as a change in
middle ear impedance in response to high-intensity
sound.
COCHLEA
Anatomy
The cochlea is a fluid-filled duct in the temporal bone
that in humans has a length of B35 mm and is coiled
for 234 turns. The cochlear duct is subdivided into
three compartments (scala vestibuli, scala media, and
scala tympani) by two membranes: the basilar
AUDITORY SYSTEM, PERIPHERAL 307
membrane, which separates scala tympani from scala
media, and Reissner’s membrane, which separates
scala media from scala vestibuli. Sound pressure is
transmitted into scala vestibuli by the stapes, which
fits into the oval window. Scala tympani ends at the
round window, which faces the middle ear. Scala
vestibuli merges with scala tympani at the helico-
trema located at the apex or upper end of the
cochlea. Pressure introduced into scala vestibuli by
inward stapes motion is transmitted up the cochlear
duct, through the helicotrema, and down the duct via
scala tympani, where it is relieved by outward
movement of the round window membrane. The
organ of Corti sits on the basilar membrane and
contains receptor and supporting cells.
Mechanics
The basilar membrane is the main mechanical
element of the inner ear. It possesses graded mass
and stiffness properties over its length, and its
vibration patterns have the effect of separating
incoming sound into its component frequencies that
activate different cochlear regions. High frequencies
generate vibration at sites near the stapes and low
frequencies cause vibration at sites near the cochlear
apex. The layout of frequency in cochlear space is
approximately logarithmic, similar to the notes of a
piano. Basilar membrane vibrations arise from
alternating pressure increases and decreases in scala
vestibuli and scala media that in turn are caused by
the piston-like, inward-and-outward motion of the
stapes.
The type of motion that the basilar membrane
undergoes is termed a traveling wave and it
resembles waves on the ocean (Fig. 2). At high
intensities, traveling wave patterns appear to begin
Figure 2
Depiction of a traveling wave, frozen in time and possessing
greatly exaggerated amplitude, arising from in–out stapes motion.
308 AUDITORY SYSTEM, PERIPHERAL
at the cochlear base (near the stapes), increasing in
amplitude as they move up the cochlear duct. The
traveling wave reaches a peak at a point that depends
on the frequency of the input sound and then rapidly
dies out. At near-threshold intensities, traveling
waves are restricted to localized sites. Vibration
amplitude increases with intensity, spreading primar-
ily in a basalward direction (toward the stapes). Peak
vibration amplitude at audiometric threshold is only
1 or 2 nm. Cochlear traveling waves have the
following properties: (i) A sound containing multiple
frequencies will produce traveling waves that achieve
multiple peaks whose locations along the cochlear
duct depend on the frequency content of the sound,
and (ii) each frequency in a complex sound is
removed from the composite traveling wave after
its peak has been attained, in high- to low-frequency
order. Basilar membrane vibrations are termed
passive because they do not consume energy and
persist after death.
Cochlear Receptors and the
‘‘Active Process’’
The effect of up-and-down basilar membrane motion
is to cause flexion of stereocilia or hair-like appen-
dages of two types of specialized receptor cells,
termed hair cells. Outer hair cells (OHCs) are three
times more numerous than inner hair cells (IHCs),
and each human ear contains B7500 OHCs (Fig. 3).
OHCs possess unique motile properties that have the
effect of amplifying basilar membrane vibration over
a restricted portion of its spatial extent. OHC
motility operates via a contractile protein called
prestin, which causes OHCs to expand and contract
Figure 3
Cross section of the organ of Corti showing the relationship of hair
cells to the basilar and tectorial membranes.
by 1–3% as stereocilia are displaced from their
resting positions. Cycle-by-cycle OHC motility has
been demonstrated at frequencies as high as
100,000 Hz in animals capable of hearing those
frequencies. It forms the basis of the cochlear
amplifier, which is a 20- to 80-dB increase in effective
vibration amplitude that occurs when OHC contrac-
tions add energy to basilar membrane motion
through a positive feedback operation. Amplification
is least at low frequencies and greatest at high
frequencies, and it only occurs over a restricted
segment of the basilar membrane vibration pattern,
specifically on the side of the pattern apical to the
(passive) traveling wave peak. The reason for spatial
restriction of amplification likely stems from fre-
quency-dependent differences in timing between
basilar membrane vibrations and OHC contractions.
That is, amplification occurs when the timing
difference is advantageous and attenuation occurs
when it is not, similar to the timing of the push
needed to make a playground swing go higher. The
amplification afforded by OHC motility is a princi-
pal determinant of the relatively high sensitivity
observed in mammalian hearing. It is often referred
to as the active process because it consumes
metabolic energy provided by OHCs and can be
influenced by manipulations that affect cochlear
metabolism (e.g., anoxia and reduced blood flow).
Otoacoustic Emissions
An interesting consequence of the active process is
that OHC contractions, in addition to promoting
activation of receptor cells and neurons in the
ascending auditory system, generate basilar mem-
brane motion that travels backward to the cochlear
base, through the ossicular chain, and into the
external ear canal. This produces faint sounds that
are collectively known as otoacoustic emissions or
cochlear echoes. Otoacoustic emissions are of two
types, evoked and spontaneous, depending on
whether they do or do not need an external sound
to be presented to record them. Testing for the
presence of otoacoustic emissions is rapidly gaining
popularity as a cost-effective way to screen for hearing
loss in infants since 490% of observed neonatal
hearing loss is a result of defects in hair cell function.
Cochlear Excitation and Homeostasis
OHC stereocilia are bent by a shearing force that
occurs when up-and-down movements of the basilar
membrane cause it to slide relative to the tectorial
membrane, a jelly-like sheet that covers the organ of

Corti and in which many OHC stereocilia are
embedded. OHCs (and IHCs) are depolarized or
excited in a graded manner when their stereocilia are
bent toward the longest stereocilia, and they are
hyperpolarized when stereocilia are bent in the
opposite direction. Similar to most other receptor
cells, depolarization causes hair cells to release a
neurotransmitter substance that activates the neurons
connected to them. The identity of the neurotrans-
mitter released by hair cells is unclear, but evidence is
accruing that it is glutamic acid. Mammalian hair
cells do not regenerate following traumatic injury
and loss. However, hair cells of certain birds, reptiles,
and amphibians are sometimes replaced following
loss. Considerable research is currently directed at
understanding the molecular and genetic basis of hair
cell regeneration, with the hope that in the future this
will be possible for humans.
Unlike OHCs, IHCs are activated by fluid motion
in the subtectorial space bordered by the tectorial
membrane and the apical hair cell surfaces. It is this
fluid motion that is amplified by OHC motility. IHCs
receive the majority (B95%) of connections from
neurons of the spiral ganglion, with each IHC
connecting to 15–50 spiral ganglion cells and 1
spiral ganglion cell connecting to only 1 IHC.
Neither OHCs nor IHCs possess a direct blood
supply. Rather, they are nourished by metabolites
deposited in scala media by cells of the stria
vascularis, which possesses numerous capillaries
and appears as a dark band on the outer wall of
scala media. Stria vascularis cells operate a powerful
sodium–potassium pump that maintains a 80-mV
resting potential in the fluid in scala media. This
potential is called the endocochlear potential. Com-
bining this with the 30- to 70-mV resting
potentials of hair cells forms a massive 110- to
150-mV battery across hair cell membranes that
generates the highest electrochemical driving force in
the body. The fluid in scala media is called
endolymph and is characterized by relatively high
potassium and low sodium concentrations. The fluid
in scala vestibuli and scala tympani is called
perilymph, and its ionic composition resembles that
of cerebrospinal fluid. The voltage present in
perilymph is B0 mV, similar to that of other
extracellular spaces.
Biochemically, the cochlea resembles the kidney;
not surprisingly, agents that affect kidney function
also tend to affect cochlear function. Hair cells and
the endocochlear potential (and, by extension, the
active process) are affected by various drugs, includ-
AUDITORY SYSTEM, PERIPHERAL 309
ing ototoxic drugs such as the aminoglycosides (kana-
mycin, neomycin, gentamycin, etc.) that can cause
permanent hearing loss when administered chroni-
cally in large amounts and other drugs, such as diure-
tics (furosemide, ethacrynic acid, etc.), acetylsalicylic
acid (aspirin), and quinine, which cause transient
hearing loss by impairing the cochlear amplifier.
Ion movement into and out of OHCs and IHCs
may be recorded from extracochlear sites. The
summed electrical response of hair cells produces
the cochlear microphonic, a waveform that resem-
bles the electrical equivalent of the sound that was
presented to the ear. Electrocochleography is the
clinical test that records cochlear microphonics and
other neural responses elicited by calibrated sounds
presented to the ear (Fig. 4). The other responses
present in an electrocochleogram are the summating
potential, which reflects asymmetry in voltages
produced by hair cells when their stereocilia are
moved in opposite directions, and the compound
action potential, which usually contains two nega-
tive-moving waves (N1 and N2) that represent the
summed, synchronous response of the auditory nerve
at signal onset. Electrocochleograms are often useful
in detecting the presence of endolymphatic hydrops,
a defect of stria vascularis function that often occurs
in Mèniére’s disease and results in an increase in the
amount of fluid in scala media, leading to fluctuating
hearing loss that typically affects low frequencies
more than high frequencies.
SPIRAL GANGLION AND AUDITORY NERVE
Hair cells are connected to bipolar neurons of the
spiral ganglion. The axons or central processes of the
spiral ganglion collect in the modiolus or central core
of the cochlea and form the cochlear branch of the
statoacoustic or eighth cranial nerve. These termi-
Figure 4
An electrocochleogram recorded from the ear canal in response to
an 8000-Hz tone showing the cochlear microphonic (CM), N1 and
N2 of the compound action potential, and the summarizing
potential (SP).
310 AUDITORY SYSTEM, PERIPHERAL
Figure 5
ANF tuning curves for fibers tuned to 2000 Hz (left) and
15,000 Hz (right). The y axis is threshold in decibels sound
pressure level.
nate in the cochlear nucleus, a brainstem center. The
cochlear nerve in humans is composed of the axons
of B30,000 spiral ganglion cells. These axons, often
called auditory nerve fibers (ANFs), transmit to the
brain all information that exists about sound. ANFs
exhibit all-or-none responses or action potentials and
possess homogeneous physiological response char-
acteristics. ANFs exhibit spontaneous activity (action
potentials or ‘‘spikes’’ that occur in the absence of a
stimulus) that forms two or perhaps three groups.
ANFs with high spontaneous discharge rates (20–
150 spikes/sec) typically exhibit the lowest thresh-
olds to sound and comprise B60% of the ANF
population. ANFs with low and medium sponta-
neous rates (0–20 spikes/sec) normally have higher
thresholds and comprise the remainder of the
population. ANFs are tonic responders that exhibit
a moderate amount of adaptation. That is, dis-
charges occur throughout the duration of an input
signal, but discharge rates tend to be greatest at
response onset, usually settling to a lower, steady-
state rate within 100 msec. Consistent with the fact
that the basilar membrane performs mechanical
frequency filtering on sound, each ANF exhibits a
tuning curve (threshold plotted as a function of
frequency). The frequency to which an ANF is most
sensitive, the characteristic frequency (CF), reflects
the cochlear location at which it connects to an IHC.
Thus, ANFs emanating from the cochlear base are
tuned to high frequencies, and ANFs emanating from
the cochlear apex are tuned to low frequencies.
Tuning curves (Fig. 5) have two portions—(i) a
sensitive, sharply tuned ‘‘tip’’ that contains the CF
and is determined by the active process and (ii) a
high-threshold, broadly tuned ‘‘tail’’ that reflects
passive basilar membrane tuning. Deficits involving
OHCs reduce sensitivity in tuning curve tips but have
little effect on tail sensitivity. In the extreme case of
complete loss of OHC function, ANF tuning curves
exhibit no tip and possess only a high-threshold,
broadly tuned tail.
Input–output functions of ANFs (Fig. 6) are
described by four parameters: spontaneous rate,
threshold, maximum or saturation discharge rate,
and dynamic range. Thresholds at CF for ANFs with
high spontaneous rates generally follow the beha-
vioral sensitivity curve, and thresholds at CF for
ANFs with low spontaneous rates progressively
increase by 10–40 dB as the spontaneous rate
decreases to zero. Maximum discharge rates for
ANFs range from 100 to 400 spikes/sec and, like
threshold, correlate with spontaneous rate. That is,
the higher the spontaneous rate, the higher the
maximum discharge rate tends to be. Dynamic range
refers to the intensity range over which an ANF’s
response increases from the resting rate to the
maximum rate. Dynamic ranges for most ANFs are
typically 20–30 dB, but some low-spontaneous-rate
ANFs can have dynamic ranges up to 70 dB.
AUDITORY STIMULUS CODING
Spatial filtering of sound by the basilar membrane
permits information about frequency to be encoded
by the area in the cochlea in which vibration occurs.
However, the fact that hair cells are depolarized only
Figure 6
Input–output functions of ANFs with different spontaneous rates.

when their stereocilia move in one direction means
that neurotransmitter is released and action poten-
tials will arise in ANFs only on excitatory half-cycles
of basilar membrane vibration. This allows fre-
quency information to be encoded in the temporal
or phase-locked characteristics of ANF responses.
However, the electrical properties of hair cell
membranes are such that the degree of phase locking
decreases as frequency increases and in mammalian
species is essentially nonexistent at frequencies
44000 Hz. It is likely that the brain can utilize
either frequency-coding mechanism, depending on
which one provides the most salient information.
Internally, sound intensity is represented logarith-
mically, similar to the near-logarithmic spatial layout
of frequency along the basilar membrane. The
expansion of basilar membrane vibrations toward
the cochlear base that occurs as intensity increases
permits intensity to be encoded by the spatial extent
of vibration and hence the total number of discharges
elicited in the auditory nerve. However, the existence
of subpopulations of ANFs with higher thresholds
suggests the possibility of a second intensity-coding
mechanism in which intensity is encoded as a labeled
line. In this scheme, the brain receives information
that sound level is increasing because ANFs with
progressively higher thresholds (and lower sponta-
neous-rates) become active. Which mechanism the
brain actually uses is not clear.
To a first approximation, ANF coding of complex
tones or speech can be analyzed by considering
cochlear and ANF responses to individual frequencies
comprising a given sound. Likewise, auditory stimu-
lus coding in cases of hearing loss can be analyzed by
considering the effects of losing sensitivity improve-
ments generated by the cochlear amplifier. In reality,
however, several nonlinear aspects of cochlear
processing also come into play in these cases, making
the actual situation more complicated.
—Eric Javel
See also–Auditory System, Central; Balance;
Hearing Loss; Neuroophthalmology; Sensory
System, Overview; Vestibulocochlear Nerve
(Cranial Nerve VIII)
Further Reading
Altschuler, R. A., Bobbin, R. P., and Hoffman, D. W. (Eds.) (1986).
Neurobiology of Hearing: The Cochlea. Lippincott–Raven,
New York.
Dallos, P., Popper, A. N., and Fay, R. R. (Eds.) (1996). The
Cochlea, Vol. 8. Springer-Verlag, New York.
AUTISM 311
Pickles, J. O. (1998). Introduction to the Physiology of Hearing,
2nd ed. Academic Press, New York.
Autism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AUTISM is a disorder that is characterized by
significant social deficits, delays in communication
skills, and difficulty with changes. Leo Kanner first
described it in the literature almost 60 years ago.
Since then, much has been learned about autism as
well as other pervasive developmental disorders.
Although previously thought to be caused by a
disturbance in parent–child interactions, it is now
thought to be associated with multiple risk factors
and to have an underlying neurological etiology. This
entry provides an introduction to autism and the
pervasive developmental disorders with diagnostic
and treatment implications.
DIAGNOSIS
The accurate diagnosis of autism is very important
because it will facilitate obtaining the proper treat-
ment and educational services for this group of
individuals. There is no single test for autism. Rather,
it is a diagnosis that is made through a thorough
clinical evaluation. In the United States, the majority
of clinicians use the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSM-
IV), of the American Psychiatric Association. The
diagnostic criteria for autistic disorder include (i)
impairments in social interaction; (ii) delays in verbal
and nonverbal communication; and (iii) restricted,
repetitive, and stereotyped patterns of behavior,
interests, and activities. It is important that an
individual has significant impairment in all three areas
to meet the diagnostic criteria for autistic disorder.
The pervasive developmental disorders (PDDs) are
a group of disorders in which affected individuals
have difficulty in social interactions, communication,
and need for sameness. Autistic disorder is therefore
considered to be one of the PDDs. However, some
individuals do not meet the full criteria for autistic
disorder but have many features of it and are
therefore given the diagnosis of pervasive develop-
mental disorder NOS (not otherwise specified).
Other diagnoses within the PDD group are Asper-
ger’s disorder, Rett’s disorder, and childhood disin-
tegrative disorder.

when their stereocilia move in one direction means
that neurotransmitter is released and action poten-
tials will arise in ANFs only on excitatory half-cycles
of basilar membrane vibration. This allows fre-
quency information to be encoded in the temporal
or phase-locked characteristics of ANF responses.
However, the electrical properties of hair cell
membranes are such that the degree of phase locking
decreases as frequency increases and in mammalian
species is essentially nonexistent at frequencies
44000 Hz. It is likely that the brain can utilize
either frequency-coding mechanism, depending on
which one provides the most salient information.
Internally, sound intensity is represented logarith-
mically, similar to the near-logarithmic spatial layout
of frequency along the basilar membrane. The
expansion of basilar membrane vibrations toward
the cochlear base that occurs as intensity increases
permits intensity to be encoded by the spatial extent
of vibration and hence the total number of discharges
elicited in the auditory nerve. However, the existence
of subpopulations of ANFs with higher thresholds
suggests the possibility of a second intensity-coding
mechanism in which intensity is encoded as a labeled
line. In this scheme, the brain receives information
that sound level is increasing because ANFs with
progressively higher thresholds (and lower sponta-
neous-rates) become active. Which mechanism the
brain actually uses is not clear.
To a first approximation, ANF coding of complex
tones or speech can be analyzed by considering
cochlear and ANF responses to individual frequencies
comprising a given sound. Likewise, auditory stimu-
lus coding in cases of hearing loss can be analyzed by
considering the effects of losing sensitivity improve-
ments generated by the cochlear amplifier. In reality,
however, several nonlinear aspects of cochlear
processing also come into play in these cases, making
the actual situation more complicated.
—Eric Javel
See also–Auditory System, Central; Balance;
Hearing Loss; Neuroophthalmology; Sensory
System, Overview; Vestibulocochlear Nerve
(Cranial Nerve VIII)
Further Reading
Altschuler, R. A., Bobbin, R. P., and Hoffman, D. W. (Eds.) (1986).
Neurobiology of Hearing: The Cochlea. Lippincott–Raven,
New York.
Dallos, P., Popper, A. N., and Fay, R. R. (Eds.) (1996). The
Cochlea, Vol. 8. Springer-Verlag, New York.
AUTISM 311
Pickles, J. O. (1998). Introduction to the Physiology of Hearing,
2nd ed. Academic Press, New York.
Autism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AUTISM is a disorder that is characterized by
significant social deficits, delays in communication
skills, and difficulty with changes. Leo Kanner first
described it in the literature almost 60 years ago.
Since then, much has been learned about autism as
well as other pervasive developmental disorders.
Although previously thought to be caused by a
disturbance in parent–child interactions, it is now
thought to be associated with multiple risk factors
and to have an underlying neurological etiology. This
entry provides an introduction to autism and the
pervasive developmental disorders with diagnostic
and treatment implications.
DIAGNOSIS
The accurate diagnosis of autism is very important
because it will facilitate obtaining the proper treat-
ment and educational services for this group of
individuals. There is no single test for autism. Rather,
it is a diagnosis that is made through a thorough
clinical evaluation. In the United States, the majority
of clinicians use the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSM-
IV), of the American Psychiatric Association. The
diagnostic criteria for autistic disorder include (i)
impairments in social interaction; (ii) delays in verbal
and nonverbal communication; and (iii) restricted,
repetitive, and stereotyped patterns of behavior,
interests, and activities. It is important that an
individual has significant impairment in all three areas
to meet the diagnostic criteria for autistic disorder.
The pervasive developmental disorders (PDDs) are
a group of disorders in which affected individuals
have difficulty in social interactions, communication,
and need for sameness. Autistic disorder is therefore
considered to be one of the PDDs. However, some
individuals do not meet the full criteria for autistic
disorder but have many features of it and are
therefore given the diagnosis of pervasive develop-
mental disorder NOS (not otherwise specified).
Other diagnoses within the PDD group are Asper-
ger’s disorder, Rett’s disorder, and childhood disin-
tegrative disorder.
312 AUTISM

SOCIAL INTERACTIONS they need to look in the direction that others are
pointing. The child will not use facial expressions
Impairment in social interaction is the core diagnos-
and has difficulty understanding others’ facial
tic feature for children and adults with autistic
expressions as well. Frequently, these children have
disorder. Children with autism are socially isolated
echolalia, which is defined as repeating things that
and often have no interest in interactions with others.
they have heard. A child may repeat the last word of
They seem to be in their own world, uninterested in
a sentence that they hear, or may memorize entire
what is going on around them. Parents often notice
songs or scenes from movies. Often, when obtaining
that their child is not interested in interactions with
a developmental history, parents may state that their
other peers and prefers to be alone. They may see
child has the ability to put together sentences, but
their child sitting in the corner of the room as all the
with further probing their child may simply be
other children are playing together. As these children
repeating phrases that they have memorized, not
get older, they may start to develop interest in
really understanding that they are putting together
interacting with peers, but they often do not know
words to make up a phrase.
how to interact with others.
As children with autism grow and develop more
The interactions that these individuals do have
communication skills, they often have quite stilted
with others tend to be instrumental. That is, they
language. Also, they often have difficulty reading the
tend to use other people as if they were objects to get
social aspects of language, such as picking up on how
their needs met. For instance, if a normal toddler
others are responding to them and being able to read
could not open a door, they may go to the parent,
others’ facial expressions (i.e., happy, bored, inter-
look at the parent and then the door, and motion and/
ested, etc.). They often have difficulty participating in
or verbalize for the parent to help them. In contrast, a
conversations, which has a significant impact on
child with autism would grab their parent’s hand and
their social functioning.
put it on the doorknob without looking at the parent.
Closely related to the difficulties in communica-
It is as though the parent is a tool that the child used
tion, children with autism have significant delays in
to get the door open.
imaginative play. They enjoy engaging in physical
People with autism also frequently have poor eye
play activities, such as running around, playing on a
contact and actively avoid looking into others’ eyes.
slide, or tickling. When presented with a stuffed
They have difficulty ‘‘reading’’ social interactions.
animal or a doll, however, the child is frequently
Children with autism also have an inability to
uninterested, not understanding that it represents a
understand others’ feelings, and they are unable to
person or animal. To have imaginative play, one must
discriminate when others are happy, sad, angry, or
have the ability to abstract. That is, one needs the
bored. Additionally, they often are not interested in
ability to recognize that one thing can represent
sharing experiences with others.
another. Children with autism have significant
impairment in this ability. However, as their com-
munication skills improve, one will see improvement
COMMUNICATION
in imaginative play.
Communication delays are often the first problem
that parents notice about their child with autism.
RANGE OF INTERESTS AND ACTIVITIES
They notice that their child is not speaking and does
not attend when spoken to. Parents frequently Individuals with autism are often quite dependent on
believe that their child may be deaf, until hearing the maintenance of routines, and they can become
tests reveal that the child has normal hearing. The quite upset when there are small changes to their
critical difference between children with autism and routine. For example, parents have often reported
those with language delays or deafness is that the that their child will start screaming and having a
child with autism has significant delays in both tantrum when they drive a different way to school.
verbal and nonverbal communication. A child with Additionally, if a small item is moved from one place
language delays will compensate by using more to another in the house, the child may get upset and
nonverbal communication, such as pointing and try to move the object back to its original location.
using facial expressions and body language to This may reach such an extreme that the family
communicate with others. In contrast, children with maintains a very rigid schedule for fear that the child
autism will not point to objects or understand that may have a tantrum.

MOTOR AND SENSORY ASPECTS
Individuals with autism frequently present with
repetitive motor movements, such as hand flapping,
rocking, or spinning in circles. Although this
frequently happens for only short periods of time
during their early years of development, it may be
longer lasting and occur throughout much of the day.
These movements often occur when the child is
excited or upset or when demands are placed on
them. It is important to note that not all individuals
with autism display repetitive motor movements, and
having these movements does not necessarily mean
that an individual has autism.
The sensory abnormalities of individuals with
autism can take on a wide variety of presentations.
Frequently, they present with sensitivity to sounds.
The child may cover their ears when the vacuum
cleaner is on or when a truck drives by their house.
However, it does not necessarily need to be a loud
sound, and a child may have an extreme sensitivity to
a sound that one would not expect to bother them.
With regard to vision, individuals with autism may
like to look at objects out of the corner of their eye or
watch things spin. Regarding touch, they may walk
around the house feeling certain textures, and they
may pick a favorite object or toy because of its
texture.
MENTAL RETARDATION
It is important to note that approximately 70% of
individuals with autism have some degree of mental
retardation. Because this will play an important role
in educational planning and determining the expec-
tations for rate of progress, it is essential that
cognitive testing be part of the initial diagnostic
assessment for a child with autism. For individuals
with autism and mental retardation, it is often the
mental retardation that will have the greatest impact
on their rate of progress.
GENETICS AND OTHER RISK FACTORS
A specific genetic abnormality, fragile X, is asso-
ciated with autism or PDD NOS in boys. Another
disorder, tuberous sclerosis, also has a strong
association with autistic disorder. It is an autosomal
dominant disorder with identified genes on chromo-
somes 9 and 14. Individuals present with benign
tumors (harmartomas) in the brain and other organs.
AUTISM 313
They also often present with mental retardation and
seizures.
The majority of individuals with autism or PDDs
have no identifiable chromosomal abnormality.
However, family and twin studies indicate an
increased risk of autism, even when there is no
identifiable chromosomal abnormality. In the litera-
ture, it is reported that if parents have a child with
autism, the risk for having a subsequent child with
autism is 3–7%, which is much greater that the risk
in the general population.
Immunization with the measles–mumps–rubella
(MMR) vaccine has been reported to be associated
with an increased incidence of autism and pervasive
developmental disorders. However, large epidemio-
logical studies have not shown an increased risk of
the development of autism in children receiving the
MMR vaccine.
EPILEPSY
As children with autism grow into adulthood,
approximately 20–35% of these individuals will
develop a seizure disorder. It is more common in
those with severe mental retardation and autism. The
onset of the seizures is often in childhood or
adolescence, but it can occur anytime throughout
an individual’s lifetime. In adolescence, the onset of
seizures may correspond with a worsening of
behavior. They may present with major motor or
complex seizures, and it can often be quite difficult to
identify a seizure disorder because the presentation
may initially be thought to be part of their autism.
The autistic individual’s seizure disorder will often
respond well to antiseizure medication.
EDUCATION AND TREATMENT OF CHILDREN
WITH AUTISM
Early intervention is very important for these
children. Some young children with autistic disorder
do not yet have the skills (such as communication,
imitation, and interest in surroundings) necessary to
learn in a classroom environment. These children
may need individual intervention with a focus on the
development of these skills to prepare them to learn
in a classroom. As these children enter the school
system, it is important that they are placed in a
classroom with a significant amount of structure and
a strong focus on the development of communica-
tion, social, and self-help skills. The selection of the
educational setting needs to take into consideration
314 AUTONOMIC DYSREFLEXIA
the particular strengths and needs of the child, and
it is critically important that this be reviewed on
a regular basis. Their needs will change as they
mature.
PSYCHOPHARMACOLOGICAL TREATMENT
Psychoactive medications are not used to treat
autism but are used to treat some of the troubling
symptoms that may be associated with the disorder.
Medications that target the serotonin function in the
brain (fluoxetine, sertraline, clomipramine, and
fluvoxamine) have been shown to help with hyper-
activity, concentration, and obsessive symptoms.
Clomipramine should be used cautiously because it
may decrease the seizure threshold. Medications that
target dopamine function (haloperidol and risper-
idone) have been shown to be helpful with hyper-
activity, agitation, and aggression. However, these
medications may lower the seizure threshold and
lead to dyskinesias (abnormal involuntary move-
ments). Stimulant medications such as methylpheni-
date may be helpful for autistic children with
hyperactivity, but they may lead to worsening of
these behaviors in some individuals and thus should
be used cautiously. Finally, buspirone may be helpful
in reducing hyperactivity and aggression in indivi-
duals with autism.
—Brian Zimnitzky
See also–Asperger’s Syndrome; Child Neurology,
History of; Epilepsy, Risk Factors; Language and
Discourse; Language Disorders, Overview;
Mental Retardation; Rett Syndrome; Socially
Inept Children
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual, 4th ed. American Psychiatric Association,
Washington, DC.
Cohen, D. J., and Volkmar, F. R. (1997). Handbook of Autism and
Pervasive Developmental Disorders, 2nd ed. Wiley, New York.
Kanner, L. (1943). Autistic disturbances of affective contact.
Nervous Child 2, 217–250.
Siegel, B. (1996). The World of the Autistic Child. Oxford Univ.
Press, Oxford.
Autoimmunity
see Immune System
Autonomic Dysreflexia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AUTONOMIC DYSREFLEXIA is a paroxysmal stereo-
typed autonomic response presenting with pulsating
headache, flushing, hypertension, and hyperhidrosis.
It is provoked by afferent stimulation caudal to the
complete or incomplete spinal cord lesion, usually at
or above the T5 level.
PATHOPHYSIOLOGY
A lesion at or above the T5 level disconnects the
caudal spinal region, including splanchnic sympa-
thetic outflow, from the supraspinal control. Over a
period of several months, morphological and phys-
iological changes occur above and below the injury.
There is remodeling of synapses and increased
reactivity rostral to the lesion. The vagus nerve is
usually unaffected. Caudally, there is degeneration of
descending tracts, sprouting of ascending sensory
fibers, a decrease in inhibitory neurotransmission, an
increase in substance P, and reduction of g-amino-
butyric acid. The muscle and skin sympathetic
activity is markedly reduced at rest; upon stimula-
tion, it shows parallel instead of sequential activa-
tion. The visceral or somatic, noxious or innocuous
stimulation below the lesion is carried by pelvic
parasympathetic, pudendal somatic, and hypogastric
sympathetic (T9 or higher) afferents to the spinal
cord. During its ascent in the dorsal and spinotha-
lamic tracts to the lesion level, collateral branches
activate the intermediolateral column neurons. An
increased norepinephrine ‘‘spillover,’’ coupled with
target organ hyper-responsiveness, causes hyperten-
sion. The blood pressure elevation activates barore-
flexes (cartoid sinus and aortic body-
glossopharyngeal and vagus nerves-medulla-
heart and blood vessels) to produce vagally induced
bradycardia and vasodilation.
PRECIPITATING FACTORS
Most stimuli, exogenous and endogenous, whether
felt by the patient or not, can trigger autonomic
dysreflexia. The afferent impulses may arise from
genitourinary, gastrointestinal, or somatic structures.
Sources of stimulation from the urogenital tract
include bladder distension due to an obstructed
catheter, detrusor–sphincter dyssynergia, catheter
314 AUTONOMIC DYSREFLEXIA
the particular strengths and needs of the child, and
it is critically important that this be reviewed on
a regular basis. Their needs will change as they
mature.
PSYCHOPHARMACOLOGICAL TREATMENT
Psychoactive medications are not used to treat
autism but are used to treat some of the troubling
symptoms that may be associated with the disorder.
Medications that target the serotonin function in the
brain (fluoxetine, sertraline, clomipramine, and
fluvoxamine) have been shown to help with hyper-
activity, concentration, and obsessive symptoms.
Clomipramine should be used cautiously because it
may decrease the seizure threshold. Medications that
target dopamine function (haloperidol and risper-
idone) have been shown to be helpful with hyper-
activity, agitation, and aggression. However, these
medications may lower the seizure threshold and
lead to dyskinesias (abnormal involuntary move-
ments). Stimulant medications such as methylpheni-
date may be helpful for autistic children with
hyperactivity, but they may lead to worsening of
these behaviors in some individuals and thus should
be used cautiously. Finally, buspirone may be helpful
in reducing hyperactivity and aggression in indivi-
duals with autism.
—Brian Zimnitzky
See also–Asperger’s Syndrome; Child Neurology,
History of; Epilepsy, Risk Factors; Language and
Discourse; Language Disorders, Overview;
Mental Retardation; Rett Syndrome; Socially
Inept Children
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual, 4th ed. American Psychiatric Association,
Washington, DC.
Cohen, D. J., and Volkmar, F. R. (1997). Handbook of Autism and
Pervasive Developmental Disorders, 2nd ed. Wiley, New York.
Kanner, L. (1943). Autistic disturbances of affective contact.
Nervous Child 2, 217–250.
Siegel, B. (1996). The World of the Autistic Child. Oxford Univ.
Press, Oxford.
Autoimmunity
see Immune System
Autonomic Dysreflexia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AUTONOMIC DYSREFLEXIA is a paroxysmal stereo-
typed autonomic response presenting with pulsating
headache, flushing, hypertension, and hyperhidrosis.
It is provoked by afferent stimulation caudal to the
complete or incomplete spinal cord lesion, usually at
or above the T5 level.
PATHOPHYSIOLOGY
A lesion at or above the T5 level disconnects the
caudal spinal region, including splanchnic sympa-
thetic outflow, from the supraspinal control. Over a
period of several months, morphological and phys-
iological changes occur above and below the injury.
There is remodeling of synapses and increased
reactivity rostral to the lesion. The vagus nerve is
usually unaffected. Caudally, there is degeneration of
descending tracts, sprouting of ascending sensory
fibers, a decrease in inhibitory neurotransmission, an
increase in substance P, and reduction of g-amino-
butyric acid. The muscle and skin sympathetic
activity is markedly reduced at rest; upon stimula-
tion, it shows parallel instead of sequential activa-
tion. The visceral or somatic, noxious or innocuous
stimulation below the lesion is carried by pelvic
parasympathetic, pudendal somatic, and hypogastric
sympathetic (T9 or higher) afferents to the spinal
cord. During its ascent in the dorsal and spinotha-
lamic tracts to the lesion level, collateral branches
activate the intermediolateral column neurons. An
increased norepinephrine ‘‘spillover,’’ coupled with
target organ hyper-responsiveness, causes hyperten-
sion. The blood pressure elevation activates barore-
flexes (cartoid sinus and aortic body-
glossopharyngeal and vagus nerves-medulla-
heart and blood vessels) to produce vagally induced
bradycardia and vasodilation.
PRECIPITATING FACTORS
Most stimuli, exogenous and endogenous, whether
felt by the patient or not, can trigger autonomic
dysreflexia. The afferent impulses may arise from
genitourinary, gastrointestinal, or somatic structures.
Sources of stimulation from the urogenital tract
include bladder distension due to an obstructed
catheter, detrusor–sphincter dyssynergia, catheter

insertion, cystometry, urethral dilation, infection,
renal stones, and extracorporeal shock wave litho-
tripsy, and also sexual intercourse, vaginal stimula-
tion, menstruation, ejaculation, labor, electroejacu-
lation, and vibrator stimulation. Of all precipitating
factors, urinary bladder involvement is the most
common. Gastrointestinal stimulation may result
from gastroesophageal reflux, gastric ulcer, gastric
dilation, fecal retention, enemas, digital evacuation,
insertion of a rectal tube, hemorrhoids, anal fissure,
and even flatulence. Sources of somatic stimulation
include tight clothing, strapping, application of
tourniquets, pressure sores, burns, ingrown toe nails,
paronychia, skeletal muscle spasms, skeletal frac-
tures, and hip dislocation. Occasionally, nasal
decongestants containing sympathomimetic drugs
and orthostatic hypotension may precipitate auto-
nomic dysreflexia. Sometimes, especially in cases of
severe episodes, there may be multiple trigger factors.
CLINICAL FEATURES
Symptoms and signs vary in frequency and severity
from patient to patient. Headache, nasal stuffiness,
sweating of the upper body, and piloerection are
common. Other symptoms are anxiety, apprehen-
sion, restlessness, dizziness, diffuse or patchy flushing
of the face, fullness in the head, cold limbs, chills,
shivering, metallic taste, shortness of breath, tight-
ness in the chest, nausea, and desire to void.
Common signs of autonomic dysreflexia are
hypertension, hyperhidrosis, bradycardia, penile
erection, seminal fluid emission, and flushing. Hy-
pertension has been observed in 90% of patients.
Blood pressure may be as high as 250–300/200–220
mmHg. How much elevation of blood pressure is
necessary for the diagnosis and when to treat this
increase in blood pressure are debated. Guttman
believed that a systolic blood pressure elevation of
20–40 mmHg above the baseline is diagnostic of
dysreflexia. Lindan et al. considered the diagnosis
established if the systolic blood pressure exceeds 10
mmHg over the baseline during a cystometric
examination. This is accompanied by flushing and
blockage of nasal air passages (vasodilation) above
the lesion and cold limbs below the lesion. One-third
of patients may show bradycardia.
Hyperhidrosis may be the initial manifestation in
40% of patients with traumatic myelopathy. It is
important to realize that the abnormal sweat
patterns are dictated by the level of injury to the
thoracolumbar sympathetic pathways and not the
AUTONOMIC DYSREFLEXIA 315
spinal segments. Thermoregulatory sweating is pre-
served above the lesion level (e.g., a lesion at the T3–
T4 level spares sweating of the head and neck region,
and sweating is normal with lesion at or below the
T11 level). A minority of patients may show a band-
like area of hyperhidrosis at the level of the lesion.
Below the level of the lesion, thermoregulatory
sweating is absent but reflex sweating may occur.
For example, a lesion at the C5–C6 level produces a
total anhidrosis. However, the reflex spinal sweating
may be quite striking and it affects the head, neck,
arms, and trunk to the umbilicus level.
DIAGNOSIS
The location of the lesion can be assessed clinically
and by magnetic resonance imaging. The thermo-
regulatory sweat test delineates the level of involve-
ment of the sympathetic sudomotor pathways. The
absence of skin sympathetic reflex suggests predilec-
tion for autonomic dysreflexia. Twenty-four-hour
ambulatory blood pressure monitoring can be used
to assess the occurrence of hypotension as well as
autonomic dysreflexia. If in doubt, monitoring of
cardiovascular and sweat responses during urody-
namic evaluation may be useful.
Attacks of pheochromocytoma can resemble auto-
nomic dysreflexia. Patients with dysreflexia can be
distinguished by flushing above and pallor below the
lesion and by elevation of norepinephrine and
dopamine b-hydroxylase levels but without an
increase in epinephrine level. The posterior fossa
neoplasms may present with paroxysmal hyperten-
sion mimicking autonomic dysreflexia. However,
papilledema, patterns of neurological deficit, and
neuroimaging should help to exclude it. Occasionally,
primary hypertension, migraine, and cluster headache
may mimic the diagnosis of autonomic dysreflexia.
TREATMENT
Treatment for autonomic dysreflexia needs to be
individualized since it may occur in minor episodes
that do not require treatment or it may be severe
and life threatening. An acute episode with a
markedly elevated blood pressure constitutes an
emergency, and recurrent attacks of autonomic
dysreflexia, if unrecognized and inconsistently trea-
ted, can lead to serious neurological, cardiac, and
renal complications.
Primary pharmacological prophylaxis is usually
not indicated, but appropriate care of bowel,
bladder, and skin is essential. Premedication before
316 AUTONOMIC NERVOUS SYSTEM, HEART RATE AND
urological procedures with sublingual nifedipine or
oral mecamylamine is recommended in patients with
suspected or documented autonomic dysreflexia.
Nifedipine is the currently favored agent. It inhibits
voltage-dependent Ca2 þ channels in vascular
smooth muscle and selectively dilates arterial resis-
tance vessels. The contents of a 10-mg capsule are
squeezed under the tongue. Mecamylamine, a gang-
lionic blocking agent, is given in a dosage of 2.5 or 5
mg three times a day to reduce sympathetic and
parasympathetic responses.
A systematic approach is indicated when a patient
presents with symptoms of autonomic dysreflexia.
Blood pressure should be checked. If blood pressure
in not elevated, monitoring of symptoms and blood
pressure should be continued for 2 hr. If blood
pressure is elevated but does not exceed 150/100
mmHg, the patient should be made to sit up to lower
blood pressure and all clothing should be loosened.
The catheter tubing should be checked to determine
whether urine is flowing out from the bladder and to
ensure that there are no kinks, or the patient should
be catheterized after instilling 2% lidocaine jelly into
the urethra. The bowels should be emptied if no
cause is found in the urinary tract. Also, a search for
pressure sores and ingrown toe nails should be made.
Blood pressure should be reassessed if no cause is
found. If blood pressure elevation does not exceed
150/100 mmHg, the patient should continue to be
observed. If hypertension exceeds 150/100 mmHg
and a cause is either not found or found but not
feasible to eradicate quickly, pharmacological treat-
ment should be initiated.
If blood pressure elevation is between 150/100 and
180/120 mmHg, the patient should be treated with
sublingual nifedipine, oral mecamylamine, or oral
clonidine. Clonidine reduces sympathetic drive by
activating a2 adrenoreceptors in the lower brainstem.
If blood pressure exceeds 180/120 mmHg, drugs
that directly relax smooth muscle are used. They are
administered intravenously for a quick response.
These include hydralazine, nitroprusside, and diaz-
oxide. Hydralazine, which directly relaxes the
arteriolar smooth muscle, is administered as a 10-
to 20-mg dose by slow intravenous push. Nitroprus-
side dilates arterioles and venules and its dose can be
adjusted from 0.25 to 1.5 mg/kg/min. Diazoxide acts
by hyperpolarizing arterial smooth muscle cells. Its
dosage ranges from 50 to 300 mg.
In patients with recurrent life-threatening auto-
nomic dysreflexia in whom no cause is found, radical
measures may be necessary, including pudendal and
sacral nerve blocks, pelvic or pudendal nerve section,
sacral posterior rhizotomy, sympathectomy, subar-
achnoid block with alcohol or phenol, dosal root
ganglionectomy, and even cordectomy.
—Ramesh Khurana
See also–Autonomic Nervous System, Overview;
Sweating Disorders; Sympathetic System,
Overview
Further Reading
Braddon, R. L., and Rocco, J. F. (1991). Autonomic dysreflexia. A
survey of current treatment. Am. J. Phys. Med. Rehab. 70, 234–
241.
Curt, A., Nitsche, B., Rodic, B., et al. (1997). Assessment of
autonomic dysreflexia in patients with spinal cord injury. J.
Neurol. Neurosurg. Psychiatry 62, 473–477.
Guttman, L., and Whittridge, D. (1947). Effects of bladder
distension on autonomic mechanisms after spinal cord injuries.
Brain 70, 361–404.
Head, H., and Riddoch, G. (1917). The autonomic bladder,
excessive sweating and some other reflex conditions in gross
injuries of the spinal cord. Brain 46, 188–263.
Karlsson, A., Friberg, P., Lönnroth, P., et al. (1998). Regional
sympathetic function in high spinal cord injury during mental
stress and autonomic dysreflexia. Brain 121, 1711–1719.
Kewalramani, L. S. (1980). Autonomic dysreflexia in traumatic
myelopathy. Am. J. Phys. Med. 59, 1–21.
Lee, B. Y., Karmakar, M. G., Herz, B. L., et al. (1995). Autonomic
dysreflexia revisited. J. Spinal Cord Med. 18, 75–87.
Lindan, R., Joyner, E., Freehafer, A. A., et al. (1980). Incidence and
clinical features of autonomic dysreflexia in patients with spinal
cord injury. Paraplegia 18, 285–292.
Mathias, C. J., and Frankel, H. L. (1999). Autonomic disturbances
in spinal cord lesions. In Autonomic Failure (C. J. Mathias and
R. Bannister, Eds.), 4th ed., pp. 494–513. Oxford Univ. Press,
New York.
Stjernberg, L., Blumberg, H., and Wallin, B. G. (1986). Sympa-
thetic activity in man after spinal cord injury. Brain 109,
695–715.
Autonomic Nervous System,
Heart Rate and
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
HEART RATE in healthy individuals is dependent on
the discharge frequency of the pacemaker cells of the
sinoatrial node. Heart rate and stroke volume are the
determinants of cardiac output. The regulation of
both these cardiac activities is essential for the
appropriate maintenance of cardiovascular home-
ostasis. The mean heart rate in healthy adults is
316 AUTONOMIC NERVOUS SYSTEM, HEART RATE AND
urological procedures with sublingual nifedipine or
oral mecamylamine is recommended in patients with
suspected or documented autonomic dysreflexia.
Nifedipine is the currently favored agent. It inhibits
voltage-dependent Ca2 þ channels in vascular
smooth muscle and selectively dilates arterial resis-
tance vessels. The contents of a 10-mg capsule are
squeezed under the tongue. Mecamylamine, a gang-
lionic blocking agent, is given in a dosage of 2.5 or 5
mg three times a day to reduce sympathetic and
parasympathetic responses.
A systematic approach is indicated when a patient
presents with symptoms of autonomic dysreflexia.
Blood pressure should be checked. If blood pressure
in not elevated, monitoring of symptoms and blood
pressure should be continued for 2 hr. If blood
pressure is elevated but does not exceed 150/100
mmHg, the patient should be made to sit up to lower
blood pressure and all clothing should be loosened.
The catheter tubing should be checked to determine
whether urine is flowing out from the bladder and to
ensure that there are no kinks, or the patient should
be catheterized after instilling 2% lidocaine jelly into
the urethra. The bowels should be emptied if no
cause is found in the urinary tract. Also, a search for
pressure sores and ingrown toe nails should be made.
Blood pressure should be reassessed if no cause is
found. If blood pressure elevation does not exceed
150/100 mmHg, the patient should continue to be
observed. If hypertension exceeds 150/100 mmHg
and a cause is either not found or found but not
feasible to eradicate quickly, pharmacological treat-
ment should be initiated.
If blood pressure elevation is between 150/100 and
180/120 mmHg, the patient should be treated with
sublingual nifedipine, oral mecamylamine, or oral
clonidine. Clonidine reduces sympathetic drive by
activating a2 adrenoreceptors in the lower brainstem.
If blood pressure exceeds 180/120 mmHg, drugs
that directly relax smooth muscle are used. They are
administered intravenously for a quick response.
These include hydralazine, nitroprusside, and diaz-
oxide. Hydralazine, which directly relaxes the
arteriolar smooth muscle, is administered as a 10-
to 20-mg dose by slow intravenous push. Nitroprus-
side dilates arterioles and venules and its dose can be
adjusted from 0.25 to 1.5 mg/kg/min. Diazoxide acts
by hyperpolarizing arterial smooth muscle cells. Its
dosage ranges from 50 to 300 mg.
In patients with recurrent life-threatening auto-
nomic dysreflexia in whom no cause is found, radical
measures may be necessary, including pudendal and
sacral nerve blocks, pelvic or pudendal nerve section,
sacral posterior rhizotomy, sympathectomy, subar-
achnoid block with alcohol or phenol, dosal root
ganglionectomy, and even cordectomy.
—Ramesh Khurana
See also–Autonomic Nervous System, Overview;
Sweating Disorders; Sympathetic System,
Overview
Further Reading
Braddon, R. L., and Rocco, J. F. (1991). Autonomic dysreflexia. A
survey of current treatment. Am. J. Phys. Med. Rehab. 70, 234–
241.
Curt, A., Nitsche, B., Rodic, B., et al. (1997). Assessment of
autonomic dysreflexia in patients with spinal cord injury. J.
Neurol. Neurosurg. Psychiatry 62, 473–477.
Guttman, L., and Whittridge, D. (1947). Effects of bladder
distension on autonomic mechanisms after spinal cord injuries.
Brain 70, 361–404.
Head, H., and Riddoch, G. (1917). The autonomic bladder,
excessive sweating and some other reflex conditions in gross
injuries of the spinal cord. Brain 46, 188–263.
Karlsson, A., Friberg, P., Lönnroth, P., et al. (1998). Regional
sympathetic function in high spinal cord injury during mental
stress and autonomic dysreflexia. Brain 121, 1711–1719.
Kewalramani, L. S. (1980). Autonomic dysreflexia in traumatic
myelopathy. Am. J. Phys. Med. 59, 1–21.
Lee, B. Y., Karmakar, M. G., Herz, B. L., et al. (1995). Autonomic
dysreflexia revisited. J. Spinal Cord Med. 18, 75–87.
Lindan, R., Joyner, E., Freehafer, A. A., et al. (1980). Incidence and
clinical features of autonomic dysreflexia in patients with spinal
cord injury. Paraplegia 18, 285–292.
Mathias, C. J., and Frankel, H. L. (1999). Autonomic disturbances
in spinal cord lesions. In Autonomic Failure (C. J. Mathias and
R. Bannister, Eds.), 4th ed., pp. 494–513. Oxford Univ. Press,
New York.
Stjernberg, L., Blumberg, H., and Wallin, B. G. (1986). Sympa-
thetic activity in man after spinal cord injury. Brain 109,
695–715.
Autonomic Nervous System,
Heart Rate and
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
HEART RATE in healthy individuals is dependent on
the discharge frequency of the pacemaker cells of the
sinoatrial node. Heart rate and stroke volume are the
determinants of cardiac output. The regulation of
both these cardiac activities is essential for the
appropriate maintenance of cardiovascular home-
ostasis. The mean heart rate in healthy adults is

approximately 70 beats per minutes, although heart
rate may range from less than 50 beats per minute
(e.g., in resting healthy athletes) to more than 180
beats per minute during physical activity.
The sinoatrial node is controlled by both divisions
of the autonomic nervous system, which usually act
reciprocally to control heart rate. At rest, heart rate
control is primarily mediated by the parasympathetic
division of the autonomic nervous system. Incremen-
tal doses of the muscarinic receptor blocker atropine
increase resting heart rate significantly, whereas
incremental doses of the b-adrenoreceptor blocker
propranolol minimally slow heart rate. The intrinsic
heart rate, which is the heart rate when both divisions
of the autonomic nervous system are effectively
blocked, is approximately 100 beats per minute.
Cardiac parasympathetic innervation is mediated
by the vagus nerves, which have their cells of origin
in the nucleus ambiguus (primarily) and the dorsal
motor nucleus of the vagus in the medulla oblongata.
These nerves synapse with postganglionic cells with-
in cardiac muscle or on the surface of the epicardium.
Cardiac parasympathetic innervation is predomi-
nantly localized in the region of the sinoatrial node
and, to a lesser extent, the atrioventricular (AV)
node. There is some asymmetry with respect to the
distribution of the right and left vagus nerves. The
right vagus nerve predominantly innervates the
sinoatrial node, whereas the left vagus nerve
predominantly innervates the AV node.
Acetylcholine, released from the nerve terminals of
the vagus nerves, acts on M2 muscarinic receptors
that are coupled directly to acetylcholine-regulated
potassium channels by a G protein. The cardiac
response following vagus nerve activation has a short
latency (50–100 msec) because the potassium chan-
nels that are opened by acetylcholine have no second
messenger system. The effects of vagal activation are
of short duration because acetylcholine is rapidly
hydrolyzed by acetylcholinesterase (which is found in
abundance in the sinoatrial and atrioventricular
nodes) and no reuptake mechanism is required for
the inactivation of this neurotransmitter. Thus, vagus
nerve stimulation results in a rapid decrease in heart
rate and, once stimulation ceases, a rapid return to
baseline. There is a curvilinear relationship between
heart rate and vagus nerve stimulus frequency,
whereas the relationship between stimulus frequency
and R-R interval (the reciprocal of heart rate) is
linear. Thus, the effects of a change in vagal efferent
activity on heart rate are dependent on the magni-
tude of the heart rate.
AUTONOMIC NERVOUS SYSTEM, HEART RATE AND 317
Cardiac sympathetic innervation has its cells of
origin in the lower cervical and upper thoracic
segments of the intermediolateral column. The
sympathetic fibers destined for the heart travel to
the paravertebral sympathetic chain via white rami
communicantes. The preganglionic and postganglio-
nic neurons synapse in the stellate or middle cervical
ganglia. The postganglionic sympathetic fibers travel
to the heart on the adventitial surface of the great
vessels and penetrate the ventricular wall along the
surface of the coronary arteries. The neurons form an
extensive plexus on the epicardial surface of the
heart. Cardiac adrenoreceptors are predominantly
b1-adrenoreceptors. The sympathetic cardiac inner-
vation has an asymmetric distribution: The right
sympathetic fibers influence heart rate more than
myocardial contractility, whereas the left sympa-
thetic fibers influence contractility more than heart
rate. In contrast to vagal nerve activation, the heart
rate response to sympathetic nerve stimulation of the
sinoatrial node has a more gradual onset. The
response requires activation of a second messenger
(predominantly cyclic AMP) in the pacemaker cells
of the sinoatrial node. In addition, the heart rate
slows more gradually after sympathetic impulses
cease because norepinephrine, the neurotransmitter
released at the adrenergic nerve terminals, must be
taken up by the sympathetic nerve terminals (requir-
ing an active reuptake mechanism) or be carried off
into the bloodstream. An additional factor contri-
buting to the difference between the two divisions of
the autonomic nervous system is that sufficient
acetylcholine to slow the heart rate significantly can
be released within one cardiac cycle, whereas the
amount of norepinephrine released during one
cardiac cycle has a minimal effect on heart rate.
—Roy Freeman and Istvan Bonyhay
See also–Acetylcholine; Autonomic Nervous
System, Overview; Cardiovascular Regulation;
Parasympathetic System, Overview; Vagus
Nerve (Cranial Nerve X)
Further Reading
Ellison, J. P., and Williams, T. H. (1969). Sympathetic nerve
pathways to the human heart, and their variations. Am. J. Anat.
124, 149–162.
Kalia, M. (1981). Brain stem localization of vagal preganglionic
neurons. J. Auton. Nerv. Syst. 3, 451–481.
Katona, P. G., McLean, M., Dighton, D. H., et al. (1982).
Sympathetic and parasympathetic cardiac control in athletes
and nonathletes at rest. J. Appl. Physiol. 52, 1652–1657.
318 AUTONOMIC NERVOUS SYSTEM, OVERVIEW

Leon, D. F., Shaver, J. A., and Leonard, J. J. (1970). Reflex heart

rate control in man. Am. Heart J. 80, 729–739.
Levy, M. N., Martin, P. J., and Stuesse, S. L. (1981). Autonomic Nervous
Neural regulation of the heart beat. Annu. Rev. Physiol. 43,
443–453. System, Overview
Loewy, A. D., and Spyer, K. M. (1990). Vagal preganglionic Encyclopedia of the Neurological Sciences
neurons. In Central Regulation of Autonomic Functions (A. D. Copyright 2003, Elsevier Science (USA). All rights reserved.

Loewy and K. M. Spyer, Eds.), pp. 68–87. Oxford Univ. Press,

New York.
Opie, L. H. (1998). The Heart: Physiology, from Cell to
Circulation. Lippincott–Raven, Philadelphia.
Parker, P., Celler, B. G., Potter, E. K., et al. (1984). Vagal
stimulation and cardiac slowing. J. Auton. Nerv. Syst. 11, 226–
231.
THE TERM autonomic nervous system (ANS) was
introduced by Langley in 1903 to describe ‘‘the
system of nerves which controls the unstriated tissue,
the cardiac muscle, and the glandular tissue of
mammals.’’ The word autonomic (autonomous,

Eye

Lacrimal &
Submandibular Glands

Lung

Superior
Heart Cervical
Ganglion
C1
C2
C3
C4
C5
C6
Stellate C7
Ganglion C8
Gastro Celiac T1
Intestinal Ganglion T2
T3
Tract T4
Greater
Splanchnic T5
T6
T7
T8
T9
Lesser T10
Splanchnic T11
Colon Superior Nerve T12
Mesenteric L1
Ganglion
L2
L3
L4
L5
S1
Inferior Mesenteric S2
Bladder
S3
Ganglion
S4
S5
Reproductive Hypogastric
Organs Ganglion

Figure 1
Schematic diagram of the sympathetic division of the peripheral autonomic nervous system. (See color plate section.)
318 AUTONOMIC NERVOUS SYSTEM, OVERVIEW

Leon, D. F., Shaver, J. A., and Leonard, J. J. (1970). Reflex heart

rate control in man. Am. Heart J. 80, 729–739.
Levy, M. N., Martin, P. J., and Stuesse, S. L. (1981). Autonomic Nervous
Neural regulation of the heart beat. Annu. Rev. Physiol. 43,
443–453. System, Overview
Loewy, A. D., and Spyer, K. M. (1990). Vagal preganglionic Encyclopedia of the Neurological Sciences
neurons. In Central Regulation of Autonomic Functions (A. D. Copyright 2003, Elsevier Science (USA). All rights reserved.

Loewy and K. M. Spyer, Eds.), pp. 68–87. Oxford Univ. Press,

New York.
Opie, L. H. (1998). The Heart: Physiology, from Cell to
Circulation. Lippincott–Raven, Philadelphia.
Parker, P., Celler, B. G., Potter, E. K., et al. (1984). Vagal
stimulation and cardiac slowing. J. Auton. Nerv. Syst. 11, 226–
231.
THE TERM autonomic nervous system (ANS) was
introduced by Langley in 1903 to describe ‘‘the
system of nerves which controls the unstriated tissue,
the cardiac muscle, and the glandular tissue of
mammals.’’ The word autonomic (autonomous,

Eye

Lacrimal &
Submandibular Glands

Lung

Superior
Heart Cervical
Ganglion
C1
C2
C3
C4
C5
C6
Stellate C7
Ganglion C8
Gastro Celiac T1
Intestinal Ganglion T2
T3
Tract T4
Greater
Splanchnic T5
T6
T7
T8
T9
Lesser T10
Splanchnic T11
Colon Superior Nerve T12
Mesenteric L1
Ganglion
L2
L3
L4
L5
S1
Inferior Mesenteric S2
Bladder
S3
Ganglion
S4
S5
Reproductive Hypogastric
Organs Ganglion

Figure 1
Schematic diagram of the sympathetic division of the peripheral autonomic nervous system. (See color plate section.)
 AUTONOMIC NERVOUS SYSTEM, OVERVIEW 319

self-governing) was chosen because the system
operates largely unconsciously. It is also referred to
as the involuntary or visceral nervous system. The
ANS controls moment-to-moment cardiovascular,
gastrointestinal, urinary, thermal, and metabolic
function and plays a prominent role in the body
response to stress (e.g., the flight-or-fight response, a
term used by Cannon). It ensures body homeostasis
producing adaptive responses to changes in the
internal milieu and external environment.
The autonomic nervous system has afferent,
central, and efferent neurons. Sensors located
throughout the body detect changes in blood pressure
(baroreceptors), blood content of oxygen and other
chemical signals (chemoreceptors), and pain (sensory
afferents). The cell bodies of afferent neurons that
carry these signals are in the dorsal root ganglia of
spinal or cranial nerves. These afferents, together
with visual, vestibular, and auditory cues, are
integrated in autonomic neurons located at several
levels of the central nervous system (CNS): cerebral
cortex, basal forebrain, hypothalamus, midbrain,
pons, medulla, and spinal cord. This network of
central neurons generates adaptive responses by
modulating the activity of efferent autonomic neu-
rons organized in two major outflows: the sympa-
thetic and parasympathetic systems (Figs. 1 and 2).
The final autonomic innervation to effector organs

Ciliary
Ganglion

Eye
Pterygopalatine
Ganglion
Lacrimal &
Palatine Glands
III
Submandibular
Submandibular & Ganglion
Sublingual Glands VII

Parotid Otic
Gland IX
Ganglion
Edinger−Westphal Nucleus
Superior Salivatory Nucleus
Lung Inferior Salivatory Nucleus
Dorsal Motor Nucleus
C1
X C2
Nucleus Ambiguus
C3
Heart C4
C5
C6
C7
C8
T1
T2
T3
Gastro T4
Intestinal T5
T6
Tract T7
T8
T9
T10
T11
T12
L1
L2
Colon L3
L4
L5
S1
S2
Bladder Pelvic Nerve S3
S4
Reproductive S5

Organs

Figure 2
Schematic diagram of the parasympathetic division of the peripheral autonomic nervous system.
320 AUTONOMIC NERVOUS SYSTEM, OVERVIEW
consists of a two-neuron pathway. The central
neuron, called preganglionic, leaves the CNS and
synapses in autonomic ganglia outside the CNS with
a ganglionic neuron, called postganglionic, which in
turn innervates the effector cell. There are significant
differences between the sympathetic and parasympa-
thetic efferent pathways. Sympathetic fibers project
from rostral neurons [e.g., hypothalamic neurons and
neurons in the rostral ventrolateral medulla,
(RVLM)] to cell bodies of preganglionic sympathetic
neurons located in the thoracolumbar segments in the
intermediolateral column of the spinal cord (Fig. 1).
These preganglionic neurons leave the spinal cord
through the anterior root and synapse with post-
ganglionic sympathetic neurons located in paraver-
tebral ganglia (bilaterally along the vertebral column
from the superior cervical ganglia, at the bifurcation
of the internal carotid arteries, to the sacral region),
preveretebral ganglia (anterior to the aorta and
vertebral column, including the celiac, aorticorenal,
superior mesenteric, and inferior mesenteric ganglia),
or visceral ganglia located close to target structures.
In general, preganglionic fibers are short and myeli-
nated, whereas postganglionic axons are long,
unmyelinated, and of small diameter (45 mm).
Medulla
NTS
CVLM
NA RVLM
IX DVN
Carotid
Preganglionic
Aortic arch Sympathetic
Neuron
Baroreflex
Afferents
Cardio-
Pulmonary
Figure 3
Schematic diagram of the baroreflex. CVLM, caudal ventrolateral medulla; DVN, dorsal motor nucleus of the vagus; IML, intermediolateral
column of the spinal cord; NA, nucleus ambiguus; NTS, nucleus tractus solitarii; RVLM, rostral ventrolateral medulla.
The parasympathetic nervous system has a cranio-
sacral distribution (Fig. 2). Preganglionic cell bodies
are located in brainstem nuclei of cranial nerves III,
VII, IX, and X and in the intermedilateral column of
the second, third, and fourth sacral segments. In
contrast to sympathetic neurons, preganglionic para-
sympathetic fibers are long, whereas postganglionic
fibers are short.
Preganglionic sympathetic and parasympathetic
neurons use acetylcholine as their main neurotrans-
mitter, as do parasympathetic postganglionic neu-
rons. Sympathetic postganglionic neurons use
norepinephrine as their main neurotransmitter, ex-
cept for sudomotor postganglionic sympathetic
fibers, which use acetylcholine.
The baroreflex is a classic example of regulatory
feedback control as exerted by the ANS (Fig. 3).
Information is collected by pressure-sensitive recep-
tors located in the walls of cardiopulmonary veins,
the right atrium, and within almost every large artery
of the neck and thorax but particularly within the
carotid and aortic arteries. Venous and the aortic
arch baroreceptors relay information via fibers that
course within the vagus nerve (cranial nerve X).
Carotid sinus baroreceptor nerve activity is relayed
Heart
IML
Postanglionic
sympathetic
neuron
Arterioles

centrally by the carotid sinus (Hering’s) nerve and
then through the glossopharyngeal nerve (cranial
nerve IX). Afferent fibers from baroreceptors first
synapse in the nucleus tractus solitarii (NTS) of the
medulla oblongata, a structure that also receives
input from many other cardiovascular brain centers
such as the area postrema. The NTS provides
excitatory input to the caudal ventrolateral medulla,
which in turn provides inhibitory influence on the
RVLM. The pacemaker neurons that originate
sympathetic tone are located in the RVLM. These
cell bodies send their efferent axons to the inter-
mediolateral column of the spinal cord, where the
cell bodies of preganglionic sympathetic neurons that
send axons outside the CNS are located. Parasympa-
thetic activity is also modulated by the NTS through
projections to the nucleus ambiguus and the dorsal
motor nucleus of the vagus, where preganglionic
parasympathetic neurons are located. An increase in
blood pressure will stretch baroreceptors and in-
crease firing of afferent fibers, resulting in activation
of the NTS and the caudal VLM, which will in turn
inhibit the RVLM to produce sympathetic with-
drawal. Activation of the NTS also results in
activation of the motor nucleus of the vagus, leading
to parasympathetic activation. The end result is a
decrease in vascular tone, myocardial contractility,
and heart rate, which brings blood pressure back to
‘‘baseline’’ levels. In general, sympathetic activation
is accompanied by parasympathetic withdrawal and
vice versa. This is likely explained by the central
integration of both pathways, as exemplified by the
role of the NTS in baroreflex responses. Sympathetic
activation to the different organs is not homoge-
neously distributed but depends on the stimuli; for
example, presyncope and hypoglycemia produce a
much greater increase in plasma epinephrine (denot-
ing adrenal stimulation) than norepinephrine. The
fight-or-flight response produces greater increase in
plasma norepinephrine (denoting sympathetic post-
ganglionic stimulation) than epinephrine.
Gastrointestinal function is not only modulated by
centrally mediated signals but also by the enteric
nervous system, a network of afferent, integrative,
and motor neurons embedded throughout the
gastrointestinal wall that operates largely indepen-
dent of central control.
—Italo Biaggioni and Horacio Kaufmann
See also–Autonomic Nervous System, Heart Rate
and; Central Nervous System, Overview; Motor
System, Overview; Parasympathetic System,
AWARENESS 321
Overview; Sensory System, Overview;
Sympathetic System, Overview; Vagus Nerve
(Cranial Nerve X); Vertebrate Nervous System,
Development of
Further Reading
Benarroch, E., Freeman, R., and Kaufmann, H. (1999). Autonomic
function. In Textbook of Clinical Neurology (C. G. Goetz and
E. J. Pappert, Eds.), pp. 350–371. Saunders, New York.
Loewy, A. D. (1990). Central autonomic pathways. In Central
Regulation of Autonomic Functions (A. D. Loewy and K. M.
Spyer, Eds.), pp. 88–103. Oxford University Press, New York.
Loewy, A. D. (1991). Forebrain nuclei involved in autonomic
control. Prog. Brain Res. 87, 253–268.
Robertson, D., Low, P. A., and Polinsky, R. J. (Eds.) (1996).
Primer on the Autonomic Nervous System. Academic Press,
San Diego.
Awareness
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AWARENESS and alertness are the two principal
components of consciousness. Awareness requires
the functional integrity of the ascending reticular
activating system, thalamus, and cerebral cortex and
is composed of a number of interconnected func-
tions, including sensation, perception, attention,
memory, self-awareness, motivation, executive fron-
tal lobe functions, and associated cognitive opera-
tions. Awareness has multiple interdependent
components and requires networking of numerous
brain regions, each with some degree of regional
specialization of function. Furthermore, many ad-
vanced cortical functions, including sensory proces-
sing and sensorimotor integration, are covert or
implicit and do not achieve full cognitive awareness
as full realization. An example is a long-distance
truck driver who can negotiate every turn in the road
but may not be consciously aware of each curve and
the movements required. Cognitive awareness im-
plies that a person is fully aware in his or her mind of
the present phenomenon being perceived or initiated
and could describe it if verbal abilities allowed.
Consciousness of self is probably necessary for
cognitive awareness.
—G. Bryan Young
See also–Acute Confusional State (Delirium);
Alertness; Concentration; Consciousness; Self-
Awareness

centrally by the carotid sinus (Hering’s) nerve and
then through the glossopharyngeal nerve (cranial
nerve IX). Afferent fibers from baroreceptors first
synapse in the nucleus tractus solitarii (NTS) of the
medulla oblongata, a structure that also receives
input from many other cardiovascular brain centers
such as the area postrema. The NTS provides
excitatory input to the caudal ventrolateral medulla,
which in turn provides inhibitory influence on the
RVLM. The pacemaker neurons that originate
sympathetic tone are located in the RVLM. These
cell bodies send their efferent axons to the inter-
mediolateral column of the spinal cord, where the
cell bodies of preganglionic sympathetic neurons that
send axons outside the CNS are located. Parasympa-
thetic activity is also modulated by the NTS through
projections to the nucleus ambiguus and the dorsal
motor nucleus of the vagus, where preganglionic
parasympathetic neurons are located. An increase in
blood pressure will stretch baroreceptors and in-
crease firing of afferent fibers, resulting in activation
of the NTS and the caudal VLM, which will in turn
inhibit the RVLM to produce sympathetic with-
drawal. Activation of the NTS also results in
activation of the motor nucleus of the vagus, leading
to parasympathetic activation. The end result is a
decrease in vascular tone, myocardial contractility,
and heart rate, which brings blood pressure back to
‘‘baseline’’ levels. In general, sympathetic activation
is accompanied by parasympathetic withdrawal and
vice versa. This is likely explained by the central
integration of both pathways, as exemplified by the
role of the NTS in baroreflex responses. Sympathetic
activation to the different organs is not homoge-
neously distributed but depends on the stimuli; for
example, presyncope and hypoglycemia produce a
much greater increase in plasma epinephrine (denot-
ing adrenal stimulation) than norepinephrine. The
fight-or-flight response produces greater increase in
plasma norepinephrine (denoting sympathetic post-
ganglionic stimulation) than epinephrine.
Gastrointestinal function is not only modulated by
centrally mediated signals but also by the enteric
nervous system, a network of afferent, integrative,
and motor neurons embedded throughout the
gastrointestinal wall that operates largely indepen-
dent of central control.
—Italo Biaggioni and Horacio Kaufmann
See also–Autonomic Nervous System, Heart Rate
and; Central Nervous System, Overview; Motor
System, Overview; Parasympathetic System,
AWARENESS 321
Overview; Sensory System, Overview;
Sympathetic System, Overview; Vagus Nerve
(Cranial Nerve X); Vertebrate Nervous System,
Development of
Further Reading
Benarroch, E., Freeman, R., and Kaufmann, H. (1999). Autonomic
function. In Textbook of Clinical Neurology (C. G. Goetz and
E. J. Pappert, Eds.), pp. 350–371. Saunders, New York.
Loewy, A. D. (1990). Central autonomic pathways. In Central
Regulation of Autonomic Functions (A. D. Loewy and K. M.
Spyer, Eds.), pp. 88–103. Oxford University Press, New York.
Loewy, A. D. (1991). Forebrain nuclei involved in autonomic
control. Prog. Brain Res. 87, 253–268.
Robertson, D., Low, P. A., and Polinsky, R. J. (Eds.) (1996).
Primer on the Autonomic Nervous System. Academic Press,
San Diego.
Awareness
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AWARENESS and alertness are the two principal
components of consciousness. Awareness requires
the functional integrity of the ascending reticular
activating system, thalamus, and cerebral cortex and
is composed of a number of interconnected func-
tions, including sensation, perception, attention,
memory, self-awareness, motivation, executive fron-
tal lobe functions, and associated cognitive opera-
tions. Awareness has multiple interdependent
components and requires networking of numerous
brain regions, each with some degree of regional
specialization of function. Furthermore, many ad-
vanced cortical functions, including sensory proces-
sing and sensorimotor integration, are covert or
implicit and do not achieve full cognitive awareness
as full realization. An example is a long-distance
truck driver who can negotiate every turn in the road
but may not be consciously aware of each curve and
the movements required. Cognitive awareness im-
plies that a person is fully aware in his or her mind of
the present phenomenon being perceived or initiated
and could describe it if verbal abilities allowed.
Consciousness of self is probably necessary for
cognitive awareness.
—G. Bryan Young
See also–Acute Confusional State (Delirium);
Alertness; Concentration; Consciousness; Self-
Awareness
322 AXONS
Axons
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
WHEN ONE THINKS of nerve fibers, whether those in
the white matter of the brain or spinal cord or those
in peripheral nerves, one is thinking of axons. Axons
are a type of cytoplasmic prolongation of neurons
that carry a message, sometimes over considerable
distances in the body, to the nerve terminals to
deliver the output signal (Fig. 1).
The signal that axons carry is known as an action
potential, and it is essentially the same in all neurons.
It is an all-or-none signal that varies only in speed of
propagation and rate of repetition. In other words,
the individuality of function of a neuron is not
determined by the type of signal conducted by the
axon but rather by where the axon goes and what
transmitter is released at its terminal.
Action potential is discussed in detail elsewhere in
this encyclopedia. Suffice it to say that the axon
potential depends on opening of voltage-sensitive
sodium channels in the axolemma, allowing sudden
massive influx of sodium from the extracellular
space, in which its concentration is high, into the
axon, in which its concentration is low. This flow
Figure 1
An electron micrograph of axons in a normal peripheral nerve. In
the center is a small myelinated axon (M). It is surrounded by
unmyelinated axons (U), which are wrapped in Schwann cell
cytoplasm. Neurofilaments are cut across and appear as small dots
or dashes. Neurotubules appear as small circles (arrow).
reverses the membrane polarity briefly, causing
adjacent sodium channels to open. The action
potential thus propagates down the axon to the
terminal.
This, however, is only half the story. To make
possible rapid repetition of action potentials, there
must be a mechanism to rapidly restore the normal
membrane potential. This is achieved by voltage-
sensitive potassium channels that, like sodium
channels, open when the membrane is depolarized
but do so with a significant delay. The concentration
of potassium is much higher within the axons than
outside. The delay allows the sodium ions to pour
into the axon and reverse the membrane potential
before the potassium ions begin to pour out and
restore it.
The larger the axons, the faster the transmission of
the action potential. Two factors come into play.
First, increasing the axonal diameter reduces the
axial resistance. Second, and more important, axons
more than 2 mm in diameter are completely covered
by myelin sheaths except for the small gap between
two successive sheaths, which is known as the node
of Ranvier. At this gap, the axonal sodium channels
are concentrated. The myelin, which is formed of
layer upon layer of membrane derived from an
oligodendroglial or Schwann cell, greatly reduces the
membrane capacitance of the part of the axon
between nodes. In this part, sodium channels are
virtually absent. The action potential in these axons
thus moves from one node of Ranvier to the next,
with a great gain in speed. In axons without myelin,
the sodium channels are uniformly distributed and
conduction is much slower. In general, the thicker the
axon, the thicker and longer the segments of myelin
that ensheathe it and the faster its transmission.
After electrically stimulating a peripheral nerve, it
is possible to record the sum of its action potentials
at a distance of some centimeters. This is called the
compound action potential. Because of the presence
of axons with various speeds of transmission, there is
dispersion of the signal, resulting in three distinct
components: the Aa, Ad, and C components, which
correspond respectively to large myelinated fibers,
small myelinated fibers, and unmyelinated fibers.
These peaks can be correlated with histograms of the
axonal content of the nerve, and in diseases of the
peripheral nerves they can give valuable information
about the degree of damage to the various types of
fibers. When the action potential arrives at terminals,
it does not directly cause release of synaptic vesicles.
Instead, it causes voltage-sensitive calcium channels

to open, and it is the resultant calcium current that
drives the release of synaptic vesicles. Some neurons
release more than one type of transmitter at their
terminals, often in response to different patterns of
arrival of action potentials. As shown by electron
microscopy, axons contain long neurofilaments and
neurotubules as well as mitochondria, vesicles, and
smooth endoplasmic reticulum. The lack of ribo-
somes means that protein synthesis does not take
place in axons, and they have to depend on axonal
transport from the perikaryon for the proteins and
other membrane components that they need to
survive and function.
Axonal transport or axonal flow can be separated
into various components that have been identified
using radioautography. Slow axonal transport in turn
is divided into two components, a and b. Neurofila-
ments and microtubules form the bulk of component
a, which travels at a rate of 0.25–1 mm per day.
Component b contains actin monomers and various
enzymes, which travel 2–4 mm per day. Fast
transport reaches 400 mm per day and involves
organelles, such as mitochondria and vesicles. The
latter may contain precursors of transmitter mole-
cules or membrane components. Retrograde trans-
port back toward the cell body moves at 200 mm per
day. It carries damaged organelles, lysosomes, and
vesicles, which may contain molecules taken up by
the terminal such as trophic factors.
Neurotubules are approximately 24 mm in dia-
meter. They are essential for fast axonal transport.
Vesicles or mitochondria become attached to the
neurotubules through a molecular motor called
kinesin, which inches its way toward the plus end
AXONS 323
of the tubule, carrying the organelle. Retrograde
axonal transport occurs by an analogous mechanism,
but the motor molecule involved, which moves
toward the minus end of neurotubules, is called
dynein. The neurotubules exist in equilibrium with
soluble monomers of tubulin, which can be added to
their plus end.
Neurofilaments are 10 nm in diameter. They are
one of the most prominent components of axons.
The routine histological stains used to identify axons
stain their neurofilaments. They belong to the family
of intermediate filaments, which includes keratin
in epithelial cells, desmin in muscle cells, vimentin
in fibroblasts and endothelium, and glial fibril-
lary acidic protein in astrocytes. Three types of
neurofilament protein copolymerize to form the
neurofilament. Neurofilaments probably contribute
mechanical stability to the axon. They slowly move
along the axon toward the terminals, where they are
broken down. Special methods of preparation for
electron microscopy show that axons also contain an
abundant fine microtrabecular matrix that intercon-
nects neurofilaments.
—Stirling Carpenter
See also–Action Potential, Generation of;
Dendrites; Myelin; Nervous Tissue, Non-Neural
Components of; Neurons, Overview; White
Matter
Further Reading
Waxman, S. G., Kocsis, J. D., and Stys, P. K. (Eds.) (1995). The
Axon: Structure, Function, and Pathophysiology. Oxford Univ.
Press, New York.

Ballism is frequently unilateral and is referred to as
hemiballism. This is usually the result of deep brain
lesions including the contralateral subthalamic nu-
cleus. The most common cause is stroke, but other
processes that produce focal central nervous system
disease have also been implicated, such as metabolic
and endocrine disturbances; drugs such as levodopa,
ibuprofen, oral contraceptives, and anticonvulsi-
vants; inflammation (including systemic lupus
erythematosus, Sydenham’s chorea, and antipho-
spholipid antibody syndrome); and neoplasms.
Because an increased dopamine turnover is prob-
ably involved in the pathophysiology of ballistic
movements, antidopaminergic drugs, especially reser-
pine and tetrabenazine, have been reported to show
marked benefit. Recently, high-frequency electrical
stimulation of deep brain regions (nucleus ventralis
intermedius of the thalamus) has been proposed as an
alternative option when medical therapy fails.
—Esther Cubo and Christopher G. Goetz
See also–Basal Ganglia, Diseases of; Dopamine;
Dyskinesias; Lacunar Infarcts; Movement
Disorders, Overview
Further Reading
Shannon, K. (1998). Ballism. In Parkinson’s Disease and Move-
ment Disorders (J. Jankovic and E. Tolosa, Eds.), pp. 365–376.
Williams & Wilkins, Philadelphia.
Bárány, Robert
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ROBERT BÁRÁNY (1876–1936) was the founder of
modern clinical neuro-otology. A gifted theoretician,
BÁRÁNY, ROBERT 343
possessed with a keen sense of observation, Bárány
had the unique ability to synthesize a multitude of
clinical observations and investigations into a cogent
theoretical framework. Through his work, he has
provided the basis for our modern understanding of
labyrinthine function and established several classic
components of the neuro-otologic exam.
Born in Vienna in 1876, Bárány was raised and
educated in a city at the zenith of medical science.
After graduating with a degree in medicine in 1900,
Bárány studied internal medicine, neurology, and
psychiatry with some of the greatest minds of his
time: von Noorden, Kraepelin, and Freud. In 1905,
he was appointed to the ear clinic in Vienna and
restricted his work to otology. Intrigued by the
nystagmus produced by syringing patient’s ears,
Bárány astutely discovered that the phenomenon
was dependent on the temperature of the water.
Combining detailed clinical observations with phy-
sical theory, he penned his classic thesis ‘‘Investiga-
tions on the Rhythmical Nystagmus which Is Created
by Reflexes from the Vestibular Apparatus of the Ear
and Its Associated Phenomena.’’ In this epic work,
Bárány developed the modern physical theory of
caloric nystagmus. Bárány noticed that many pa-
tients in his clinic complained of dizziness after
flushing their ears. He keenly observed that the
patients’ dizziness and the direction of the accom-
panying nystagmus were dependent on the tempera-
ture of the water. Using the analogy of a bath oven,
Bárány hypothesized that the water used to flush the
ears produced convection currents in the labyrinth by
heating or cooling the adjacent endolymph fluid. He
was subsequently able to prove this theory through a
series of eloquent clinical experiments.
In the next several years, Bárány published
additional observations on the vestibular effects of
rotational and optokinetic stimuli. His research was
rapidly adopted in the clinic, and caloric and
rotational testing quickly became essential elements
of the neurootologic evaluation. In 1910, Bárány
introduced rapid passive movements as a standard
part of the vestibular exam and described their utility
in diagnosing unilateral vestibular pathology of
various etiologies.
In 1914, Bárány’s tremendous contributions to
medicine were recognized by his receipt of the Nobel
Prize in physiology and medicine. At the time of the
award, Bárány was a Russian prisoner of war in
Turkestan. Through the thoughtful interventions of
the Swedish royal family, the Russian Academy of
Sciences, and the Swedish Red Cross, he was released
344 BARTONELLA INFECTIONS
in 1916 to receive his award. He was quickly given
refuge in Sweden and subsequently made professor of
otolaryngology at Uppsala.
After settling in his adoptive Sweden, Bárány
continued to make significant contributions to vesti-
bular science and clinical otology. He was the first to
describe positional nystagmus and to investigate the
roles of the cerebellum and neck proprioceptors in
vestibulo-ocular control. As a surgeon, he performed
some of the earliest procedures for otosclerosis and
described a novel operation for the treatment of
chronic frontal sinusitis. His contributions to science,
however, were not restricted to vestibular research.
Bárány published on the division of the granular
layer of the binocular visual cortex and the forma-
tion of psychiatric neuroses. He authored numerous
manuscripts and edited several scientific journals.
Bárány possessed the unique ability to combine the
old with the new, to meld established data with new
theories. Modern vestibular research stands firmly on
his groundbreaking ideas, and current clinical
vestibular testing is rooted in his clinical methods.
His contributions to modern neuro-otology are
enormous and continue to reap benefits more than
60 years after his death.
—Jeffrey L. Bennett
See also–Neuro-Otology; Nystagmus and
Saccadic Intrusions and Oscillations; Optokinetic
Nystagmus; Vestibular System (see Index entry
Biography for complete list of biographical
entries)
Further Reading
Bárány, R. (1906). Untersuchungen über den vom Vestibularap-
parat des Ohres reflektorisch ausgelösten rhytmischen Nystag-
mus und seine Begleiterscheinungen. Monatsschr. Ohrenheilkd.
40, 193–297.
Lanska, D. J., and Remler, B. (1997). Benign paroxysmal
positioning vertigo: Classic descriptions, origins of the provo-
cative positioning technique, and conceptual developments.
Neurology 48, 1167–1177.
Stevenson, L. G. (1953). Nobel Prize Winners in Medicine and
Physiology, 1901–1950. Schuman, New York.
Bartonella Infections
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CAT-SCRATCH disease was first described in 1950 at
the Societé Medical des Hôpitaux by Robert Debre, a
professor of pediatrics at the University of Paris.
Pierre Mollaret, professor of infectious diseases and
Chief of Service at the Pasteur Institute, was the
senior author of 14 papers written on cat-scratch
disease in 1950 and 1951 and, in conjunction with J.
Reuilly, made an antigen (from pus aspirated from the
lymph nodes of patients with clinical features of cat-
scratch disease) for intradermal testing. The causative
organism of the majority of cases of cat-scratch
disease is Bartonella (Rochalimaea) henselae, a small,
pleomorphic, gram-negative, rod-shaped bacterium.
Some cases of cat-scratch disease may be caused by
Bartonella quintana or Afipia felis. Bartonella quin-
tana is the causative organism of trench fever.
Cat-scratch disease presents as fever with unilat-
eral regional lymphadenopathy. There is often
evidence of cat scratches on the hand or arm in the
region of the lymphadenopathy.
A variety of clinical syndromes have been reported
in immunocompetent patients with B. henselae
infection, including unilateral lymphadenitis, ence-
phalopathy with adenopathy and seizures, Leber’s
stellate neuroretinitis, Parinaud’s oculoglandular
syndrome (conjunctival granuloma with preauricular
adenopathy), a chronic fatigue syndrome-like dis-
ease, and aseptic meningitis with relapsing fever due
to B. henselae bacteremia. Lymphadenitis is the most
frequently observed syndrome. Neuroretinitis, pre-
senting with painless unilateral loss of visual acuity
and retinal edema with some degree of optic disk
swelling and a macular star, is the second most
common presentation of B. henselae infection.
Family members may develop lymphadenitis or
neuroretinitis simultaneously.
Bacillary angiomatosis was first described in
HIV-infected individuals who had subcutaneous and
vascular lesions mimicking Kaposi’s sarcoma. Bacil-
lary angiomatosis derives its name from the prolifera-
tion of blood vessels seen on histological examination
of affected tissues with numerous gram-negative
bacilli demonstrated by Warthin–Starry silver stain. In
HIV-infected individuals, B. henselae and B. quintana
have been isolated from cutaneous bacillary angio-
matosis lesions. Disseminated disease may involve
skin, lymph nodes, liver, spleen, the gastrointestinal or
respiratory tract, and the central nervous system.
Acute psychosis has been reported in association with
cerebral bacillary angiomatosis. Cognitive difficulty
and dementia in HIV-infected individuals has been
associated with serum antibodies to Bartonella,
suggesting Bartonella infection may be a treatable
cause of dementia in some HIV-infected individuals.
326 BABINSKI SIGN
pathology affecting motor function. Later neurolo-
gists seized upon the idea and introduced many
variations on the method of eliciting the reflex, but
the fundamental clinical insight remained valid, and
the Babinski sign is now a standard and indispen-
sable component of the neurological examination.
Babinski was a quintessential clinical neurologist
who emphasized above all the value of careful and
thorough observation. In this respect, he personified
the emerging reputation of neurology as a meticulous
medical discipline in which clinical data provide the
foundation for detailed understanding of the nervous
system and its many afflictions. He was one of the
illustrious pupils of Charcot who ably carried on the
tradition of his predecessor and also paved the way
for his successors.
—Christopher Mark Filley
See also–Babinski Sign; Charcot, Jean-Martin
(see Index entry Biography for complete list of
biographical entries)
Further Reading
Babinski, J. F. F. (1896). Sur le réflexe cutané plaintaire dans
certains affections organiques du système nerveux centrale. C.
R. Soc. Séances Biol. 48, 207–208.
Haymaker, W. (1953). The Founders of Neurology. Thomas,
Springfield, IL.
van Gijn, J. (1996). The Babinski Sign: A Centenary. Universiteit
Utrecht, Utrecht, The Netherlands.
Babinski Sign
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BABINSKI SIGN is a cutaneous reflex in which the
great toe moves upward on stimulation of the sole of
the foot. However, it is more complicated than
simply toe movements. The plantar reflex was
known to physicians in the mid-19th century in the
sense of reflex withdrawal of the entire leg.
Analogous phenomena were known from animal
studies; they were mediated by the spinal cord (i.e.,
involuntary). In this reflex response, several flexor
muscles (muscles that shorten the limb) are activated
at the same time (a flexor synergy). In humans,
sometimes movements of the toes were noted as part
of the synergy, in one direction or another. Little
importance was attached to these observations.
Babinski (1857–1932) was the first to perform a
systematic study of toe responses after stimulation of
the sole of the foot. In a famous brief communication
published in 1896, he noted that normally the toes,
especially the great toe, move downward during the
withdrawal response, but that in diseases of the brain
and spinal cord they move upward. It is this upward
toe response that has become known as the Babinski
sign. It was not a chance observation. Babinski
devoted himself to a systematic study of hemiplegic
patients with the aim of finding objective signs that
were characteristic of organic disease and thereby
could help in distinguishing this from hysterical
hemiplegia.
In 1897, Babinski more specifically associated the
‘‘toe phenomenon’’ with dysfunction of the pyrami-
dal tract, the descending fiber system that connects
the motor cortex of the brain with motor neurons of
limb muscles, especially those of hands and feet. At
the same time, he drew a parallel with the plantar
reflex in the newborn, in whom the pyramidal system
is not yet fully developed. One year later, he added a
few more details; for example, reflex extension of the
toes is most easily elicited from the outer side of the
sole, whereas it is the opposite for the normal
downward response of the toes. Also, he observed
the abnormal response in metabolic disorders (epi-
lepsy, intoxication with strychnine, and meningitis).
PATHOPHYSIOLOGY
From a physiological standpoint, it makes sense that
in the newborn the toes move up as part of the
flexion synergy: The limb is shortened by this
movement, at least if one stands on tiptoes, as most
animals do. That the anatomists have given the name
‘‘extensor’’ to muscles moving the toes upward is a
confusing detail best forgotten here. As the pyrami-
dal tract becomes fully developed between the first
and second years of life, two functional changes
occur. First, reflex withdrawal of the leg becomes less
marked. Second, and most important, the influence
of the pyramidal tract is strongest on distal muscles
and, in the leg, on flexor muscles; due to this
influence, the upward movement of the great toe
becomes excluded from the flexion synergy of the leg.
This suppression clears the way for the normal
(downward) response of the toes; this response is not
part of a reflex synergy but a unisegmental skin
response, very similar to the abdominal reflexes. In
this way, lesions of the pyramidal system cause a
return of the neonatal form of the withdrawal
response.

Figure 1
The upward toe response (Babinski sign) after stimulation of the
sole of the foot. The toe moves up with respect to the foot; the
tendon of the active muscle protrudes under the skin (thin arrow).
At the same time, the foot moves upward in the ankle, by action of
the muscle that can be seen and felt at the outer rim of the shin
(arrowhead), the hamstring muscles tighten (arrow), and
contraction of a superficial flexor muscle in the thigh causes
rippling of the skin (short arrow).
PRACTICALITIES
In the practical interpretation of toe responses, it is
important to consider the rest of the leg (i.e., to take
account of the entire flexion synergy). First, the great
toe should move upward, not just the foot (and the
toe with it). The tendon overlying the great toe
should be seen to tighten. There may be simultaneous
spreading of the smaller toes, but this is also seen in
some healthy people. Second, if the great toe moves
upward, it should do so at the same time as
contraction of other flexor muscles in the leg. These
may not cause large displacement, but tendons can
be seen or felt to tighten near the shin, at the back of
the knee (hamstring muscles), and in the thigh
(Fig. 1). Third, it should be possible to evoke the
response several times; each time stimulation of the
skin stops, the response should stop as well.
—J. van Gijn
See also–Babinski, Josef-Francois-Felix; Remak,
Robert
Further Reading
Babinski, J. (1896). Sur le réflexe cutané plantaire dans certaines
affections organiques du système nerveux centrale. C. R.
Séances Soc. Biol. 48, 207–208.
van Gijn, J. (1996). The Babinski Sign: A Centenary. Universiteit
Utrecht, Utrecht, The Netherlands.
BACTERIAL ABSCESS, CEREBRAL 327
Bacterial Abscess, Cerebral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN ABSCESS is a focal, suppurative process
within the brain parenchyma that begins in an
area of cerebritis or devitalized brain tissue and
develops into a collection of pus surrounded by a
well-vascularized capsule. A brain abscess may arise
from a contiguous cranial infection, of which the
most important are chronic otitis media, frontoeth-
moidal sinusitis, and acute dental infections, or from
hematogeneous spread of infection from a remote
site. Contiguous infections lead to brain abscess
formation by one of two mechanisms: either via
direct extension through osteomyelitic bone or via
retrograde transit of infecting bacteria through the
valveless emissary veins that drain the sinuses, middle
ear, and teeth into the venous drainage system of the
brain. Abscesses that develop as a result of direct
spread of infection from the frontal, ethmoidal, or
sphenoidal sinuses, and those that occur due to
dental infections, are usually located in the frontal
lobes, often in the frontal lobe ipsilateral to the
involved sinus. The most common pathogens in brain
abscess associated with paranasal sinusitis are
microaerophilic and anaerobic streptococci, Haemo-
philus species, Bacteroides species (non-fragilis), and
Enterobacteriaceae. The most common pathogens in
brain abscess from dental infections are streptococci,
Bacteroides fragilis, and Fusobacterium species.
Brain abscesses that are due to spread of infection
from chronic otitis media are located in the temporal
lobe in 50–70% of cases and in the cerebellum in 20–
30% of cases. The improved therapy of ear infections
in children during the past few decades has led to a
decreasing incidence of both temporal lobe and
cerebellar abscesses. Chronic otitis media remains a
significant predisposing cause of brain abscess in
developing countries. Cholesteatoma is an important
risk factor for the development of a brain abscess.
The majority of brain abscesses associated with otitis
media and mastoiditis are solitary lesions that are
caused by streptococci, Bacteroides species (includ-
ing B. fragilis), Pseudomonas aeruginosa, and
Enterobacteriaceae.
Twenty-five percent of brain abscesses occur as a
result of hematogeneous spread of infection from a
remote site, most commonly from a cardiac or
pulmonary source. Brain abscess formation occurs
in areas of devitalized brain tissue from hypoxia,
Babinski, Joseph Francois Felix
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE NAME of Joseph Babinski (1857–1932) is one of
the most familiar in neurology, and indeed all of
medicine, because of the important cutaneous reflex
named after him. Students of neurology have long
learned to test assiduously for the extensor plantar
response as a sign of corticospinal tract dysfunction,
and the ‘‘Babinski sign’’ is justifiably well-known as
one of the most simple and informative tests in
clinical medicine. For this as well as other contribu-
tions, Babinski is remembered as a notable figure in
the history of neurology.
Babinski was born in Paris and was educated in
both general medicine and neurology. After graduat-
ing from the University of Paris in 1884, he was a
student at the Salpêtrière Hospital under the famed
neurologist Jean Marie Charcot (1825–1893). In
1890, Babinski founded the neurology service at the
Hospital de la Pitié, where he worked until 1927.
During his long and productive career, he wrote on
many topics in neurology, including the Argyll
Robertson pupil in neurosyphilis, cerebellar dysfunc-
tion, and many reflexes including the plantar
response. He became well-known for his ideas on
hysteria, which grew out of the interest in this
disorder generated by Charcot. Babinski proposed
that hysteria, or ‘‘pithiatisme’’ in his terminology,
was produced by suggestion and abolished by
countersuggestion. Although the diagnosis of hyster-
ia has since fallen into disfavor, the recognition of
suggestibility as a feature of many patients seen in
neurological practice was a valuable clinical lesson.
Later in his career, Babinski also became interested in
neurosurgical disorders, and in 1922 he diagnosed
the first spinal cord tumor to be removed in France.
He thus helped inaugurate the modern era of
neurosurgery in France and elsewhere. Babinski
was a steady and conscientious investigator in
neurology, and he authored an impressive 288
publications over a period extending from 1882 to
1930.
The initial description of what would become the
most famous sign in neurology was a 28-line note
delivered by Babinski at the Société de Biologie in
1896. He observed that, in cases of hemiplegia or
crural monoplegia from disease of the brain or spinal
cord, stimulation of the plantar surface of the foot
elicited extension of the great toe rather than the
expected flexion. Although the full significance of
this readily obtained reflex was not appreciated
until after the turn of the century, Babinski cor-
rectly realized that an extensor plantar response
was a reliable indicator of central nervous system
325
326 BABINSKI SIGN
pathology affecting motor function. Later neurolo-
gists seized upon the idea and introduced many
variations on the method of eliciting the reflex, but
the fundamental clinical insight remained valid, and
the Babinski sign is now a standard and indispen-
sable component of the neurological examination.
Babinski was a quintessential clinical neurologist
who emphasized above all the value of careful and
thorough observation. In this respect, he personified
the emerging reputation of neurology as a meticulous
medical discipline in which clinical data provide the
foundation for detailed understanding of the nervous
system and its many afflictions. He was one of the
illustrious pupils of Charcot who ably carried on the
tradition of his predecessor and also paved the way
for his successors.
—Christopher Mark Filley
See also–Babinski Sign; Charcot, Jean-Martin
(see Index entry Biography for complete list of
biographical entries)
Further Reading
Babinski, J. F. F. (1896). Sur le réflexe cutané plaintaire dans
certains affections organiques du système nerveux centrale. C.
R. Soc. Séances Biol. 48, 207–208.
Haymaker, W. (1953). The Founders of Neurology. Thomas,
Springfield, IL.
van Gijn, J. (1996). The Babinski Sign: A Centenary. Universiteit
Utrecht, Utrecht, The Netherlands.
Babinski Sign
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BABINSKI SIGN is a cutaneous reflex in which the
great toe moves upward on stimulation of the sole of
the foot. However, it is more complicated than
simply toe movements. The plantar reflex was
known to physicians in the mid-19th century in the
sense of reflex withdrawal of the entire leg.
Analogous phenomena were known from animal
studies; they were mediated by the spinal cord (i.e.,
involuntary). In this reflex response, several flexor
muscles (muscles that shorten the limb) are activated
at the same time (a flexor synergy). In humans,
sometimes movements of the toes were noted as part
of the synergy, in one direction or another. Little
importance was attached to these observations.
Babinski (1857–1932) was the first to perform a
systematic study of toe responses after stimulation of
the sole of the foot. In a famous brief communication
published in 1896, he noted that normally the toes,
especially the great toe, move downward during the
withdrawal response, but that in diseases of the brain
and spinal cord they move upward. It is this upward
toe response that has become known as the Babinski
sign. It was not a chance observation. Babinski
devoted himself to a systematic study of hemiplegic
patients with the aim of finding objective signs that
were characteristic of organic disease and thereby
could help in distinguishing this from hysterical
hemiplegia.
In 1897, Babinski more specifically associated the
‘‘toe phenomenon’’ with dysfunction of the pyrami-
dal tract, the descending fiber system that connects
the motor cortex of the brain with motor neurons of
limb muscles, especially those of hands and feet. At
the same time, he drew a parallel with the plantar
reflex in the newborn, in whom the pyramidal system
is not yet fully developed. One year later, he added a
few more details; for example, reflex extension of the
toes is most easily elicited from the outer side of the
sole, whereas it is the opposite for the normal
downward response of the toes. Also, he observed
the abnormal response in metabolic disorders (epi-
lepsy, intoxication with strychnine, and meningitis).
PATHOPHYSIOLOGY
From a physiological standpoint, it makes sense that
in the newborn the toes move up as part of the
flexion synergy: The limb is shortened by this
movement, at least if one stands on tiptoes, as most
animals do. That the anatomists have given the name
‘‘extensor’’ to muscles moving the toes upward is a
confusing detail best forgotten here. As the pyrami-
dal tract becomes fully developed between the first
and second years of life, two functional changes
occur. First, reflex withdrawal of the leg becomes less
marked. Second, and most important, the influence
of the pyramidal tract is strongest on distal muscles
and, in the leg, on flexor muscles; due to this
influence, the upward movement of the great toe
becomes excluded from the flexion synergy of the leg.
This suppression clears the way for the normal
(downward) response of the toes; this response is not
part of a reflex synergy but a unisegmental skin
response, very similar to the abdominal reflexes. In
this way, lesions of the pyramidal system cause a
return of the neonatal form of the withdrawal
response.

Figure 1
The upward toe response (Babinski sign) after stimulation of the
sole of the foot. The toe moves up with respect to the foot; the
tendon of the active muscle protrudes under the skin (thin arrow).
At the same time, the foot moves upward in the ankle, by action of
the muscle that can be seen and felt at the outer rim of the shin
(arrowhead), the hamstring muscles tighten (arrow), and
contraction of a superficial flexor muscle in the thigh causes
rippling of the skin (short arrow).
PRACTICALITIES
In the practical interpretation of toe responses, it is
important to consider the rest of the leg (i.e., to take
account of the entire flexion synergy). First, the great
toe should move upward, not just the foot (and the
toe with it). The tendon overlying the great toe
should be seen to tighten. There may be simultaneous
spreading of the smaller toes, but this is also seen in
some healthy people. Second, if the great toe moves
upward, it should do so at the same time as
contraction of other flexor muscles in the leg. These
may not cause large displacement, but tendons can
be seen or felt to tighten near the shin, at the back of
the knee (hamstring muscles), and in the thigh
(Fig. 1). Third, it should be possible to evoke the
response several times; each time stimulation of the
skin stops, the response should stop as well.
—J. van Gijn
See also–Babinski, Josef-Francois-Felix; Remak,
Robert
Further Reading
Babinski, J. (1896). Sur le réflexe cutané plantaire dans certaines
affections organiques du système nerveux centrale. C. R.
Séances Soc. Biol. 48, 207–208.
van Gijn, J. (1996). The Babinski Sign: A Centenary. Universiteit
Utrecht, Utrecht, The Netherlands.
BACTERIAL ABSCESS, CEREBRAL 327
Bacterial Abscess, Cerebral
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN ABSCESS is a focal, suppurative process
within the brain parenchyma that begins in an
area of cerebritis or devitalized brain tissue and
develops into a collection of pus surrounded by a
well-vascularized capsule. A brain abscess may arise
from a contiguous cranial infection, of which the
most important are chronic otitis media, frontoeth-
moidal sinusitis, and acute dental infections, or from
hematogeneous spread of infection from a remote
site. Contiguous infections lead to brain abscess
formation by one of two mechanisms: either via
direct extension through osteomyelitic bone or via
retrograde transit of infecting bacteria through the
valveless emissary veins that drain the sinuses, middle
ear, and teeth into the venous drainage system of the
brain. Abscesses that develop as a result of direct
spread of infection from the frontal, ethmoidal, or
sphenoidal sinuses, and those that occur due to
dental infections, are usually located in the frontal
lobes, often in the frontal lobe ipsilateral to the
involved sinus. The most common pathogens in brain
abscess associated with paranasal sinusitis are
microaerophilic and anaerobic streptococci, Haemo-
philus species, Bacteroides species (non-fragilis), and
Enterobacteriaceae. The most common pathogens in
brain abscess from dental infections are streptococci,
Bacteroides fragilis, and Fusobacterium species.
Brain abscesses that are due to spread of infection
from chronic otitis media are located in the temporal
lobe in 50–70% of cases and in the cerebellum in 20–
30% of cases. The improved therapy of ear infections
in children during the past few decades has led to a
decreasing incidence of both temporal lobe and
cerebellar abscesses. Chronic otitis media remains a
significant predisposing cause of brain abscess in
developing countries. Cholesteatoma is an important
risk factor for the development of a brain abscess.
The majority of brain abscesses associated with otitis
media and mastoiditis are solitary lesions that are
caused by streptococci, Bacteroides species (includ-
ing B. fragilis), Pseudomonas aeruginosa, and
Enterobacteriaceae.
Twenty-five percent of brain abscesses occur as a
result of hematogeneous spread of infection from a
remote site, most commonly from a cardiac or
pulmonary source. Brain abscess formation occurs
in areas of devitalized brain tissue from hypoxia,
328 BACTERIAL ABSCESS, CEREBRAL
ischemia, or infarction. The majority of brain
abscesses that arise from a contiguous infection are
solitary, whereas those that arise from hematoge-
neous spread of infection tend to be multiple and to
occur at the junction of the cortex and the
subcortical white matter in the territory of the
middle cerebral artery. Chronic lung infections,
pulmonary arteriovenous fistulas, cardiac malforma-
tions that produce a right-to-left shunt (especially
tetralogy of Fallot, atrial and ventricular septal
defects, and transposition of the great vessels), and
hereditary hemorrhagic telangiectasia (Rendu–
Osler–Weber syndrome) are predisposing conditions
for brain abscess formation. Cyanotic congenital
heart disease is a significant predisposing factor for
brain abscess in children. Decreased arterial oxyge-
nation and saturation due to the right-to-left shunt
results in polycythemia and increased blood viscosity
that leads to cerebral microinfarction, creating focal
areas of brain ischemia that serve as a nidus for
infection for microorganisms that bypass the pul-
monary circulation to form an abscess. Streptococci
are the most common pathogens in this setting. A
brain abscess associated with a pyogenic lung
infection (lung abscess and empyema) is often due
to Streptococcus species, Actinomyces species, Fuso-
bacterium species, and Nocardia asteroides.
When brain abscess formation complicates
endocarditis, the abscesses are often small, multiple,
and due to viridans streptococci or Staphylococcus
aureus. Approximately 15–30% of brain abscesses
have no identifiable predisposing source of infection
and are referred to as cryptogenic.
Penetrating craniocerebral trauma or a neurosur-
gical procedure can also be the cause of a brain
abscess. Brain abscess formation can complicate
craniotomy if organisms are introduced at the time
of surgery or spread intracranially from an overlying
wound or bone infection. Meningitis, however, is a
much more common complication of a neurosurgical
procedure than brain abscess formation. Penetrating
craniocerebral trauma can be the source of a brain
abscess when contaminated retained bone fragments
and debris produce a nidus of infection that evolves
into an abscess. An abscess that complicates a
neurosurgical procedure is usually due to staphylo-
cocci, Enterobacteriaceae, or Pseudomonas species,
and those that follow penetrating head trauma are
typically due to S. aureus, Clostridium species, or
Enterobacteriaceae.
A brain abscess presents as an expanding
intracranial mass lesion rather than as an infectious
process. The most common symptom is headache,
occurring in 475% of patients. The headache is
often characterized as a constant, dull, aching
sensation that is either hemicranial or generalized
and gets progressively more severe and refractory to
therapy. Fever is present in only 50% of patients at
the time of diagnosis. The clinical presentation of a
brain abscess is influenced by the size and location of
the abscess, the severity of the cerebral edema, and
the degree of increased intracranial pressure. In most
large series, 460% of patients have a focal
neurological deficit at the time of presentation.
Frontal lobe abscesses present with hemiparesis,
temporal lobe abscesses with a disturbance of
language and visual field defects (superior quadran-
tanopsia), and cerebellar abscess with ataxia, nys-
tagmus, nausea, vomiting, and headache. As cerebral
edema develops, there may be signs of increased
intracranial pressure, including an altered level of
consciousness, nausea, vomiting, and papilledema.
Seizures occur in 25–40% of patients. Meningismus
is not present unless the abscess has ruptured into the
ventricle or infection has spread to the subarachnoid
space.
The diagnosis of a brain abscess is made by
neuroimaging studies. Computed tomography (CT)
has the advantage of being easy to do in acutely ill
patients, but magnetic resonance imaging (MRI) is
better able to demonstrate abscesses in their early
(cerebritis) stages and is superior to CT for identifying
abscesses in the posterior fossa. On MRI, cerebritis
has the appearance of low signal intensity on
T1-weighted images with irregular enhancement
postgadolinium. On T2-weighted images, cerebritis
is evident as an area of increased signal intensity. As
the abscess matures, the appearance of the lesion
changes. On gadolinium-enhanced T1-weighted
images, the central cavity of a mature brain abscess
is hypointense, and the capsule is hyperintense. On
T2-weighted images, the central area of pus is
hyperintense and surrounded by a well-defined
hypointense capsule. The surrounding edema is
hyperintense on T2-weighted images (Fig. 1). On
CT scan, cerebritis appears as a focal area of
hypodensity that may enhance following contrast
administration. With development of the abscess, the
abscess center appears as an area of hypointense
signal surrounded by a contrast-enhancing ring that
represents the abscess capsule. This is surrounded by
a region of hypointensity representing edema. Lesions
that may have an appearance similar to a brain
abscess on CT or MRI include tumors and infarctions.

Figure 1
(A) T1-weighted cranial MRI postgadolinium administration
demonstrating brain abscess. Central cavity is hypointense,
and the capsule is hyperintense. (B) T2-weighted cranial MRI
demonstrating brain abscess. The central area of pus is
hyperintense, surrounded by a well-defined hypointense
capsule. Surrounding edema is hyperintense (courtesy of
Thomas Witt).
BACTERIAL ABSCESS, CEREBRAL 329
The microbiological diagnosis is made at the time
of surgery by Gram’s stain and culture of abscess
material obtained by stereotactic needle aspiration.
Lumbar puncture should not be performed in
patients with focal intracranial infections, such as
abscess or empyema, because cerebrospinal fluid
analysis contributes nothing to diagnosis or therapy
and lumbar puncture increases the risk of herniation.
On routine laboratory studies, approximately 50%
of patients will have a peripheral leukocytosis
(410,000 cells/mm) and 60% will have an elevated
erythrocyte sedimentation rate. Blood cultures can be
expected to be positive in patients with brain abscess
due to hematogeneous spread of infection from an
extracranial site of infection.
The predisposing conditions associated with a
brain abscess help predict the etiological organism
and can be used in decisions regarding initial
empirical therapy (Table 1). A brain abscess that
arises from sinusitis is usually due to streptococci and
anaerobic organisms. Haemophilus species may also
be the causative organisms. Empirical therapy of a
sinusitis-associated brain abscess should include a
combination of penicillin G and metronidazole.
Penicillin has excellent activity against streptococci;
metronidazole has excellent bactericidal activity
against anaerobes. Most anaerobes in brain abscesses
are also susceptible to penicillin, with the exception
of B. fragilis. Microaerophilic streptococci are
resistant to metronidazole. In addition, a third-
generation cephalosporin, either ceftriaxone or cefo-
taxime, can be added to provide coverage for
Haemophilus species. The most common organisms
isolated in a brain abscess from an otitic source are
Streptococcus species, Enterobacteriaceae, Bacter-
oides species, and P. aeruginosa. Empirical therapy
of an otogenic abscess should include a combination
of penicillin G, metronidazole, and ceftazidime. A
brain abscess due to a dental infection is most often
caused by B. fragilis, streptococci, or Fusobacterium
species, and empirical therapy should include a
combination of penicillin or cefotaxime or ceftriax-
one plus metronidazole. Brain abscesses that are a
complication of infective endocarditis are usually due
to viridans streptococci or S. aureus. Empirical
therapy should be a combination of penicillin G or
a third-generation cephalosporin plus vancomycin. A
brain abscess as a result of penetrating head trauma
is most often due to S. aureus, Clostridium species, or
Enterobacteriaceae. Empirical therapy should in-
clude a combination of either cefotaxime or ceftriax-
one plus vancomycin.
330 BACTERIAL ABSCESS, CEREBRAL

Table 1 ETIOLOGICAL ORGANISMS OF BACTERIAL BRAIN ABSCESS AND EMPIRICAL THERAPY

Predisposing condition Organisms Antibiotics

Paranasal sinusitis
Dental infections
Otitis media or mastoiditis
Pyogenic lung infection (lung
abscess, empyema)
Cyanotic congenital heart disease
Endocarditis
Penetrating head trauma
Neurosurgical procedure
Microaerophilic and anaerobic Penicillin G plus metronidazole plus third-generation
streptococci cephalosporin
Haemophilus species
Bacteroides species
Enterobacteriaceae
Streptococci Penicillin G plus metronidazole plus cefotaxime
Bacteroides fragilis
Fusobacterium species
Streptococci Penicillin G plus metronidazole plus ceftazidime
Bacteroides species
Pseudomonas aeruginosa
Enterobacteriaceae
Streptococci Penicillin G plus metronidazole plus
Actinomyces species ceftazidime7trimethoprim sulfamethoxazole
Fusobacterium species
Nocardia asteroides
Anaerobic and microaerophilic Penicillin G plus cefotaxime plus metronidazole
streptococci (viridans
streptococci)
Haemophilus species
Staphylococcus aureus Nafcillin or vancomycin plus cefotaxime
Microaerophilic streptococci
Staphylococci Vancomycin plus cefotaxime
Enterobacteriaceae
Clostridium species
Staphylococci Vancomycin plus ceftazidime
Gram-negative bacilli

When a brain abscess complicates a neurosurgical antimicrobial sensitivities. Intravenous antibiotic

procedure, staphylococci, Enterobacteriaceae, and
Pseudomonas species are the usual etiological
organisms. Empirical therapy should include a
combination of ceftazidime plus vancomycin. Pro-
pionibacterium acnes, an anaerobic gram-positive
rod, is a common skin contaminant that may cause
brain abscess as a complication of head trauma or a
neurosurgical procedure. This organism is suscepti-
ble to penicillin and metronidazole. Brain abscesses
that are due to cyanotic congenital heart disease
should be treated empirically with a combination of
penicillin, cefotaxime, or ceftriaxone plus metroni-
dazole to cover Streptococcus species and Haemo-
philus species. The specific etiological organism is
identified by Gram’s stain and culture of brain
abscess pus obtained by stereotactic CT-guided
aspiration. When the results of culture and sensitiv-
ities are known, antimicrobial therapy can be
modified based on the infecting organism and its
therapy is continued for 6–8 weeks followed by
a 2- or 3-month course of oral antimicrobial
therapy.
Closed needle biopsy, by either the stereotactic or
free-hand procedure, and drainage are required in
the management of the majority of bacterial brain
abscesses. Complete excision of the abscess is
usually necessary only in patients with multilocu-
lated abscesses or in cases due to pathogens that are
more resistant to antimicrobial therapy, such as
Nocardia species. Abscesses in the early cerebritis
stage and lesions less than 2 cm in size are more
likely than larger abscesses to respond to antibiotic
therapy alone. Corticosteroid therapy is reserved for
patients with cerebral edema causing mass effect,
increased intracranial pressure, and impending
cerebral herniation. Dexamethasone 10 mg intrave-
nously every 6 hr is recommended initially and is
tapered over 3–7 days as the patient improves.

Corticosteroids should be used cautiously because
they have been shown in experimental models to
delay collagen deposition and therefore to slow the
‘‘walling off’’ process for suppurative abscesses.
Seizures are the most common reported sequelae
of brain abscess. Prophylactic anticonvulsant ther-
apy is recommended during the early stages of
treatment and for a minimum of 3 months after
surgery.
—Karen L. Roos
See also–Abscess, Surgery; Bacterial Meningitis;
Fungal Abscess, Cerebral
Further Reading
Heilpern, K. L., and Lorber, B. (1996). Focal intracranial
infections. Infect. Dis. Clin. North Am. 10, 879–898.
Mamelak, A. N., Mampalam, T. J., Obana, W. G., et al. (1995).
Improved management of multiple brain abscesses: A
combined surgical and medical approach. Neurosurgery 36,
76–86.
Mathison, G. E., and Johnson, J. P. (1997). Brain abscess. Clin.
Infect. Dis. 25, 763–781.
Osenbach, R. K., and Loftus, C. M. (1992). Diagnosis and
management of brain abscess. Neurosurg. Clin. North Am. 3,
403–420.
Bacterial Meningitis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BACTERIAL meningitis is an acute purulent infection
within the subarachnoid space that is followed by a
central nervous system (CNS) inflammatory reaction
that causes coma, seizure activity, increased intra-
cranial pressure, and stroke. The meninges, the
subarachnoid space, and the brain parenchyma are
all involved in the inflammatory reaction; as such,
meningoencephalitis is the more accurate descriptive
term. Bacterial meningitis is the most common form
of suppurative intracranial infection, with an annual
incidence of 2.5 cases per 100,000 population. Prior
to the availability of the Haemophilus influenzae
type b (Hib) conjugate vaccines in 1987, Hib was the
most common cause of bacterial meningitis in the
United States. The incidence of H. influenzae
meningitis has declined dramatically since 1987.
Currently, the most common causative organisms of
community-acquired bacterial meningitis are Strep-
tococcus pneumoniae, Neisseria meningitidis, group
BACTERIAL MENINGITIS 331
B streptococci, and Listeria monocytogenes. There
has been an increase in the incidence of meningo-
coccal disease in North America and Europe due to
the emergence of a virulent strain of serogroup C,
Neisseria meningitidis. There has been a major
change in the epidemiology of pneumococcal disease,
with a global emergence and increasing prevalence of
penicillin and cephalosporin-resistant strains of S.
pneumoniae. As of 1998, approximately 44% of
clinical isolates of S. pneumoniae in the United States
had intermediate or high levels of resistance to
penicillin. Streptococcus pneumoniae is the most
common cause of meningitis in adults older than 20
years of age.
A number of predisposing conditions increase the
risk of pneumococcal meningitis, the most common
of which is pneumonia. Additional risk factors
include acute and chronic otitis media, alcoholism,
diabetes, splenectomy, hypogammaglobulinemia, and
head trauma with basilar skull fracture and cere-
brospinal fluid rhinorrhea. An increasing incidence of
N. meningitidis strains with moderate or relative
resistance to penicillin and a decreased susceptibility
to ampicillin has been reported worldwide, but the
clinical significance of these strains is unknown.
There continues to be annual epidemics of meningitis
in the meningitis belt of sub-Saharan Africa caused
primarily by the serogroup A meningococcus.
Serogroup B meningococcal disease also occurs in
epidemics that are typically spread over periods of
years, and recently epidemics have been reported in
Europe, Latin America, and New Zealand. Neisseria
meningitidis accounts for the majority of cases of
bacterial meningitis in children and young adults.
The nasopharynx is initially colonized by this
organism, resulting in either an asymptomatic carrier
state or invasive meningococcal disease. The risk of
invasive disease depends on both bacterial virulence
factors and host immune defense mechanisms,
including the ability to produce anti-meningococcal
antibodies and the ability to lyse meningococci by
both the classic and alternative complement path-
ways. Individuals with complement deficiencies of
any of the complement components are highly
susceptible to meningococcal infections. Group B
streptococcus or Streptococcus agalactiae is a me-
ningeal pathogen in the neonatal age group and
in individuals older than 50 years, particularly
those with preexisting underlying diseases. Listeria
monocytogenes is a causative organism of bac-
terial meningitis in individuals with impaired cell-
mediated immunity—primarily individuals receiving

Corticosteroids should be used cautiously because
they have been shown in experimental models to
delay collagen deposition and therefore to slow the
‘‘walling off’’ process for suppurative abscesses.
Seizures are the most common reported sequelae
of brain abscess. Prophylactic anticonvulsant ther-
apy is recommended during the early stages of
treatment and for a minimum of 3 months after
surgery.
—Karen L. Roos
See also–Abscess, Surgery; Bacterial Meningitis;
Fungal Abscess, Cerebral
Further Reading
Heilpern, K. L., and Lorber, B. (1996). Focal intracranial
infections. Infect. Dis. Clin. North Am. 10, 879–898.
Mamelak, A. N., Mampalam, T. J., Obana, W. G., et al. (1995).
Improved management of multiple brain abscesses: A
combined surgical and medical approach. Neurosurgery 36,
76–86.
Mathison, G. E., and Johnson, J. P. (1997). Brain abscess. Clin.
Infect. Dis. 25, 763–781.
Osenbach, R. K., and Loftus, C. M. (1992). Diagnosis and
management of brain abscess. Neurosurg. Clin. North Am. 3,
403–420.
Bacterial Meningitis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BACTERIAL meningitis is an acute purulent infection
within the subarachnoid space that is followed by a
central nervous system (CNS) inflammatory reaction
that causes coma, seizure activity, increased intra-
cranial pressure, and stroke. The meninges, the
subarachnoid space, and the brain parenchyma are
all involved in the inflammatory reaction; as such,
meningoencephalitis is the more accurate descriptive
term. Bacterial meningitis is the most common form
of suppurative intracranial infection, with an annual
incidence of 2.5 cases per 100,000 population. Prior
to the availability of the Haemophilus influenzae
type b (Hib) conjugate vaccines in 1987, Hib was the
most common cause of bacterial meningitis in the
United States. The incidence of H. influenzae
meningitis has declined dramatically since 1987.
Currently, the most common causative organisms of
community-acquired bacterial meningitis are Strep-
tococcus pneumoniae, Neisseria meningitidis, group
BACTERIAL MENINGITIS 331
B streptococci, and Listeria monocytogenes. There
has been an increase in the incidence of meningo-
coccal disease in North America and Europe due to
the emergence of a virulent strain of serogroup C,
Neisseria meningitidis. There has been a major
change in the epidemiology of pneumococcal disease,
with a global emergence and increasing prevalence of
penicillin and cephalosporin-resistant strains of S.
pneumoniae. As of 1998, approximately 44% of
clinical isolates of S. pneumoniae in the United States
had intermediate or high levels of resistance to
penicillin. Streptococcus pneumoniae is the most
common cause of meningitis in adults older than 20
years of age.
A number of predisposing conditions increase the
risk of pneumococcal meningitis, the most common
of which is pneumonia. Additional risk factors
include acute and chronic otitis media, alcoholism,
diabetes, splenectomy, hypogammaglobulinemia, and
head trauma with basilar skull fracture and cere-
brospinal fluid rhinorrhea. An increasing incidence of
N. meningitidis strains with moderate or relative
resistance to penicillin and a decreased susceptibility
to ampicillin has been reported worldwide, but the
clinical significance of these strains is unknown.
There continues to be annual epidemics of meningitis
in the meningitis belt of sub-Saharan Africa caused
primarily by the serogroup A meningococcus.
Serogroup B meningococcal disease also occurs in
epidemics that are typically spread over periods of
years, and recently epidemics have been reported in
Europe, Latin America, and New Zealand. Neisseria
meningitidis accounts for the majority of cases of
bacterial meningitis in children and young adults.
The nasopharynx is initially colonized by this
organism, resulting in either an asymptomatic carrier
state or invasive meningococcal disease. The risk of
invasive disease depends on both bacterial virulence
factors and host immune defense mechanisms,
including the ability to produce anti-meningococcal
antibodies and the ability to lyse meningococci by
both the classic and alternative complement path-
ways. Individuals with complement deficiencies of
any of the complement components are highly
susceptible to meningococcal infections. Group B
streptococcus or Streptococcus agalactiae is a me-
ningeal pathogen in the neonatal age group and
in individuals older than 50 years, particularly
those with preexisting underlying diseases. Listeria
monocytogenes is a causative organism of bac-
terial meningitis in individuals with impaired cell-
mediated immunity—primarily individuals receiving
332 BACTERIAL MENINGITIS

immunosuppressive therapy, organ transplant recipi- Table 1 MENINGEAL PATHOGENS AND ASSOCIATED OR
ents, and the elderly. The routine use of trimethoprim PREDISPOSING CONDITIONS
sulfamethoxazole to prevent Pneumocystis carinii Causative organism Associated or predisposing factors
pneumonia and toxoplasmosis has had the benefit of
decreasing the incidence of L. monocytogenes Streptococcus Pneumonia
pneumoniae Acute and chronic otitis media
meningitis in immunosuppressed individuals because
Acute sinusitis
trimethoprim sulfamethoxazole has bactericidal ac-
Diabetes
tivity against L. monocytogenes.
Splenectomy
Enteric gram-negative bacilli are the causative
Hypogammaglobulinemia
organisms of meningitis that is associated with
Head trauma
chronic and debilitating diseases, such as diabetes,
CSF rhinorrhea
cirrhosis, or alcoholism, and following neurosurgical
Extremes of age (neonate, elderly)
procedures, particularly craniotomy for tumor or
Alcoholism, cirrhosis, peritonitis
trauma. Staphylococcus aureus and coagulase-
Neisseria meningitidis College dormitory living
negative staphylococci are predominant organisms
Residence in or travel to an endemic
causing meningitis following invasive neurosurgical
area
procedures, particularly shunting procedures for
Complement deficiencies
hydrocephalus, and as a complication of the use of
Splenectomy
subcutaneous Ommaya reservoirs or lumbar punc-
Hypogammaglobulinemia
ture for the administration of intrathecal chemother-
Listeria monocytogenes Immunosuppressive therapy
apy. Table 1 lists the meningeal pathogen and
Organ transplantation
associated or predisposing conditions. Pregnancy
The most common bacteria that cause meningitis,
Diabetes
S. pneumoniae and N. meningitidis, initially colonize
Alcoholism
the nasopharynx by attaching to the nasopharyngeal
Extremes of age (neonate, elderly)
epithelial cells. The bacteria are then either carried
Enteric gram-negative Diabetes
across the cell in membrane-bound vacuoles to the bacilli Cirrhosis, alcoholism
intravascular space or invade the intravascular space Craniotomy
by creating separations in the apical tight junctions Head trauma
of columnar epithelial cells. Once the bacteria gain Staphylococci CSF shunt
access to the bloodstream, they are able to avoid Ommaya reservoir
phagocytosis by neutrophils and classic complement- Lumbar puncture
mediated bactericidal activity because of the presence Infective endocarditis
of a polysaccharide capsule. Once in the blood- Parameningeal infection (empyema,
stream, bacteria are able to enter the cerebrospinal epidural abscess, osteomyelitis)
fluid (CSF) through the epithelial cells of the choroid Streptococcus Neonates, elderly
plexus of the lateral ventricles and through the agalactiae Diabetes
cerebrocapillary endothelium. It is known that the Alcoholism
pneumococci are able to adhere to the cerebrocapil- Acquired immunodeficiency
lary endothelium and pass through or between cells syndrome
to invade the CSF. The exact locus of entry for the Haemophilus influenzae Age over 60
type b Otitis media
meningococcus into the CSF is not known. Bacteria
Sinusitis
are able to multiply rapidly within the CSF because
CSF leak
of the absence of effective host immune defenses.
Immunodeficiency
Normal uninfected CSF contains few white blood
Diabetes
cells and small amounts of complement proteins and
Alcoholism
immunoglobulins. The insufficient numbers of com-
plement proteins and immunoglobulins prevent
effective opsonization of bacteria, an essential step
for phagocytosis by neutrophils. Phagocytosis of The critical event in the pathogenesis of bacterial
bacteria is further impaired by the fluid medium of meningitis, however, is the inflammatory reaction to
the CSF. the invading bacteria. It is not the pathogen that

causes the neurological complications. In bacterial
meningitis, brain damage progresses long after the
CSF has been sterilized by antibiotic therapy. The
lysis of bacteria with the release of bacterial cell wall
components in the subarachnoid space is the initial
step in the induction of the inflammatory process and
the formation of a purulent exudate in the subar-
achnoid space. Components of bacterial cell walls,
such as lipopolysaccharide molecules (endotoxin; a
cell wall component of gram-negative bacteria) and
teichoic acid and peptidoglycan (cell wall compo-
nents of the pneumococcus), induce meningeal
inflammation by stimulating the production of
inflammatory cytokines and chemokines by micro-
glia, astrocytes, monocytes, microvascular endothe-
lial cells, and CSF leukocytes. In experimental
models of meningitis, 1–3 hr after the intracisternal
inoculation of lipopolysaccharide, tumor necrosis
factor (TNF) and interleukin-1 (IL-1) are present in
CSF, followed by the onset of increased concentra-
tions of protein and leukocytes in the CSF. Chemo-
kines (cytokines that induce chemotactic migration
in leukocytes) and a variety of other proinflamma-
tory cytokines are also produced and secreted by
leukocytes and tissue cells that are stimulated by IL-1
and TNF.
There are a number of pathophysiological con-
sequences that result from the presence of the
inflammatory cytokines in CSF. Tumor necrosis
factor and IL-1 act synergistically to alter the
permeability of the blood–brain barrier, resulting in
vasogenic cerebral edema and the leakage of serum
proteins into the subarachnoid space. The subarach-
noid exudate of proteinaceous material and leuko-
cytes obstructs the flow of CSF through the
ventricular system and diminishes the resorptive
capacity of the arachnoid granulations in the dural
sinuses, leading to obstructive and communicating
hydrocephalus and interstitial edema.
The inflammatory cytokines recruit polymorpho-
nuclear leukocytes from the bloodstream and upre-
gulate the expression of selectins on cerebrocapillary
endothelial cells and leukocytes, which allows for
leukocytes to adhere to vascular endothelial cells and
to subsequently migrate into the CSF. The results of
experimental models of meningitis suggest that
bacterial eradication from the CSF is not a leuko-
cyte-dependent phenomena. The adherence of leu-
kocytes to capillary endothelial cells increases the
permeability of blood vessels, allowing for the
leakage of plasma proteins into the CSF, further
contributing to the inflammatory exudate in the
BACTERIAL MENINGITIS 333
subarachnoid space. Neutrophil degranulation re-
sults in the release of toxic metabolites that
contribute to cytotoxic edema, cell injury, and death.
During the very early stages of meningitis there is
an increase in cerebral blood flow, followed soon
thereafter by a decrease in cerebral blood flow and a
loss of cerebrovascular autoregulation. Cerebral
perfusion pressure (CPP) is defined as the difference
between the mean arterial pressure (MAP) and the
intracranial pressure (ICP): CPP ¼ MAP
ICP. Cere-
bral perfusion pressure is protected by cerebrovas-
cular autoregulation, which dilates or constricts
cerebral resistance vessels in response to alterations
in CPP due to either changes in the MAP or changes
in ICP. Loss of cerebral autoregulation means that an
increase in systemic blood pressure leads to an
increase in cerebral blood flow and ICP. Conversely,
a decrease in mean systemic arterial pressure, due to
septic shock, results in a decrease in cerebral blood
flow and also cerebral ischemia and infarction. The
cerebrovascular complications of bacterial meningi-
tis include not only a loss of cerebrovascular
autoregulation but also narrowing of the large
arteries of the base of the brain due to encroachment
on the vessels by the purulent exudate in the
subarachnoid space, infiltration of the arterial wall
by inflammatory cells with intimal thickening,
obstruction of branches of the middle cerebral artery,
and thrombosis of the major sinuses and throm-
bophlebitis of the cerebral cortical veins.
The cerebrovascular complications of bacterial
meningitis cause cerebral ischemia, seizure activity,
focal neurological deficits, and stroke. The presence
of a purulent exudate in the subarachnoid space
leads to communicating and obstructive hydroce-
phalus, interstitial edema, and cranial nerve palsies.
The mechanisms previously described that alter
blood–brain permeability cause vasogenic edema.
The degranulation of leukocytes and cerebral ische-
mia from alterations in cerebral blood flow cause
cytotoxic edema. In addition, bacteria and the
inflammatory cytokines induce the production of
excitatory amino acids, reactive oxygen and nitrogen
species (free oxygen radicals, nitric oxide, and
peroxynitrite), and other mediators that induce
massive apoptosis of brain cells. The combination
of these pathophysiological abnormalities leads to
cerebral edema, increased ICP, coma, and seizure
activity.
The classic triad of symptoms and signs of
meningitis is fever, headache, and stiff neck. When
this triad is accompanied by lethargy, stupor, or
334 BACTERIAL MENINGITIS
seizure activity, the presentation is highly suggestive
of bacterial meningitis. The tempo of the illness may
be either that of an acute fulminant illness that
progresses rapidly in a few hours or that of a
subacute infection that gets progressively worse over
several days. Nausea, vomiting, and photophobia are
also common complaints.
A stiff neck is the pathognomonic sign of menin-
geal irritation. Nuchal rigidity is present when the
neck resists passive flexion. Meningismus can also be
detected with the patient in the supine position when
passive flexion of the neck results in spontaneous
flexion of the hips and knees (Brudzinski’s sign).
Seizures occur as part of the initial presentation of
bacterial meningitis or during the course of the illness
in 40% of patients. Seizure activity that has a focal
onset is due to focal arterial ischemia or infarction,
cortical venous thrombosis with hemorrhage, or
focal edema. Generalized seizure activity and status
epilepticus are due to fever, hyponatremia, anoxia
from decreased cerebral perfusion, spread from a
focal onset to a generalized tonic–clonic convulsion,
or toxicity from antimicrobial agents.
The rash of meningococcemia begins as a diffuse
erythematous maculopapular rash resembling a viral
exanthem, but the skin lesions of meningococcemia
rapidly become petechial. Initially, petechiae are
found predominantly on the trunk and lower
extremities, in the mucous membranes and conjunc-
tiva, and occasionally on the palms and soles.
Increased ICP is an expected complication of
bacterial meningitis and is the major cause of
obtundation and coma in this disease. The most
common signs of increased ICP in bacterial meningi-
tis are a deteriorating or reduced level of conscious-
ness and papilledema. Dilated, poorly reactive
pupils, cranial nerve sixth palsies, decerebrate
posturing, and the Cushing reflex (bradycardia,
hypertension, and irregular respirations) are also
signs of increasing ICP. Increased ICP can lead to
cerebral herniation.
When the clinical presentation is suggestive of
bacterial meningitis, blood cultures should be ob-
tained and empirical antimicrobial therapy initiated
immediately. The diagnosis of bacterial meningitis is
made by examination of the spinal fluid. The
necessity of cranial magnetic resonance imaging or
computed tomography prior to lumbar puncture is a
controversial issue and the decision needs to be made
on an individual basis. If lumbar puncture is delayed
to perform neuroimaging studies, empirical antibio-
tic therapy should be initiated after blood cultures
are obtained. Antibiotic therapy for several hours
prior to lumbar puncture will not significantly alter
the CSF white blood cell count or glucose concentra-
tion so that a diagnosis of bacterial meningitis is not
suspected, and it is not likely to sterilize the CSF so
that the organism cannot be identified on Gram’s
stain or grown in culture. In patients with clinical
signs of increased ICP, increased ICP should be
treated and lumbar puncture performed with a 22- or
25-gauge needle and a minimum amount of CSF
removed for analysis. Approximately 4.5 ml of CSF
is sufficient to obtain a cell count (1.0 ml), glucose
and protein concentrations (1.0 ml), latex agglutina-
tion test (0.5 ml), Gram’s stain and bacterial culture
(1.0 ml), and polymerase chain reaction (PCR) assay
(1.0 ml). Mannitol and/or hyperventilation can be
used to decrease the risk of herniation from lumbar
puncture in patients with increased ICP.
The following are classic CSF abnormalities in
bacterial meningitis: increased opening pressure, a
pleocytosis of polymorphonuclear leukocytes, a
decreased glucose concentration (o45 mg/dl and/or
CSF:serum glucose ratio of o0.31), and an increased
protein concentration. CSF bacterial cultures are
positive in 480% of patients and CSF Gram’s stain
is positive in 70–90% of untreated cases of bacterial
meningitis (Table 2).
The latex particle agglutination (LA) test for the
detection of bacterial antigens of S. pneumoniae, N.
meningitidis, H. influenzae type b, group B strepto-
coccus, and Escherichia coli K1 strains in the CSF is
useful for making a rapid diagnosis of bacterial
meningitis and for making this diagnosis in those
patients who have been pretreated with oral or
parenteral antibiotics and in whom Gram’s stain and
CSF culture are negative. A negative LA test for
bacterial antigens does not rule out bacterial
meningitis. The Limulus amebocyte lysate assay is a
rapid diagnostic test for the detection of gram-
negative endotoxin in CSF. PCR assays are available
for detecting bacterial DNA from N. meningitidis, H.
influenzae, S. pneumoniae, S. agalactiae, and L.
monocytogenes in CSF, but their sensitivity and
specificity have not been defined.
If there are petechial skin lesions, these should be
biopsied. The rash of meningococcemia results from
the dermal seeding of organisms with vascular
endothelial damage, and biopsy may reveal the
organism on Gram’s stain. As a general rule, Gram’s
stain and culture of CSF obtained 24 hr after the
initiation of antimicrobial therapy should be negative
if the organism is sensitive to the antibiotic.
 BACTERIAL MENINGITIS 335

Table 2 CEREBROSPINAL FLUID ABNORMALITIES IN BACTERIAL MENINGITIS IN CHILDREN AND ADULTS

Uninfected CSF Bacterial meningitis

Opening pressure r180 mmH2O (r250 if obese) 4180 mmH2O

Cell count r5 WBCs/mm3 4100 cells/mm3, pleocytosis of
polymorphonuclear leukocytes
Glucose 45–80 mg/dl with a serum glucose of o45 mg/dl
70–120 mg/dl
CSF/serum glucose ratio 0.6 r0.40
Protein (lumbar puncture) o50 mg/dl 450 mg/dl
Gram’s stain Negative Positive in 70–90% untreated cases
Bacterial culture Negative Positive in 480%
Latex agglutination for bacterial antigens Negative Positive
(S. pneumoniae, N. meningitidis, Hib,
group B streptococcus, E. coli)
Limulus amebocyte lysate assay Negative Positive in meningitis due to gram-negative
bacilli
PCR Negative Positive, but sensitivity and specificity
unknown

The leading disease in the differential diagnosis of
bacterial meningitis is viral meningoencephalitis,
including herpes simplex virus (HSV) encephalitis
and the arthropod-borne viral encephalitides. Rocky
Mountain spotted fever, focal intracranial infectious
mass lesions, and subarachnoid hemorrhage are also
in the differential diagnosis. Table 3 is a guide to the
diagnostic studies that can be performed on CSF and
sera in the patient with fever, headache, altered level
of consciousness, and/or seizure activity.
Antimicrobial therapy is initiated when bacterial
meningitis is suspected before the results of CSF
Table 3 CEREBROSPINAL FLUID AND SEROLOGICAL
DIAGNOSTIC STUDIES FOR CLINICAL PRESENTATION OF
FEVER, HEADACHE, ALTERED LEVEL OF CONSCIOUSNESS,
AND/OR SEIZURE ACTIVITY
CSF
Cell count with differential
Chemistries
Gram’s stain, bacterial culture
Latex agglutination, Limulus amebocyte lysate assay
PCR HSV-1 DNA (do not send on bloody CSF), and HSV
antibodies
Fungal smear and culture
Cryptococcal polysaccharide antigen, histoplasma
polysaccharide antigen
TB smear, culture, and molecular diagnostic tests
Blood
Acute and convalescent sera for arthropod-borne virus
antibodies
Acute and convalescent sera for Rickettsia rickettsii antibodies
Gram’s stain and culture and antimicrobial suscept-
ibility tests are known. Empirical therapy should be
based on the possibility that penicillin-resistant
pneumococci are the causative organisms of the
meningitis. Due to the emergence of penicillin and
cephalosporin-resistant pneumococcal organisms,
empirical therapy of community-acquired bacterial
meningitis in children and adults should include a
third-generation cephalosporin, either ceftriaxone or
cefotaxime, plus vancomycin. Ampicillin should be
added to the empirical regimen for coverage of L.
monocytogenes in individuals with suspected im-
paired cell-mediated immunity due to chronic ill-
ness, organ transplantation, AIDS, pregnancy,
malignancies, or immunosuppressive therapy. In
hospital-acquired meningitis and in neurosurgical
patients in whom staphylococcal and gram-negative
organisms are possible etiological organisms, em-
pirical therapy should include a combination of
vancomycin and ceftazidime. Ceftazidime should be
substituted for ceftriaxone or cefotaxime in neuro-
surgical patients and in neutropenic patients because
P. aeruginosa may be the meningeal pathogen and
ceftazidime is the only third-generation cephalospor-
in with sufficient activity against P. aeruginosa in the
CNS.
When the results of Gram’s stain, bacterial
culture, and antimicrobial susceptibility tests are
known, antimicrobial therapy can be modified
accordingly (Table 4). All CSF isolates of S.
pneumoniae should be tested for sensitivity to
336 BACTERIAL MENINGITIS

Table 4 ANTIMICROBIAL THERAPY OF BACTERIAL MENINGITIS IN CHILDREN AND ADULTS

Total daily pediatric dose (dosing Total daily adult dose

Organism Antibiotic interval) (dosing interval)

Streptococcus pneumoniae
Sensitive to penicillin
Relatively resistant to
penicillin
Resistant to penicillin
Neisseria meningitidis
Gram-negative bacilli (E. coli,
Klebsiella species,
Haemophilus species, but
not Pseudomonas
aeruginosa)
Pseudomonas aeruginosa
Staphylococci
Methicillin-sensitive
Methicillin-resistant
Streptococcus agalactiae
Listeria monocytogenes
Penicillin G 0.2 million U/kg (every 4 hr) 20–24 million U/day
or (every 4 hr)
Ampicillin 200–300 mg/kg/day (every 4 hr) 12 g/day (every 4 hr)
Ceftriaxone 100 mg/kg/day (every 12 hr) 4 g/day (every 12 hr)
or
Cefotaxime 200 mg/kg/day (every 4 hr) 12 g/day (every 4 hr)
Vancomycin 40–60 mg/kg/day (every 6–12 hr) 2 g/day (every 6–12 hr)
plus
Cefotaxime or ceftriaxone
7
Intraventricular vancomycin 10 mg/day 20 mg/day
Pencillin G 0.2 million U/kg (every 4 hr) 20–24 million U/kg
or (every 4 hr)
Ampicillin 200–300 mg/kg/day (every 4 hr) 12 g/day (every 4 hr)
Cefotaxime or ceftriaxone
Ceftazidime 150–200 mg/kg/day (every 8 hr) 8 g/day (every 8 hr)
Nafcillin 150–200 mg/kg/day (every 4 hr) 12 g/day (every 4 hr)
Vancomycin 40–60 mg/kg/day (every 6–12 hr) 2 g/day (every 6–12 hr)
7
Intraventricular vancomycin 10 mg/day 20 mg/day
Pencillin G
Ampicillin 200–300 mg/kg/day (every 4 hr) 12 g/day (every 4 hr)
Gentamicin 7.5 mg/kg/day (every 8 hr) 5 mg/kg/day (every 8 hr)

penicillin and the third-generation cephalosporins.
According to the guidelines of the National Com-
mittee for Clinical Laboratory Standards, an isolate
of S. pneumoniae is considered to be highly resistant
to penicillin with a minimal inhibitory concentration
(MIC) of X2 mg/ml. An isolate of S. pneumoniae is
considered to have intermediate resistance to peni-
cillin with an MIC of 0.1–1 mg/ml and to be
susceptible to penicillin with an MIC of o0.1 mg/
ml. Some strains of pneumococci are sensitive to
penicillin. For S. pneumoniae meningitis, however,
an isolate is defined as penicillin susceptible when
the MIC is p0.06 mg/ml, to have intermediate
resistance when the MIC is 0.1–1.0 mg/ml, and to be
highly resistant when the MIC is X1.0 mg/ml.
Isolates of S. pneumoniae that have MICs p0.5
mg/ml are defined as susceptible to the cephalospor-
ins. Those with MICs of 1.0 mg/ml are considered
to have intermediate resistance, and those with
MICs X2.0 mg/ml are considered resistant.
Penicillin-resistant strains of S. pneumoniae are
much more common than cephalosporin-resistant
strains of S. pneumoniae. For meningitis due to
pneumococci with MICs of cefotaxime or ceftriax-
one of 0.5 mg/ml or less, treatment with cefotaxime
or ceftriaxone is probably adequate. If the MICs are
X1.0 mg/ml, vancomycin is the antibiotic of choice.
A repeat lumbar puncture should be performed 24–
36 hr after the initiation of antimicrobial therapy of
pneumococcal meningitis to document eradication
of the pathogen. Consideration should be given to
using intraventricular vancomycin in patients not
responding to parenteral vancomycin.
Penicillin G is still the antibiotic of choice for
meningococcal meningitis. Isolates of N. meningiti-
dis with moderate resistance to penicillin have been

identified, but this does not change current recom-
mendations for the use of penicillin G in meningo-
coccal meningitis because patients with relatively
penicillin-resistant strains have been successfully
treated with penicillin. Ampicillin can also be used
for meningococcal meningitis. All CSF isolates of N.
meningitidis should be tested for penicillin and
ampicillin susceptibility. The index case and all close
contacts should receive chemoprophylaxis with a
2–day regimen of rifampin. Rifampin should not be
used in pregnant women. Adults can alternatively be
treated with one dose of ciprofloxacin or one dose of
azithromycin. Close contacts are defined as those
individuals who have had contact with oropharyn-
geal secretions through kissing or sharing toys,
beverages, or cigarettes.
Meningitis due to L. monocytogenes is treated
with ampicillin. Gentamicin should be added to
ampicillin in critically ill patients.
The third-generation cephalosporins—cefotaxime,
ceftriaxone, and ceftazidime—are equally efficacious
for the treatment of gram-negative bacillary menin-
gitis, with the exception of meningitis due to P.
aeruginosa, in which case ceftazidime should be
used.
Meningitis due to S. aureus or coagulase-negative
staphylococci is treated with nafcillin or oxacillin.
Vancomycin is the drug of choice for methicillin-
resistant staphylococci and for patients allergic to
penicillin. The CSF should be monitored during
therapy, and if the spinal fluid continues to
yield viable organisms after 48 hr of intravenous
therapy, then either intrathecal or intraventricular
vancomycin can be added.
Cefepime is a fourth-generation cephalosporin that
has been demonstrated to be equivalent to cefotax-
ime in the treatment of pneumococcal and meningo-
coccal meningitis, but its efficacy in bacterial
meningitis caused by penicillin- and cephalosporin-
resistant pneumococcal organisms, Enterobacter
species, and P. aeruginosa has not been established.
Meropenem is a carbapenem antibiotic that is highly
active in vitro against L. monocytogenes, has been
demonstrated to be effective in cases of meningitis
caused by P. aeruginosa, and shows good activity
against penicillin-resistant pneumococci.
The release of bacterial cell wall components by
bactericidal antibiotics leads to the production of the
inflammatory cytokines IL-1 and TNF in the
subarachnoid space. Dexamethasone exerts its ben-
eficial effect by inhibiting the synthesis of IL-1 and
TNF at the level of mRNA, decreasing CSF outflow
BACTERIAL MENINGITIS 337
resistance and stabilizing the blood–brain barrier. A
number of clinical trials dating back to 1950 were
designed to evaluate the efficacy of corticosteroids on
mortality and morbidity in bacterial meningitis.
Corticosteroids did not become part of the manage-
ment of bacterial meningitis. Then, in 1985 there was
renewed interest in corticosteroid therapy for bacter-
ial meningitis. Since then, there have been a number
of clinical trials on dexamethasone as an adjunctive
therapy. A meta-analysis of randomized, concur-
rently controlled clinical trials of dexamethasone
therapy in childhood bacterial meningitis published
from 1988 to 1996 confirmed benefit for H.
influenzae type b meningitis if begun with or before
intravenous antibiotics and suggested benefit for
pneumococcal meningitis in children. The rationale
for giving dexamethasone 20 min before antibiotic
therapy is that dexamethasone inhibits the produc-
tion of TNF by macrophages and microglia only if it
is administered before these cells are activated by
endotoxin. Dexamethasone is unable to regulate
TNF production once induction occurs. The Amer-
ican Academy of Pediatrics recommends the con-
sideration of dexamethasone for bacterial meningitis
in infants and children 2 months of age and older.
The recommended dose is 0.6 mg/kg/day in four
divided doses given intravenously for the first 4 days
of antibiotic therapy. The first dose of dexametha-
sone should be administered before or at least with
the first dose of antibiotics. In a single clinical trial,
dexamethasone was demonstrated to reduce the
incidence of mortality in adults from pneumococcal
meningitis. There are ongoing clinical trials on
dexamethasone therapy in adults with bacterial
meningitis. Despite the paucity of clinical data in
adults, physicians and scientists studying the mole-
cular basis of the neurological complications of
bacterial meningitis favor the use of dexamethasone.
The recommended dose of dexamethasone is 0.6 mg/
kg/day in four divided doses for the first 4 days of
antimicrobial therapy. In experimental models of
pneumococcal meningitis, dexamethasone reduced
the penetration of vancomycin into CSF, raising the
concern that dexamethasone could reduce the
penetration of vancomycin into the CSF in patients
with bacterial meningitis. In a prospective rando-
mized clinical trial of bactericidal activity of vanco-
mycin against cephalosporin-resistant pneumococci
in CSF in children with acute bacterial meningitis,
vancomycin penetrated reliably into the CSF when
the children were treated concomitantly with dex-
amethasone. As stated previously, if the patient is
338 BALANCE
responding poorly to parenteral therapy, considera-
tion should be given to either increasing the dose of
vancomycin or giving vancomycin by the intraven-
tricular route.
Meningococcal meningitis and pneumococcal me-
ningitis can be prevented by vaccination. During an
outbreak of meningococcal disease, individuals who
have not been previously vaccinated should be
treated with chemoprophylaxis. Thirty-five percent
of secondary cases of meningococcal disease develop
within 2–5 days of presentation of the index case.
Vaccination is not a substitute for chemoprophylaxis
to prevent secondary disease because there is an
insufficient amount of time for optimal effective
vaccination, which requires approximately 1 to 2
weeks for good antibody production. Vaccination
against the pneumococcus is recommended for three
at-risk populations: adults older than age 65, adults
with chronic underlying diseases (cardiopulmonary
diseases, renal diseases, diabetes mellitus, splenect-
omy, and CSF fistula), and immunocompromised
patients older than age 10. Individuals infected with
the human immunodeficiency virus should also be
vaccinated against the pneumococcus.
—Karen L. Roos
See also–Bacterial Abscess, Cerebral; Fungal
Meningitis; Meningitis, Eosinophilic; Meningitis,
Viral
Further Reading
Girgis, N. I., Farid, Z., Mikhail, I. A., et al. (1989). Dexametha-
sone treatment for bacterial meningitis in children and adults.
Pediatr. Infect. Dis. J. 8, 848–851.
Klugman, K. P., Friedland, I. R., and Bradley, J. S. (1995).
Bactericidal activity against cephalosporin-resistant Streptococ-
cus pneumoniae in cerebrospinal fluid of children with acute
bacterial meningitis. Antimicrob. Agents Chemother. 39, 1988–
1992.
McIntyre, P. B., Berkey, C. S., King, S. M., et al. (1997).
Dexamethasone as adjunctive therapy in bacterial meningitis.
J. Am. Med. Assoc. 278, 925–931.
National Committee for Clinical Laboratory Standards (1994).
Performance Standards for Antimicrobial Susceptibility
Testing. National Committee for Laboratory Standards,
Villanova, PA.
Peltola, H. (1999). Prophylaxis of bacterial meningitis. Infect. Dis.
Clin. North Am. 13, 685–706.
Pfister, H. W., Borasio, G. D., Dirnagl, U., et al. (1992).
Cerebrovascular complications of bacterial meningitis in adults.
Neurology 42, 1497–1504.
Simberkoff, M. S., Moldover, N. H., and Rahal, J., Jr. (1980).
Absence of detectable bactericidal and opsonic activities in
normal and infected human cerebrospinal fluids: A regional
host defense deficiency. J. Lab. Clin. Med. 95, 362–367.
Tauber, M. G., and Moser, B. (1999). Cytokines and chemokines in
meningeal inflammation: Biology and clinical implications.
Clin. Infect. Dis. 28, 1–12.
Balance
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BALANCE and equilibrium refer to the ability of an
animal to maintain its desired position and motion in
space, resisting the forces that would tend to knock it
over or knock it off course. For humans, maintaining
balance is especially challenging because our two feet
provide only a narrow base of support and our
upright stance places our center of gravity far above
this base. In all animals, equilibrium is achieved via a
collection of reflexes acting in cooperation. These
reflexes range from wholly unconscious mechanisms
organized at the level of the spinal cord [e.g., deep
tendon (myotatic) reflex] to sophisticated, conscious
learned strategies involving the cerebral cortex
(e.g., the body postures used by a gymnast on a
balance beam). Thus, the balance system is distrib-
uted throughout all levels of the central nervous
system.
The reflexes mediating balance can be divided into
three subtypes: vestibular, visual, and propriocep-
tive. Vestibular reflexes are organized around
information flowing from the semicircular canals
and otolith organs of the inner ear. The six
semicircular canals (three on each side) sense
rotational velocity of the head in three dimensions
in space. In contrast, the otolith organs of the utricle
and saccule of the inner ear sense linear acceleration
of the head in three dimensions. Linear acceleration
could be produced by either tilt with respect to
gravity or sudden translation, such as one experi-
ences as one steps onto a moving escalator. Visual
balance reflexes are built around a subsystem that
uses patterns of image movement (optic flow) on the
retina to deduce how the animal is translating or
rotating in space. Visual balance reflexes are
responsible for the sensation of movement experi-
enced by passengers on a stationary train as another
train starts to move on an adjacent track. Likewise,
the ‘‘barrel walk’’ of many funhouses is based on the
brain’s tendency to interpret visual flow in one
direction as self-motion in the opposite direction.
The third subtype of balance reflexes, the proprio-
ceptive mechanisms, use information from stretch
338 BALANCE
responding poorly to parenteral therapy, considera-
tion should be given to either increasing the dose of
vancomycin or giving vancomycin by the intraven-
tricular route.
Meningococcal meningitis and pneumococcal me-
ningitis can be prevented by vaccination. During an
outbreak of meningococcal disease, individuals who
have not been previously vaccinated should be
treated with chemoprophylaxis. Thirty-five percent
of secondary cases of meningococcal disease develop
within 2–5 days of presentation of the index case.
Vaccination is not a substitute for chemoprophylaxis
to prevent secondary disease because there is an
insufficient amount of time for optimal effective
vaccination, which requires approximately 1 to 2
weeks for good antibody production. Vaccination
against the pneumococcus is recommended for three
at-risk populations: adults older than age 65, adults
with chronic underlying diseases (cardiopulmonary
diseases, renal diseases, diabetes mellitus, splenect-
omy, and CSF fistula), and immunocompromised
patients older than age 10. Individuals infected with
the human immunodeficiency virus should also be
vaccinated against the pneumococcus.
—Karen L. Roos
See also–Bacterial Abscess, Cerebral; Fungal
Meningitis; Meningitis, Eosinophilic; Meningitis,
Viral
Further Reading
Girgis, N. I., Farid, Z., Mikhail, I. A., et al. (1989). Dexametha-
sone treatment for bacterial meningitis in children and adults.
Pediatr. Infect. Dis. J. 8, 848–851.
Klugman, K. P., Friedland, I. R., and Bradley, J. S. (1995).
Bactericidal activity against cephalosporin-resistant Streptococ-
cus pneumoniae in cerebrospinal fluid of children with acute
bacterial meningitis. Antimicrob. Agents Chemother. 39, 1988–
1992.
McIntyre, P. B., Berkey, C. S., King, S. M., et al. (1997).
Dexamethasone as adjunctive therapy in bacterial meningitis.
J. Am. Med. Assoc. 278, 925–931.
National Committee for Clinical Laboratory Standards (1994).
Performance Standards for Antimicrobial Susceptibility
Testing. National Committee for Laboratory Standards,
Villanova, PA.
Peltola, H. (1999). Prophylaxis of bacterial meningitis. Infect. Dis.
Clin. North Am. 13, 685–706.
Pfister, H. W., Borasio, G. D., Dirnagl, U., et al. (1992).
Cerebrovascular complications of bacterial meningitis in adults.
Neurology 42, 1497–1504.
Simberkoff, M. S., Moldover, N. H., and Rahal, J., Jr. (1980).
Absence of detectable bactericidal and opsonic activities in
normal and infected human cerebrospinal fluids: A regional
host defense deficiency. J. Lab. Clin. Med. 95, 362–367.
Tauber, M. G., and Moser, B. (1999). Cytokines and chemokines in
meningeal inflammation: Biology and clinical implications.
Clin. Infect. Dis. 28, 1–12.
Balance
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BALANCE and equilibrium refer to the ability of an
animal to maintain its desired position and motion in
space, resisting the forces that would tend to knock it
over or knock it off course. For humans, maintaining
balance is especially challenging because our two feet
provide only a narrow base of support and our
upright stance places our center of gravity far above
this base. In all animals, equilibrium is achieved via a
collection of reflexes acting in cooperation. These
reflexes range from wholly unconscious mechanisms
organized at the level of the spinal cord [e.g., deep
tendon (myotatic) reflex] to sophisticated, conscious
learned strategies involving the cerebral cortex
(e.g., the body postures used by a gymnast on a
balance beam). Thus, the balance system is distrib-
uted throughout all levels of the central nervous
system.
The reflexes mediating balance can be divided into
three subtypes: vestibular, visual, and propriocep-
tive. Vestibular reflexes are organized around
information flowing from the semicircular canals
and otolith organs of the inner ear. The six
semicircular canals (three on each side) sense
rotational velocity of the head in three dimensions
in space. In contrast, the otolith organs of the utricle
and saccule of the inner ear sense linear acceleration
of the head in three dimensions. Linear acceleration
could be produced by either tilt with respect to
gravity or sudden translation, such as one experi-
ences as one steps onto a moving escalator. Visual
balance reflexes are built around a subsystem that
uses patterns of image movement (optic flow) on the
retina to deduce how the animal is translating or
rotating in space. Visual balance reflexes are
responsible for the sensation of movement experi-
enced by passengers on a stationary train as another
train starts to move on an adjacent track. Likewise,
the ‘‘barrel walk’’ of many funhouses is based on the
brain’s tendency to interpret visual flow in one
direction as self-motion in the opposite direction.
The third subtype of balance reflexes, the proprio-
ceptive mechanisms, use information from stretch

receptors in muscle and position receptors embedded
in the joint capsules to detect movement of the limbs
and activate muscles so as to compensate for the
perturbations. For example, stepping onto a moving
escalator causes the feet to move forward with
respect to the body’s center of gravity. The asso-
ciated plantar flexion at the ankle triggers relaxation
of the plantar flexors of the ankle and contraction of
the dorsiflexors of the ankle, thereby pulling the
upper body back over the feet.
Because the vestibular, visual, and proprioceptive
balance reflexes are largely unconscious, their actions
are perhaps best illustrated by the results of their
malfunction. The sense of self-rotation is determined
by the relative levels of activity from the semicircular
canals of the right and left sides. Pathological
reduction of the activity from one set of canals (as
occurs in viral labyrinthitis) is interpreted by the
brain as continuous, vigorous rotation, and patients
complain of a spinning sensation (rotational vertigo).
One’s sense of head position relative to the earth is
determined by the balance of inputs from right and
left otolith organs. Reduction of the activity from one
side (as occurs when otolith pathways are damaged
by a stroke in the lateral medulla) is interpreted by
the brain as a tilt. Lateral medullary stroke victims
suffer distortion of self-orientation and may, for
example, report that the floor lies where the wall
should be. Visual balance reflexes can be tricked into
incorrectly reporting self-motion, as occurs in the
funhouse barrel walk. Visual reflexes can also be
tricked into reporting nonmotion. Passengers in a
closed compartment of a rolling ship are told by their
visual system that they are stationary, but their
vestibular labyrinths report that they are in motion.
Since the estimates of self-motion from vestibular and
visual inputs are usually complementary, this abnor-
mal conflict induces the sensation of seasickness. As a
final example of disordered balance reflexes, patients
with peripheral neuropathy may report that the floor
feels ‘‘mushy’’ and tend to fall easily if they are
deprived of vision.
The multiple balance reflexes tend to complement
and reinforce each other. For instance, the visual
system provides information during slow continuous
head rotations, which activate the semicircular
canals only weakly. Conversely, the semicircular
canals perform optimally during rotations that vary
too rapidly to be sensed by visual mechanisms.
Proprioceptive and vestibular reflexes work in dark-
ness, in which visual mechanisms are useless.
Proprioceptive reflexes at the ankle can compensate
BALANCE 339
rapidly for instability of the supporting surface,
initiating postural corrections even before the head is
perturbed and vestibular and visual sensors are
activated. As a consequence of multiple overlapping
reflexes, patients can usually adapt to impairment of
any one input to the balance system. Patients who are
blind, who have lost all function in the vestibular
labyrinths (e.g., due to exposure to aminoglycoside
antibiotics), or who have severe peripheral nerve
damage can recover fairly normal postural stability
through an adaptive process in which the remaining,
normal reflexes are increasingly emphasized. How-
ever, compensatory mechanisms cannot fully replace
the missing sensory input, and patients usually need
to adopt strategies to avoid challenging their
impaired balance system. Patients who have lost
labyrinth function may learn to reduce head move-
ments or to avoid looking upward without first
taking hold of a fixed structure. Compensation for
one damaged sensor requires that the other sensors
are intact. Neurologists frequently encounter elderly
patients with poor balance attributable to a combi-
nation of age-related degeneration of the vestibular
labyrinth, poor vision from a variety of causes, and
abnormal proprioception due to peripheral neuro-
pathy and joint degeneration.
A range of tests have been developed to diagnose
abnormalities of balance. The functions of the
semicircular canals can be assessed by observing
eye movements during rapid, passive rotation of the
head. Observations of the vertical alignment of the
eyes and vertical head position yield insight into
otolith function. Assessing changes in sway with the
eyes open and closed (Romberg’s test) indicates the
degree to which the patient relies on vision to
supplement vestibular and visual reflexes. One can
test vestibular reflexes in isolation by having patients
stand on a foam base (which compromises the ability
of ankle proprioception to signal upper body sway)
with the eyes closed. Computerized systems that
record patient sway during perturbations of the
surface of support and the visual surround (dynamic
posturography) can detect subtle impairments of
balance and can be used to predict whether patients
will respond to vestibular rehabilitation and to
determine what strategies to use.
—John S. Stahl
See also–Dysequilibrium Syndrome; Motion and
Spatial Perception; Vertigo and Dizziness;
Vestibular Loss; Vestibular System; Visual
System, Central
340 BALINT’S SYNDROME
Further Reading
Baker, J. (1999). Supraspinal descending control: The medial
‘‘postural’’ system. In Fundamental Neuroscience (M. J.
Zigmond, F. E. Bloom, S. C. Landis, J. L. Roberts, and L. R.
Squire, Eds.). Academic Press, San Diego.
Baloh, R. W., and Halmagyi, G. M. (Eds.) (1996). Disorders of the
Vestibular System. Oxford Univ. Press, New York.
J. C. (1952). Living without a balancing mechanism. N. Engl. J.
Med. 246, 458–460.
Miles, F. A. (1993). The sensing of rotational and translational
optic flow by the primate optokinetic system. Rev. Oculomotor
Res. 5, 393–403.
Balint’s Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BALINT’S SYNDROME is an intriguing disorder of
visuospatial attention. The ability to focus attention
is necessary to make sense of the constant bombard-
ment of sensory stimuli that occurs in everyday life.
For example, in a crowded, noisy room we are
usually still able to attend to the conversation at
hand. Similar mechanisms allow us to focus on
specific visual stimuli. However, this sometimes leads
to the phenomenon of looking but not seeing. Many
of us have had the experience of looking for an object
such as a jar of mayonnaise in the refrigerator, being
unable to locate it, and then having one’s spouse grab
the jar right in front of one’s eyes. Patients with
Balint’s syndrome have an extreme form of looking
but not seeing along with several other related
deficits. Balint’s syndrome is used in the neurological
literature to designate a triad of visuospatial defects
referred to as simultanagnosia, optic ataxia, and
ocular apraxia. Patients with this triad of signs usually
have brain lesions at the junction of the occipital and
parietal lobes of both hemispheres. This entry
describes the syndrome from a historical pers-
pective, defines its individual components, and dis-
cusses the presentation and etiologies of the syndrome.
HISTORICAL PERSPECTIVE
Reszo Balint (1874–1929), a Hungarian physician, is
best known for a description of the components of a
syndrome that bears his name. In 1909, he reported a
man with three related but distinct visuospatial
abnormalities that were individually designated as a
spatial disorder of attention (simultanagnosia), optic
ataxia, and psychic paralysis of gaze (ocular apraxia).
At autopsy the man had multiple brain lesions,
including bilateral nearly symmetrical softening of
the posterior parietal, upper temporal, and occipital
lobes. These lesions likely resulted from strokes
because the patient also had severe atherosclerotic
disease of the cerebral circulation. In 1918, Gordon
Holmes reported six soldiers with missile wounds to
occipital regions; each had ‘‘disturbances of visual
orientation’’ similar to the patient of Balint’s. An
autopsy was performed on two of these patients and
each had bilateral lesions involving the parieto-
occipital area. However, the term Balint’s syndrome
did not appear in the literature until 1954, when it
was used by Hecaen and de Ajuraguerra to describe
four patients who had some similarities to Balint’s
patient. Subsequent studies and case reports have
established Balint’s syndrome as referring to the pre-
viously mentioned triad of impairments and implying
lesions in specific brain areas. However, there are
reasons to question whether this triad of signs meets
the strict operational criteria for a syndrome.
SIMULTANAGNOSIA
Balint claimed that his patient ‘‘could see one and
only one object at a single time, no matter what
size.’’ What Balint referred to as a spatial disorder of
attention has generally become known as simultan-
agnosia. Simultanagnosia is an inability to recognize
multiple elements in a simultaneously displayed
visual presentation. To demonstrate simultanagnosia,
the patient is asked to describe a complex visual
scene that has multiple items in all four quadrants of
the visual field. A patient with simultanagnosia will
be able to describe a single element of the scene but
will have difficulty in directing attention to and
describing other parts of the scene or the picture as a
whole. Although visual field defects sometimes occur
with the syndrome, they are not severe enough to
account for the difficulty in describing the scene.
Intact visual fields are demonstrated by displaying an
object at different time points in each of the different
fields on a plain background. The ability to recognize
only one object at a time does not seem to be entirely
dependent on the size or even complexity of the
object. In 1959, Luria reported a patient with Balint’s
syndrome who could only see one circle when
presented a piece of paper with two circles drawn
on it. However, when the circles were connected
with a line the patient reported seeing an object
that looked like a dumbbell or spectacles. Typi-
cally, patients do not have impairment of object
340 BALINT’S SYNDROME
Further Reading
Baker, J. (1999). Supraspinal descending control: The medial
‘‘postural’’ system. In Fundamental Neuroscience (M. J.
Zigmond, F. E. Bloom, S. C. Landis, J. L. Roberts, and L. R.
Squire, Eds.). Academic Press, San Diego.
Baloh, R. W., and Halmagyi, G. M. (Eds.) (1996). Disorders of the
Vestibular System. Oxford Univ. Press, New York.
J. C. (1952). Living without a balancing mechanism. N. Engl. J.
Med. 246, 458–460.
Miles, F. A. (1993). The sensing of rotational and translational
optic flow by the primate optokinetic system. Rev. Oculomotor
Res. 5, 393–403.
Balint’s Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BALINT’S SYNDROME is an intriguing disorder of
visuospatial attention. The ability to focus attention
is necessary to make sense of the constant bombard-
ment of sensory stimuli that occurs in everyday life.
For example, in a crowded, noisy room we are
usually still able to attend to the conversation at
hand. Similar mechanisms allow us to focus on
specific visual stimuli. However, this sometimes leads
to the phenomenon of looking but not seeing. Many
of us have had the experience of looking for an object
such as a jar of mayonnaise in the refrigerator, being
unable to locate it, and then having one’s spouse grab
the jar right in front of one’s eyes. Patients with
Balint’s syndrome have an extreme form of looking
but not seeing along with several other related
deficits. Balint’s syndrome is used in the neurological
literature to designate a triad of visuospatial defects
referred to as simultanagnosia, optic ataxia, and
ocular apraxia. Patients with this triad of signs usually
have brain lesions at the junction of the occipital and
parietal lobes of both hemispheres. This entry
describes the syndrome from a historical pers-
pective, defines its individual components, and dis-
cusses the presentation and etiologies of the syndrome.
HISTORICAL PERSPECTIVE
Reszo Balint (1874–1929), a Hungarian physician, is
best known for a description of the components of a
syndrome that bears his name. In 1909, he reported a
man with three related but distinct visuospatial
abnormalities that were individually designated as a
spatial disorder of attention (simultanagnosia), optic
ataxia, and psychic paralysis of gaze (ocular apraxia).
At autopsy the man had multiple brain lesions,
including bilateral nearly symmetrical softening of
the posterior parietal, upper temporal, and occipital
lobes. These lesions likely resulted from strokes
because the patient also had severe atherosclerotic
disease of the cerebral circulation. In 1918, Gordon
Holmes reported six soldiers with missile wounds to
occipital regions; each had ‘‘disturbances of visual
orientation’’ similar to the patient of Balint’s. An
autopsy was performed on two of these patients and
each had bilateral lesions involving the parieto-
occipital area. However, the term Balint’s syndrome
did not appear in the literature until 1954, when it
was used by Hecaen and de Ajuraguerra to describe
four patients who had some similarities to Balint’s
patient. Subsequent studies and case reports have
established Balint’s syndrome as referring to the pre-
viously mentioned triad of impairments and implying
lesions in specific brain areas. However, there are
reasons to question whether this triad of signs meets
the strict operational criteria for a syndrome.
SIMULTANAGNOSIA
Balint claimed that his patient ‘‘could see one and
only one object at a single time, no matter what
size.’’ What Balint referred to as a spatial disorder of
attention has generally become known as simultan-
agnosia. Simultanagnosia is an inability to recognize
multiple elements in a simultaneously displayed
visual presentation. To demonstrate simultanagnosia,
the patient is asked to describe a complex visual
scene that has multiple items in all four quadrants of
the visual field. A patient with simultanagnosia will
be able to describe a single element of the scene but
will have difficulty in directing attention to and
describing other parts of the scene or the picture as a
whole. Although visual field defects sometimes occur
with the syndrome, they are not severe enough to
account for the difficulty in describing the scene.
Intact visual fields are demonstrated by displaying an
object at different time points in each of the different
fields on a plain background. The ability to recognize
only one object at a time does not seem to be entirely
dependent on the size or even complexity of the
object. In 1959, Luria reported a patient with Balint’s
syndrome who could only see one circle when
presented a piece of paper with two circles drawn
on it. However, when the circles were connected
with a line the patient reported seeing an object
that looked like a dumbbell or spectacles. Typi-
cally, patients do not have impairment of object
 BALINT’S SYNDROME 341

recognition or severe language problems that would
interfere with their ability to describe what they are
visualizing.
OCULAR APRAXIA
Balint’s patient also had ‘‘psychic paralysis of gaze,’’
which is now known as ocular apraxia. Ocular
apraxia is the inability to voluntarily direct one’s
fixation of gaze from one object to another. This is
demonstrated by having the patient fixate on one
object and then introducing a second object in
another part of the visual field and asking the patient
to direct his or her gaze toward the second object.
Patients will have difficulty in directing their gaze
even if told where to look. Patients may have other
eye movement abnormalities, such as difficulty in
maintaining visual fixation and poor tracking eye
movements. Each of these eye movement abnormal-
ities can be attributed to the patient’s impaired
spatial representation of the visual scene. In fact, eye
movements that are not visually dependent are intact
so that the patient can direct his or her gaze to a part
of his or her body or to sounds.
headaches and transient left side weakness. She was
diagnosed with an inflammatory vasculitis of the
central nervous system. During her hospital stay, she
began complaining of difficulty seeing, which she
could not describe more in depth. Examination
showed that she had normal visual acuity, visual
fields, and a mild simultanagnosia, ocular apraxia,
and optic ataxia. Figure 1 shows the magnetic
resonance image (MRI) of the patient showing
bilateral lesions of the parieto-occipital junction.
The second patient was a 55-year-old woman
evaluated for 5 years of progressively distorted
vision. For example, she was unable to see two cars
at an intersection and had almost stepped from a
curb into an approaching car but her husband pulled
her to safety. She also had difficulty performing
manual tasks under visual guidance, such as reaching
for utensils. On examination, when she was shown a
picture of a man jogging next to an elephant, she said
that she saw a man jogging outside but did not
describe the elephant. When asked whether she saw
an animal, she said that she saw only a blur of colors.
She also had optic ataxia and mild language and
memory difficulties. Her MRI showed prominent

OPTIC ATAXIA
Optic ataxia is an impairment of pointing toward or
reaching for objects. This defect can be demonstrated
by asking the patient to touch with his or her
fingertip a small object that he or she has visually
fixated on. The patient will make a smooth hand
movement but will miss the target. As in ocular
apraxia, movements that are not visually guided are
intact. Patients can point toward their own body
parts or toward the source of a sound.

PRESENTATION AND ETIOLOGY

Depending on the severity of the impairments, the
patient’s complaints will range from mild difficulty
seeing with no functional impairment to being
essentially blind. Patients have been reported to
complain that objects seem to appear and disappear
spontaneously. One patient reported watching a
television show when, to her surprise, a character
involved in a heated argument suddenly went flying
across the room from a punch thrown by a character
not seen. Here, two patients illustrating the clinical
presentation of Balint’s syndrome are briefly de-
Figure 1
scribed. MRI of a 70-year-old patient. Large arrows indicate lesions in the
The first patient was a 70-year-old woman who parieto-occipital region. The small arrow indicates the lesion
was admitted to the hospital because of severe causing the left-sided weakness.
342 BALLISM
occipitoparietal atrophy (Fig. 2). The cause of her
deficits is most likely a degenerative condition such
as Alzheimer’s disease because we have three similar
cases who have come to autopsy and all had
Alzheimer’s disease.
The parieto-occipital areas most consistently
involved in patients with Balint’s syndrome are the
angular gyrus, cuneus (Brodmann’s area 19), and
precuneus (Brodmann’s area 7). Bilateral lesions
restricted to these areas are quite rare, and patients
often have confounding visual, sensory (such as
hemineglect), and language impairments. Etiologies
of these brain lesions include strokes (most com-
monly from a transient global cerebral hypoperfu-
sion causing border zone infarcts), head trauma,
primary and metastatic brain tumors, HIV encepha-
litis, progressive multifocal encephalopathy, and
carbon monoxide poisoning. As illustrated in the
second case, neurodegenerative illnesses such as
Alzheimer’s disease or Creutzfeldt–Jakob disease
can also cause Balint’s syndrome.
CONCLUSION
Balint’s syndrome refers to a unique triad of
visuospatial abnormalities. Most patients have had
brain injuries to the parieto-occipital area of both
Figure 2
MRI of a 55-year-old patient. Note the marked atrophy in the
parieto-occipital region.
cerebral hemispheres. Patients with these abnormal-
ities can essentially attend to only one visual stimulus
at a time, which may leave them profoundly
impaired in a world that requires simultaneous
synthesis of both entire visual scenes and individual
components.
—Rodney A. Short and Neill R. Graff-Radford
See also–Agnosia; Angular Gyrus Syndrome;
Apraxia; Ataxia; Attention; Brodmann’s Areas
Acknowledgments
This work was supported in part by NIA Grant AG16574 and the
State of Florida Alzheimer’s Disease Initiative Program.
Further Reading
Ayuso-Peralta, L., Jimenez-Jimenez, F. J., Tejeiro, J., et al.
(1994). Progressive multifocal leukoencephalopathy in HIV
infection presenting as Balint’s syndrome. Neurology 44,
1339–1340.
Damasio, A. R. (1985). Disorders of complex visual processing:
Agnosia, achromatopsia, Balint’s syndrome, and related diffi-
culties of orientation and construction. In Principles of
Behavioral Neurology (M. M. Mesulam, Ed.). Davis, Philadel-
phia.
Graff-Radford, N. R., Bolling, J. P., Earnest, F., et al. (1993).
Simultanagnosia as the initial sign of degenerative dementia.
Mayo Clin. Proc. 68, 955–964.
Hijdra, A., and Meerwaldt, J. D. (1984). Balint’s syndrome in a
man with border-zone infarcts caused by atrial fibrillation. Clin.
Neurol. Neurosurg. 86, 51–54.
Luria, A. R. (1959). Disorders of ‘‘simultaneous perception’’ in a
case of bilateral occipito-parietal brain injury. Brain 83, 437–449.
Montero, J., Pena, J., Genis, D., et al. (1982). Balint’s syndrome.
Report of four cases with watershed parieto-occipital lesions
from vertebrobasilar ischemia or systemic hypotension. Acta
Neurol. Belgica 82, 270–280.
Rafal, R. D. (1997). Balint syndrome. In Behavioral Neurology
and Neuropsychology (T. E. Feinberg and M. J. Farah, Eds.).
McGraw-Hill, New York.
Rizzo, M. (1993). ‘‘Balint’s syndrome’’ and associated visuospatial
disorders. Baillieres Clin. Neurol. 2, 415–437.
Ballism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE WORD ballism is derived from the Greek verb
meaning ‘‘to throw.’’ Ballism refers to very large
amplitude coordinated involuntary movements in-
volving trunk and proximal limbs musculature, ex-
pressed by rotatory throwing or kicking movements.
342 BALLISM
occipitoparietal atrophy (Fig. 2). The cause of her
deficits is most likely a degenerative condition such
as Alzheimer’s disease because we have three similar
cases who have come to autopsy and all had
Alzheimer’s disease.
The parieto-occipital areas most consistently
involved in patients with Balint’s syndrome are the
angular gyrus, cuneus (Brodmann’s area 19), and
precuneus (Brodmann’s area 7). Bilateral lesions
restricted to these areas are quite rare, and patients
often have confounding visual, sensory (such as
hemineglect), and language impairments. Etiologies
of these brain lesions include strokes (most com-
monly from a transient global cerebral hypoperfu-
sion causing border zone infarcts), head trauma,
primary and metastatic brain tumors, HIV encepha-
litis, progressive multifocal encephalopathy, and
carbon monoxide poisoning. As illustrated in the
second case, neurodegenerative illnesses such as
Alzheimer’s disease or Creutzfeldt–Jakob disease
can also cause Balint’s syndrome.
CONCLUSION
Balint’s syndrome refers to a unique triad of
visuospatial abnormalities. Most patients have had
brain injuries to the parieto-occipital area of both
Figure 2
MRI of a 55-year-old patient. Note the marked atrophy in the
parieto-occipital region.
cerebral hemispheres. Patients with these abnormal-
ities can essentially attend to only one visual stimulus
at a time, which may leave them profoundly
impaired in a world that requires simultaneous
synthesis of both entire visual scenes and individual
components.
—Rodney A. Short and Neill R. Graff-Radford
See also–Agnosia; Angular Gyrus Syndrome;
Apraxia; Ataxia; Attention; Brodmann’s Areas
Acknowledgments
This work was supported in part by NIA Grant AG16574 and the
State of Florida Alzheimer’s Disease Initiative Program.
Further Reading
Ayuso-Peralta, L., Jimenez-Jimenez, F. J., Tejeiro, J., et al.
(1994). Progressive multifocal leukoencephalopathy in HIV
infection presenting as Balint’s syndrome. Neurology 44,
1339–1340.
Damasio, A. R. (1985). Disorders of complex visual processing:
Agnosia, achromatopsia, Balint’s syndrome, and related diffi-
culties of orientation and construction. In Principles of
Behavioral Neurology (M. M. Mesulam, Ed.). Davis, Philadel-
phia.
Graff-Radford, N. R., Bolling, J. P., Earnest, F., et al. (1993).
Simultanagnosia as the initial sign of degenerative dementia.
Mayo Clin. Proc. 68, 955–964.
Hijdra, A., and Meerwaldt, J. D. (1984). Balint’s syndrome in a
man with border-zone infarcts caused by atrial fibrillation. Clin.
Neurol. Neurosurg. 86, 51–54.
Luria, A. R. (1959). Disorders of ‘‘simultaneous perception’’ in a
case of bilateral occipito-parietal brain injury. Brain 83, 437–449.
Montero, J., Pena, J., Genis, D., et al. (1982). Balint’s syndrome.
Report of four cases with watershed parieto-occipital lesions
from vertebrobasilar ischemia or systemic hypotension. Acta
Neurol. Belgica 82, 270–280.
Rafal, R. D. (1997). Balint syndrome. In Behavioral Neurology
and Neuropsychology (T. E. Feinberg and M. J. Farah, Eds.).
McGraw-Hill, New York.
Rizzo, M. (1993). ‘‘Balint’s syndrome’’ and associated visuospatial
disorders. Baillieres Clin. Neurol. 2, 415–437.
Ballism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE WORD ballism is derived from the Greek verb
meaning ‘‘to throw.’’ Ballism refers to very large
amplitude coordinated involuntary movements in-
volving trunk and proximal limbs musculature, ex-
pressed by rotatory throwing or kicking movements.

Ballism is frequently unilateral and is referred to as
hemiballism. This is usually the result of deep brain
lesions including the contralateral subthalamic nu-
cleus. The most common cause is stroke, but other
processes that produce focal central nervous system
disease have also been implicated, such as metabolic
and endocrine disturbances; drugs such as levodopa,
ibuprofen, oral contraceptives, and anticonvulsi-
vants; inflammation (including systemic lupus
erythematosus, Sydenham’s chorea, and antipho-
spholipid antibody syndrome); and neoplasms.
Because an increased dopamine turnover is prob-
ably involved in the pathophysiology of ballistic
movements, antidopaminergic drugs, especially reser-
pine and tetrabenazine, have been reported to show
marked benefit. Recently, high-frequency electrical
stimulation of deep brain regions (nucleus ventralis
intermedius of the thalamus) has been proposed as an
alternative option when medical therapy fails.
—Esther Cubo and Christopher G. Goetz
See also–Basal Ganglia, Diseases of; Dopamine;
Dyskinesias; Lacunar Infarcts; Movement
Disorders, Overview
Further Reading
Shannon, K. (1998). Ballism. In Parkinson’s Disease and Move-
ment Disorders (J. Jankovic and E. Tolosa, Eds.), pp. 365–376.
Williams & Wilkins, Philadelphia.
Bárány, Robert
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ROBERT BÁRÁNY (1876–1936) was the founder of
modern clinical neuro-otology. A gifted theoretician,
BÁRÁNY, ROBERT 343
possessed with a keen sense of observation, Bárány
had the unique ability to synthesize a multitude of
clinical observations and investigations into a cogent
theoretical framework. Through his work, he has
provided the basis for our modern understanding of
labyrinthine function and established several classic
components of the neuro-otologic exam.
Born in Vienna in 1876, Bárány was raised and
educated in a city at the zenith of medical science.
After graduating with a degree in medicine in 1900,
Bárány studied internal medicine, neurology, and
psychiatry with some of the greatest minds of his
time: von Noorden, Kraepelin, and Freud. In 1905,
he was appointed to the ear clinic in Vienna and
restricted his work to otology. Intrigued by the
nystagmus produced by syringing patient’s ears,
Bárány astutely discovered that the phenomenon
was dependent on the temperature of the water.
Combining detailed clinical observations with phy-
sical theory, he penned his classic thesis ‘‘Investiga-
tions on the Rhythmical Nystagmus which Is Created
by Reflexes from the Vestibular Apparatus of the Ear
and Its Associated Phenomena.’’ In this epic work,
Bárány developed the modern physical theory of
caloric nystagmus. Bárány noticed that many pa-
tients in his clinic complained of dizziness after
flushing their ears. He keenly observed that the
patients’ dizziness and the direction of the accom-
panying nystagmus were dependent on the tempera-
ture of the water. Using the analogy of a bath oven,
Bárány hypothesized that the water used to flush the
ears produced convection currents in the labyrinth by
heating or cooling the adjacent endolymph fluid. He
was subsequently able to prove this theory through a
series of eloquent clinical experiments.
In the next several years, Bárány published
additional observations on the vestibular effects of
rotational and optokinetic stimuli. His research was
rapidly adopted in the clinic, and caloric and
rotational testing quickly became essential elements
of the neurootologic evaluation. In 1910, Bárány
introduced rapid passive movements as a standard
part of the vestibular exam and described their utility
in diagnosing unilateral vestibular pathology of
various etiologies.
In 1914, Bárány’s tremendous contributions to
medicine were recognized by his receipt of the Nobel
Prize in physiology and medicine. At the time of the
award, Bárány was a Russian prisoner of war in
Turkestan. Through the thoughtful interventions of
the Swedish royal family, the Russian Academy of
Sciences, and the Swedish Red Cross, he was released
344 BARTONELLA INFECTIONS
in 1916 to receive his award. He was quickly given
refuge in Sweden and subsequently made professor of
otolaryngology at Uppsala.
After settling in his adoptive Sweden, Bárány
continued to make significant contributions to vesti-
bular science and clinical otology. He was the first to
describe positional nystagmus and to investigate the
roles of the cerebellum and neck proprioceptors in
vestibulo-ocular control. As a surgeon, he performed
some of the earliest procedures for otosclerosis and
described a novel operation for the treatment of
chronic frontal sinusitis. His contributions to science,
however, were not restricted to vestibular research.
Bárány published on the division of the granular
layer of the binocular visual cortex and the forma-
tion of psychiatric neuroses. He authored numerous
manuscripts and edited several scientific journals.
Bárány possessed the unique ability to combine the
old with the new, to meld established data with new
theories. Modern vestibular research stands firmly on
his groundbreaking ideas, and current clinical
vestibular testing is rooted in his clinical methods.
His contributions to modern neuro-otology are
enormous and continue to reap benefits more than
60 years after his death.
—Jeffrey L. Bennett
See also–Neuro-Otology; Nystagmus and
Saccadic Intrusions and Oscillations; Optokinetic
Nystagmus; Vestibular System (see Index entry
Biography for complete list of biographical
entries)
Further Reading
Bárány, R. (1906). Untersuchungen über den vom Vestibularap-
parat des Ohres reflektorisch ausgelösten rhytmischen Nystag-
mus und seine Begleiterscheinungen. Monatsschr. Ohrenheilkd.
40, 193–297.
Lanska, D. J., and Remler, B. (1997). Benign paroxysmal
positioning vertigo: Classic descriptions, origins of the provo-
cative positioning technique, and conceptual developments.
Neurology 48, 1167–1177.
Stevenson, L. G. (1953). Nobel Prize Winners in Medicine and
Physiology, 1901–1950. Schuman, New York.
Bartonella Infections
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CAT-SCRATCH disease was first described in 1950 at
the Societé Medical des Hôpitaux by Robert Debre, a
professor of pediatrics at the University of Paris.
Pierre Mollaret, professor of infectious diseases and
Chief of Service at the Pasteur Institute, was the
senior author of 14 papers written on cat-scratch
disease in 1950 and 1951 and, in conjunction with J.
Reuilly, made an antigen (from pus aspirated from the
lymph nodes of patients with clinical features of cat-
scratch disease) for intradermal testing. The causative
organism of the majority of cases of cat-scratch
disease is Bartonella (Rochalimaea) henselae, a small,
pleomorphic, gram-negative, rod-shaped bacterium.
Some cases of cat-scratch disease may be caused by
Bartonella quintana or Afipia felis. Bartonella quin-
tana is the causative organism of trench fever.
Cat-scratch disease presents as fever with unilat-
eral regional lymphadenopathy. There is often
evidence of cat scratches on the hand or arm in the
region of the lymphadenopathy.
A variety of clinical syndromes have been reported
in immunocompetent patients with B. henselae
infection, including unilateral lymphadenitis, ence-
phalopathy with adenopathy and seizures, Leber’s
stellate neuroretinitis, Parinaud’s oculoglandular
syndrome (conjunctival granuloma with preauricular
adenopathy), a chronic fatigue syndrome-like dis-
ease, and aseptic meningitis with relapsing fever due
to B. henselae bacteremia. Lymphadenitis is the most
frequently observed syndrome. Neuroretinitis, pre-
senting with painless unilateral loss of visual acuity
and retinal edema with some degree of optic disk
swelling and a macular star, is the second most
common presentation of B. henselae infection.
Family members may develop lymphadenitis or
neuroretinitis simultaneously.
Bacillary angiomatosis was first described in
HIV-infected individuals who had subcutaneous and
vascular lesions mimicking Kaposi’s sarcoma. Bacil-
lary angiomatosis derives its name from the prolifera-
tion of blood vessels seen on histological examination
of affected tissues with numerous gram-negative
bacilli demonstrated by Warthin–Starry silver stain. In
HIV-infected individuals, B. henselae and B. quintana
have been isolated from cutaneous bacillary angio-
matosis lesions. Disseminated disease may involve
skin, lymph nodes, liver, spleen, the gastrointestinal or
respiratory tract, and the central nervous system.
Acute psychosis has been reported in association with
cerebral bacillary angiomatosis. Cognitive difficulty
and dementia in HIV-infected individuals has been
associated with serum antibodies to Bartonella,
suggesting Bartonella infection may be a treatable
cause of dementia in some HIV-infected individuals.

Diagnosis is made by the detection of antibodies in
serum or cerebrospinal fluid (CSF) to B. henselae or
isolation of the organism from blood or tissue
specimens. The latter may take as long as 31 days.
A polymerase chain reaction assay to detect Barto-
nella nucleic acid in CSF is available in research
laboratories.
Cat-scratch disease is typically self-limited; it does
not require antimicrobial therapy unless symptoms
are prolonged, severe, or associated with neurological
complications. In any of these instances, a combina-
tion of doxycycline (100 mg twice daily) or erythro-
mycin (500 mg four times/day) with rifampin is
recommended. Leber’s stellate neuroretinitis is treated
with corticosteroid therapy, in addition to antimicro-
bial therapy, because inflammation and edema appear
to be responsible for most of the visual impairment.
Bacillary angiomatosis responds well to antimicrobial
therapy, but prolonged courses of 4–6 weeks of
doxycycline or erythromycin may be required.
—Karen L. Roos
See also–Rickettsial Infections
Further Reading
Carithers, H. A. (1970). Cat-scratch disease. Am. J. Dis. Child.
119, 200–203.
Lucey, D., Dolan, M. J., Moss, C. W., et al. (1992). Relapsing
illness due to Rochalimaea henselae in immunocompetent
hosts: Implication for therapy and new epidemiological
associations. Clin. Infect. Dis. 14, 683–688.
Marra, C. M. (1995). Neurologic complications of Bartonella
henselae infection. Curr. Opin. Neurol. 8, 164–169.
Schwartzman, W. A., Patnaik, M., Angulo, F. J., et al. (1995).
Bartonella (Rochalimaea) antibodies, dementia, and cat own-
ership among men infected with human immunodeficiency
virus. Clin. Infect. Dis. 21, 954–959.
Tappero, J. W., Mohle-Boetani, J., Koehler, J. E., et al. (1993). The
epidemiology of bacillary angiomatosis and bacillary peliosis. J.
Am. Med. Assoc. 269, 770–775.
Wong, M. T., Dolan, M. J., Lattuada, C. P., et al. (1985).
Neuroretinitis, aseptic meningitis, and lymphadenitis associated
with Bartonella (Rochalimaea) henselae infection in immuno-
competent patients and patients infected with human immuno-
deficiency virus type 1. Clin. Infect. Dis. 21, 352–360.
Basal Ganglia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BASAL GANGLIA consist of tightly intercon-
nected subcortical nuclei that play important roles in
BASAL GANGLIA 345
the control of motor, cognitive, and psychoaffective
behaviors. Surprisingly, despite the large amount of
work that has been devoted to these brain regions,
the normal functions of basal ganglia are still poorly
known. Most findings about basal ganglia functions
were originally obtained from clinical observations
and postmortem brain examination of patients with
major movement deficits, such as Parkinson’s dis-
ease, Huntington’s disease, and hemiballismus. Once
it became clear that these diseases were character-
ized by the loss of specific populations of neurons in
basal ganglia nuclei, the role of basal ganglia in
motor control generated great interest in the
scientific community. The development of animal
models of basal ganglia diseases led to major
breakthroughs in our understanding of the func-
tional circuitry of these brain structures and resulted
in the development of novel surgical and pharma-
cological therapies for movement disorders.
Although the motor aspect of basal ganglia surely
deserved most consideration, it is noteworthy that
basal ganglia are not solely involved in motor
control but also participate in high-order cognitive
and limbic functions. For instance, basal ganglia
pathology can lead to a variety of psychiatric
disorders involving cognitive impairments and def-
icits in executive functions. Furthermore, dementia
and cognitive deficits are commonly associated with
Parkinson’s and Huntington’s diseases. The devel-
opment of highly sensitive anatomical, molecular,
electrophysiological, and neural imaging techniques
has led to major advances in understanding the
organization and functions of the basal ganglia. In
this entry, we discuss some of the main chemoana-
tomical features of basal ganglia and relate them
to the current view of the functional circuitry of
these brain structures in normal and pathological
conditions.
THE BASAL GANGLIA NUCLEI
There are four main subcortical nuclei of the basal
ganglia. First, the striatum consists of the caudate
nucleus, putamen, and nucleus accumbens. The
caudate nucleus and putamen are commonly referred
to as the dorsal striatum, whereas the nucleus
accumbens and the olfactory tubercle form the
ventral striatum. In carnivores and primates, the
caudate nucleus and putamen are separated from
each other by the internal capsule, whereas in
rodents the striatum is a single nuclear mass
commonly called the caudate–putamen complex.

Diagnosis is made by the detection of antibodies in
serum or cerebrospinal fluid (CSF) to B. henselae or
isolation of the organism from blood or tissue
specimens. The latter may take as long as 31 days.
A polymerase chain reaction assay to detect Barto-
nella nucleic acid in CSF is available in research
laboratories.
Cat-scratch disease is typically self-limited; it does
not require antimicrobial therapy unless symptoms
are prolonged, severe, or associated with neurological
complications. In any of these instances, a combina-
tion of doxycycline (100 mg twice daily) or erythro-
mycin (500 mg four times/day) with rifampin is
recommended. Leber’s stellate neuroretinitis is treated
with corticosteroid therapy, in addition to antimicro-
bial therapy, because inflammation and edema appear
to be responsible for most of the visual impairment.
Bacillary angiomatosis responds well to antimicrobial
therapy, but prolonged courses of 4–6 weeks of
doxycycline or erythromycin may be required.
—Karen L. Roos
See also–Rickettsial Infections
Further Reading
Carithers, H. A. (1970). Cat-scratch disease. Am. J. Dis. Child.
119, 200–203.
Lucey, D., Dolan, M. J., Moss, C. W., et al. (1992). Relapsing
illness due to Rochalimaea henselae in immunocompetent
hosts: Implication for therapy and new epidemiological
associations. Clin. Infect. Dis. 14, 683–688.
Marra, C. M. (1995). Neurologic complications of Bartonella
henselae infection. Curr. Opin. Neurol. 8, 164–169.
Schwartzman, W. A., Patnaik, M., Angulo, F. J., et al. (1995).
Bartonella (Rochalimaea) antibodies, dementia, and cat own-
ership among men infected with human immunodeficiency
virus. Clin. Infect. Dis. 21, 954–959.
Tappero, J. W., Mohle-Boetani, J., Koehler, J. E., et al. (1993). The
epidemiology of bacillary angiomatosis and bacillary peliosis. J.
Am. Med. Assoc. 269, 770–775.
Wong, M. T., Dolan, M. J., Lattuada, C. P., et al. (1985).
Neuroretinitis, aseptic meningitis, and lymphadenitis associated
with Bartonella (Rochalimaea) henselae infection in immuno-
competent patients and patients infected with human immuno-
deficiency virus type 1. Clin. Infect. Dis. 21, 352–360.
Basal Ganglia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BASAL GANGLIA consist of tightly intercon-
nected subcortical nuclei that play important roles in
BASAL GANGLIA 345
the control of motor, cognitive, and psychoaffective
behaviors. Surprisingly, despite the large amount of
work that has been devoted to these brain regions,
the normal functions of basal ganglia are still poorly
known. Most findings about basal ganglia functions
were originally obtained from clinical observations
and postmortem brain examination of patients with
major movement deficits, such as Parkinson’s dis-
ease, Huntington’s disease, and hemiballismus. Once
it became clear that these diseases were character-
ized by the loss of specific populations of neurons in
basal ganglia nuclei, the role of basal ganglia in
motor control generated great interest in the
scientific community. The development of animal
models of basal ganglia diseases led to major
breakthroughs in our understanding of the func-
tional circuitry of these brain structures and resulted
in the development of novel surgical and pharma-
cological therapies for movement disorders.
Although the motor aspect of basal ganglia surely
deserved most consideration, it is noteworthy that
basal ganglia are not solely involved in motor
control but also participate in high-order cognitive
and limbic functions. For instance, basal ganglia
pathology can lead to a variety of psychiatric
disorders involving cognitive impairments and def-
icits in executive functions. Furthermore, dementia
and cognitive deficits are commonly associated with
Parkinson’s and Huntington’s diseases. The devel-
opment of highly sensitive anatomical, molecular,
electrophysiological, and neural imaging techniques
has led to major advances in understanding the
organization and functions of the basal ganglia. In
this entry, we discuss some of the main chemoana-
tomical features of basal ganglia and relate them
to the current view of the functional circuitry of
these brain structures in normal and pathological
conditions.
THE BASAL GANGLIA NUCLEI
There are four main subcortical nuclei of the basal
ganglia. First, the striatum consists of the caudate
nucleus, putamen, and nucleus accumbens. The
caudate nucleus and putamen are commonly referred
to as the dorsal striatum, whereas the nucleus
accumbens and the olfactory tubercle form the
ventral striatum. In carnivores and primates, the
caudate nucleus and putamen are separated from
each other by the internal capsule, whereas in
rodents the striatum is a single nuclear mass
commonly called the caudate–putamen complex.
346 BASAL GANGLIA

Second, the globus pallidus or dorsal pallidum lies

medial to the putamen and is divided into external
and internal segments (GPe and GPi, respectively).
The two pallidal segments are separated from each
other and from the putamen by bundles of axons
referred to as the internal and external medullary
lamina. An accessory medullary lamina, which
separates the GPi into a medial and lateral part, is
also found in monkeys and humans. On the other
hand, the ventral pallidum is located rostrally under
the anterior commissure. In nonprimates, the homo-
log of GPe is the globus pallidus (GP), whereas the
entopeduncular nucleus (EP) is the homolog of GPi.
Third, the subthalamic nucleus (STN) is a small
almond-shaped nucleus located just under the
thalamus at the junction between the midbrain and
diencephalon. It is tightly surrounded by major
ascending and descending fiber bundles that inter-
connect basal ganglia nuclei. Finally, the substantia
nigra consists of the pars compacta (SNc), which is
largely made up of dopaminergic neurons that
project to the dorsal striatum, and the pars reticulata
(SNr), which together with the GPi are seen as the
major output nuclei of the basal ganglia. Medial
to the SNc lies the ventral tegmental area (VTA), Figure 1
which comprises mostly dopaminergic neurons that Model of direct and indirect striatofugal pathways. Dashed lines,
project to the ventral striatum and cerebral cortex. inhibitory pathways; solid lines, excitatory pathways. Note that
Except for the STN and SNc/VTA, projection many connections have been omitted for simplification. See text
for abbreviations.
neurons of all basal ganglia nuclei use the inhibitory
gamma-aminobutyric acid (GABA) as neurotrans-
mitter. In contrast, STN neurons are glutamatergic
and act as a major excitatory drive of basal ganglia The striatum is considered the main entrance to
output neurons (Fig. 1). the basal ganglia circuitry because it receives
glutamatergic inputs from the whole cerebral cortex.
The source of cortical inputs imposes a strict
functional compartmentalization on the striatum.
THE STRIATUM: THE MAIN ENTRANCE TO
The caudate nucleus and the precommissural part of
THE BASAL GANGLIA CIRCUITRY
the putamen are referred to as the associative
The basic circuit of information flow through the striatum because they receive inputs from associa-
basal ganglia is outlined in Fig. 2. In brief, basal tive areas in the frontal, parietal, and temporal
ganglia receive inputs from the whole cerebral lobes. The postcommissural putamen is the sensor-
cortex. Once this information has been integrated imotor striatum because its cortical innervation
and processed, it is conveyed to the thalamus, which largely arises from motor and somatosensory areas
sends it back to frontal cortical areas. Another major of the cerebral cortex. Finally, the ventral striatum is
target of basal ganglia outflow is the tegmental seen as the limbic striatum because of its tight
pedunculopontine nucleus, which, via its connections connections with limbic cortical regions, the amyg-
with the lower brainstem and spinal cord, provides a dala, and hippocampus. This functional segregation
route whereby basal ganglia outflow can escape is maintained throughout the basal ganglia circuitry
thalamocortical circuits. Basal ganglia-receiving neu- and thalamus, which suggests that information
rons in both the thalamus and PPN also establish flowing through the basal ganglia is largely pro-
strong reciprocal connections with various basal cessed in parallel along functionally segregated
ganglia nuclei (Fig. 2). channels. Functionally related areas of motor and

Figure 2
Basic scheme of information flow through the basal ganglia.
Dashed lines, inhibitory pathways; solid lines, excitatory
pathways; PPN, pedunculopontine nucleus.
somatosensory cortices converge at common regions
in the sensorimotor striatum. However, functionally
interconnected associative cortical regions in the
frontal, temporal, and parietal lobes largely inner-
vate interdigitated areas of the caudate nucleus in
primates. Together, these data indicate that both
convergence and divergence of functionally related
cortical information occur along the corticostriatal
system.
The concept of parallel processing governs the
overall integration of information flow through the
basal ganglia. In 1986, Alexander and colleagues
proposed that cortical information flow through the
basal ganglia remains segregated in various closed
basal ganglia–thalamocortical loops. From the stand-
point of information processing, this model suggests
that structural convergence and functional integra-
tion are more likely to occur within than between the
separate basal ganglia–thalamocortical circuits.
Although this concept has been challenged and
revised during the past few years, the parallel
organization remains a well-accepted model of
information processing through the basal ganglia.
Interestingly, the functional specificity of the basal
ganglia–thalamocortical sensorimotor loop is dra-
matically reduced in Parkinson’s disease, which
BASAL GANGLIA 347
indicates that the nigrostriatal dopaminergic path-
way is critical for proper modulation of information
processing through the basal ganglia.
In addition to the cerebral cortex, the thalamus is
another major source of glutamatergic inputs to the
striatum. The thalamostriatal projections mainly
arise from intralaminar nuclei, although substantial
inputs originating from the ventral motor group
have also been described. In primates, the caudal
intralaminar nuclei—the center median (CM) and
parafascicular (PF) nuclei—are the main sources of
the thalamostriatal pathway. As discussed pre-
viously for the cortical afferents, thalamic inputs
terminate in the striatum according to a specific
pattern of functional organization. The CM neurons
project mainly to the sensorimotor striatum,
whereas neurons in PF are mostly connected with
the associative striatum. By contrast, rostral intra-
laminar nuclei project mainly to the limbic striatum.
The cerebral cortex and thalamus therefore repre-
sent the major sources of glutamatergic inputs to
striatal neurons. Various ionotropic and metabotro-
pic glutamate receptors mediate synaptic commu-
nication at corticostriatal and thalamostriatal
synapses.
A third main afferent to the striatum is from the
SNc. Midbrain dopaminergic neurons project to the
entire extent of the dorsal and ventral striata, where
they reciprocally interact with glutamatergic inputs.
Other extrinsic inputs to the striatum arise from GPe,
amygdala, substantia innominata, subthalamic nu-
cleus, raphe nucleus, and locus coeruleus. In addition
to these various extrinsic afferents, striatal projection
neurons and interneurons provide profuse intrastria-
tal innervation.
The striatum is made up of two main populations
of neurons—namely, the spiny and aspiny neurons
based on the presence or absence of dendritic spines,
respectively. The spiny neurons represent 90–95%
of the total striatal neuronal population and are the
main projection neurons of the striatum. They use
GABA as a neurotransmitter but also coexpress
various neuropeptides, such as substance P, dynor-
phin, and enkephalin. The relative abundance of
these peptides and the differential expression of
dopamine receptor subtypes in striatal projection
neurons led to the concept of ‘‘direct’’ and ‘‘indirect’’
striatofugal pathways (discussed later). The striatum
also contains various populations of interneurons
that are chemically characterized by their selective
expression of acetylcholine, parvalbumin/GABA,
somatostatin/neuropeptide Y/nitric oxide/GABA, and
348 BASAL GANGLIA
calretinin/GABA. Calbindin D28k, which is ex-
pressed predominantly in small GABAergic pro-
jection neurons, also labels a specific subset of large
striatal interneurons. Both projection neurons
and interneurons generate intrinsic axon colla-
terals that innervate output neurons located in the
close vicinity or far away from their parent cell
bodies.
The projection neurons are the main targets of
synaptic inputs to the striatum. Each spiny neuron
receives massive glutamatergic inputs from the
cortex and thalamus as well as substantial dopami-
nergic influences from midbrain. The heads of
dendritic spines are the major sites of cortical
afferents, whereas thalamic inputs from CM/PF
innervate preferentially dendritic shafts. Conver-
gence of dopaminergic and cortical afferents at the
level of individual spines is a common feature in the
striatum, which provides an anatomical substrate
for tight functional interactions between glutama-
tergic and dopaminergic projections. The proximal
dendrites and cell bodies of projection neurons
mostly receive GABAergic and cholinergic inputs
from interneurons. The large number of synaptic
afferents that impinge on individual spiny projection
neurons suggests that they are the site for complex
processing and synaptic integration. Interneurons
also receive extrinsic synaptic innervation from
glutamatergic and dopaminergic afferents, but to a
much lower degree than output neurons. Nigros-
triatal dopaminergic afferents and thalamostriatal
projections from CM/PF play a major role in
modulating expression of response plasticity in a
subpopulation of striatal interneurons, the tonically
active neurons (TANs; putative cholinergic inter-
neurons), during sensorimotor learning in the
primate striatum.
Huntington’s disease, a genetic disorder charac-
terized by hyperkinesia and major cognitive impair-
ments, results in a massive death of striatal projec-
tion neurons but selective sparing of interneurons.
THE MODEL OF DIRECT AND INDIRECT
PATHWAYS REVISITED
Once processed at the level of the striatum, the
information is conveyed to the output nuclei of the
basal ganglia (GPi and SNr) via two routes, the direct
and indirect pathways (Fig. 1). This functional model
of basal ganglia circuitry, which was introduced in
the late 1980s, served as a major drive for basal
ganglia research during the past 10 years. It helped
increase considerably our understanding of the
pathophysiology of disorders of movement asso-
ciated with diseases of the basal ganglia and led to
the resurgence of surgical therapies for Parkinson’s
disease. According to this model, the direct pathway
arises from a subpopulation of striatal spiny neurons
that project directly to the basal ganglia output
nuclei, whereas the indirect pathway arises from a
separate population of spiny neurons that project to
the GPe (Fig. 1). The GPe, then, conveys the
information to the STN, which relays it to the output
nuclei of the basal ganglia. The subpopulations of
striatal output neurons that give rise to the direct and
indirect pathways are further distinguished by their
expression of neuropeptides and dopamine receptor
subtypes. Thus, although all striatal spiny neurons
use GABA as their main transmitter, the subpopula-
tion that gives rise to the direct pathway is further
characterized by the presence of the neuropeptides
substance P and dynorphin and by the preferential
expression of the D1 subtype of dopamine receptors.
On the other hand, the subpopulation that gives rise
to the indirect pathway expresses preferentially
enkephalin and the D2 subtype of dopamine
receptors.
By virtue of the neurotransmitters and basal
activity in these neuronal networks, activation of
the direct and indirect pathways produces function-
ally opposite effects in neurons of the target nuclei of
the basal ganglia, thereby facilitating or attenuating
movements. Under resting conditions, the activity of
the spiny output neurons is low compared to that of
neurons in the globus pallidus and the STN.
Activation of glutamatergic pathways leads to
increased firing of striatal neurons. Increased activity
of neurons that give rise to the direct pathway
results, by virtue of their GABAergic nature, in the
inhibition of neurons in the output nuclei, which
relieves thalamocortical neurons from tonic basal
ganglia inhibitory influences, thereby facilitating
cortically initiated movements. The phenomenon
of disinhibition is fundamental to the physiology of
the basal ganglia and underlies basal ganglia-
associated functions. In contrast, activation of spiny
neurons that project to the GPe (i.e., neurons that
give rise to the indirect pathway) leads to the
opposite functional effect in the targets of the basal
ganglia. This is brought about in the following
manner: Activation of glutamatergic inputs leads to
increased activity of striatal neurons, which in turn
inhibit the tonically active neurons in the GPe.
Inhibition of these neurons releases from inhibition,
 BASAL GANGLIA 349

or disinhibits, neurons in the STN. Since STN

neurons are excitatory, their increased activity leads
to increased firing of neurons in the output nuclei
and hence greater inhibition of neurons in the target
nuclei. The increased inhibition of thalamocortical
neurons in the target nuclei is likely to have the
opposite effect of disinhibition (i.e., it is associated
with inhibition of basal ganglia functions, thereby
attenuation of cortically initiated movements). In
Parkinson’s disease, the loss of dopamine in the
striatum leads to increased activity of indirect
striatofugal neurons and decreased activity of the
direct pathway. The overall outcome of such an
imbalance of activity between the two striatofugal
pathways is a decreased cortical excitation and
problems generating movements.
The model of direct and indirect pathways, as
originally introduced, was by necessity a simplifica-
tion and only included the major projections of
subnuclei of the basal ganglia. However, since its
introduction many developments in our knowledge
and understanding of the anatomical and synaptic
organization of the basal ganglia have led to
reconsideration and updates of some aspects of the
model (Fig. 1). One of the most important new
anatomical findings is the demonstration of multiple
indirect pathways of information flow through the
basal ganglia. In addition to the classic indirect
pathway through the GPe and the STN, the GPe Figure 3
gives rise to prominent GABAergic projections that Pattern of synaptic innervation of GPe, GPi, and STN neurons by
extrinsic afferents. Note the pericellular baskets formed by GPe
terminate in basal ganglia output structures (GPi and terminals around the perikaryon of GPi neurons. Terminals from
SNr) and the striatum. An important feature that GP and striatum are inhibitory, whereas other inputs are
characterizes the GPe projection to basal ganglia excitatory.
output nuclei is the distinctive pericellular baskets
formed by GPe terminals around the perikarya of
GPi and SNr neurons (Fig. 3). To be found in such a but also express low levels of D2 receptors. The
strategic location indicates that GPe plays a major converse is true for indirect striatofugal neurons.
role in controlling the overall basal ganglia outflow. Only a small population of striatofugal neurons
In contrast, striatal and STN afferents are homo- express high levels of both D1 and D2 receptors
geneously distributed along the whole dendritic tree (Fig. 4). Similarly, recent intracellular labeling studies
of GPe and GPi neurons (Fig. 3). showed that the segregation of striatofugal neurons
It is noteworthy that recent molecular and into two separate populations is not as clear-cut as
anatomical data challenged the concept of direct originally suggested based on differential peptide
and indirect pathways. On the one hand, some expression and retrograde double-labeling studies.
investigators showed a higher degree of colocaliza- Striatal projection neurons innervate, to some
tion of D1 and D2 dopamine receptors in striatal extent, both pallidal segments and the substantia
projection neurons than originally suspected based nigra in rats and monkeys. However, as discussed
on in situ hybridization studies. These data argue for D1 and D2 receptor segregation, most striatofu-
that most striatal projection neurons coexpress both gal neurons project preferentially to either GPe or
dopamine receptor subtypes, but to varying degrees GPi/SNr (Fig. 4). An additional concern regarding
(Fig. 4). For instance, the majority of direct striato- the direct and indirect pathway model is that it does
fugal neurons are enriched in D1 dopamine receptors not take into consideration that dopamine may
350 BASAL GANGLIA
Figure 4
Proposed schematic to illustrate the current view of dopamine
receptor segregation and axon collateralization of striatofugal
neurons. A subpopulation of striatal neurons that express a high
level of D2 and a low level of D1 dopamine receptors project
massively to GPe with thin collaterals to GPi and SNr (indirect
pathway). Another population of striatal neurons that express a
high level of D1 and a low level of D2 dopamine receptors project
massively to GPi/SNr with thin collaterals to GPe (direct pathway).
Finally, a third small population of striatal neurons that express
high levels of both D1 and D2 dopamine receptors project
massively to both GPe and GPi/SNr.
influence basal ganglia activity via extrastriatal
projections to GPi and STN. Although these ob-
servations do not rule out the concept of segregation
of striatofugal neurons, they must be kept in
mind while considering the functional significance
of the direct and indirect striatofugal pathways in
normal and pathological conditions of the basal
ganglia.
Although all medium spiny striatofugal neurons
display a similar pattern of synaptic innervation,
some extrinsic afferents target preferentially direct or
indirect striatal projection neurons. For instance,
thalamic inputs from CM form synapses much more
frequently with direct than indirect striatofugal
neurons in squirrel monkeys. On the other hand,
sensorimotor cortical inputs influence preferen-
tially indirect striatofugal neurons. It is noteworthy
that such a differential pattern of synaptic innerva-
tion is also found at the level of striatal interneurons.
For example, cholinergic interneurons receive mas-
sive inputs from thalamic intralaminar nuclei but
are much less innervated by cortical afferents.
On the other hand, calretinin-immunoreactive inter-
neurons are devoid of thalamic inputs from CM,
whereas parvalbumin- and somatostatin-containing
neurons receive both CM and cortical inputs in
monkeys.
THE SUBTHALAMIC NUCLEUS:
AN ADDITIONAL ENTRANCE FOR
EXTRINSIC INFORMATION TO THE BASAL
GANGLIA CIRCUITRY
As is the case for the striatum, the STN also receives
excitatory glutamatergic projections from the cere-
bral cortex and the intralaminar thalamic nuclei
(Fig. 1). In primates, the cortico-subthalamic projec-
tion is exclusively ipsilateral and arises principally
from the primary motor cortex (area 4), with a minor
contribution of prefrontal and premotor cortices.
The somatosensory and visual cortical areas do not
project to the STN, but they project quite substan-
tially to the striatum. In rats, the cortico-subthalamic
projection originates mainly from pyramidal layer V
neurons that also project to the striatum. In both rats
and monkeys, the cortico-subthalamic projection is
topographically organized: (i) Afferents from the
primary motor cortex (M1) are confined to the
dorsolateral part of the STN; (ii) the premotor area
(areas 8, 9, and 46), the supplementary motor area,
the presupplementary motor area, and adjacent
frontal cortical areas innervate mainly the medial
third of the nucleus; whereas (iii) the prefrontal–
limbic cortices project to the medialmost tip of
the nucleus. By virtue of its cortical inputs, the
dorsolateral sector of the STN is more specifically
involved in the control of skeletomotor behavior,
whereas the ventromedial part is more concerned
with oculomotor and associative functions. Like
cortical afferents to the striatum, the cortico-sub-
thalamic projection from M1 is somatotopically
organized; the face area projects laterally, the arm
area centrally, and the leg area medially. Interest-
ingly, the arrangement of somatotopical representa-
tions from the supplementary motor area (SMA) to
the medial STN is the reverse of the ordering from
the M1 to the lateral STN in macaque monkeys.
Therefore, the cerebral cortex imposes a specific
functional segregation not only on the striatum but
also at the level of the STN. However, STN neurons
have long dendrites that may cross boundaries of
functional territories imposed by cortical projections
in rats. This anatomical arrangement opens the
possibility for some functionally segregated informa-
tion at the level of the cerebral cortex to converge on
individual STN neurons, at least in rodents.
The thalamo-subthalamic projection respects the
functional organization of the STN (i.e., sensorimo-
tor neurons in CM terminate preferentially in the
dorsolateral part of the nucleus, whereas limbic- and

associative-related neurons in PF project almost
exclusively to the medial STN). In rats, the thala-
mo-subthalamic projection is excitatory and toni-
cally drives the activity of STN neurons. Even if
cortical and thalamic inputs are relatively sparse and
terminate exclusively on the distal dendrites and
spines of STN neurons, electrophysiological experi-
ments have shown that activation of these inputs
results in very strong short-latency monosynaptic
excitatory postsynaptic potentials with multiple
spikes in STN neurons, which in turn transmit their
information to basal ganglia output structures much
faster than striatofugal pathways.
Although the exact mechanisms of action of
dopamine in the STN are obscure, the fact that
STN neurons express dopamine receptors combined
with electrophysiological data showing the local
effects of dopamine on STN neurons argues for a
potential role of extrastriatal dopamine in basal
ganglia functions. These observations emphasize the
importance of the STN in the functional organization
of the basal ganglia and strongly suggest that it may
serve as another entrance for extrinsic inputs to basal
ganglia circuitry.
THE BASAL GANGLIA OUTFLOW
The GPi and SNr are the two major output nuclei
that convey basal ganglia outflow to the thalamus
and various brainstem structures (Figs. 1 and 2). Via
these ascending and descending projections, the basal
ganglia can modulate neuronal activity over large
areas of the frontal cortex and brainstem motor
control regions.
The Pallidothalamic Projection
The pallidothalamic projection is topographically
organized and reaches the ventral anterior/ventral
lateral (VA/VL) and caudal intralaminar nuclei via
two main fiber bundles, namely the ansa lenticularis
and the lenticular fasciculus. The pallidothalamic
fibers originating from the caudal portion of the GPi,
including the motor territory, travel medially through
the lenticular fasciculus en route to the thalamus,
whereas fibers coursing below the ventral border of
the pallidum in the so-called ansa lenticularis
originate mostly from cells located in the rostral half
of GPi. Therefore, the separate designation of the
pallidothalamic pathways into ansa lenticularis and
lenticular fasciculus based on the location of GPi
cells relative to the accessory medullary laminae is
misleading and should be used with caution. This
BASAL GANGLIA 351
delineation is critical for effective surgical treatment
of various movement disorders.
Efferents from the sensorimotor GPi remain
largely segregated from the associative and limbic
projections at the level of the thalamus. The
sensorimotor GPi outputs are directed toward the
pars oralis of VL (VLo), whereas the associative and
limbic GPi innervate preferentially the parvocellular
ventral anterior (VApc) and the dorsal VL (VLd). The
ventromedial nucleus receives inputs from the limbic
GPi only. As discussed later, GPi outflow that
terminates in the ventral motor nuclei is transmitted
to SMA, MI, and PM. Segregated populations of GPi
neurons innervate thalamocortical cells directed
toward these motor cortical regions, with each of
these projections being involved in the control of
various aspects of skeletomotor activity. On the other
hand, the cognitive information from the dorsal part
of GPi is transmitted to prefrontal cortical areas 9
and 46, which are involved in planning and spatial
working memory.
The ventral anterior and mediodorsal thalamic
nuclei are the main targets of nigrothalamic projec-
tions. In monkeys, inputs from the medial part of the
SNr terminate mostly in the medial magnocellular
division of the VA (VAmc) and the mediodorsal
nucleus (MDmc), which in turn innervate anterior
regions of the frontal lobe, including the principal
sulcus (Walker’s area 46) and the orbital cortex
(Walker’s area 11). On the other hand, neurons in the
lateral SNr project preferentially to the lateral
posterior region of the VAmc and to different parts
of MD mostly related to posterior regions of the
frontal lobe, including the frontal eye field and areas
of the premotor cortex. Nigral outputs to the
thalamus flow along separate channels that target
various cortical areas involved in cognitive, sensory,
and oculomotor functions. Another thalamic target
of SNr neurons is the caudal intralaminar parafasci-
cular nucleus. The organization of this projection is
discussed later.
Pallidal, nigral, and cerebellar afferents largely
terminate in different subdivisions of the thalamic
VA/VL nuclei in primates, although a certain level of
convergence of cerebellar and GPi inputs also
exists. In contrast to the long-held belief that basal
ganglia outflow is conveyed exclusively to premotor
(PM) and SMA cortical areas, it is now established
that a substantial contingent of information from
the basal ganglia is sent to the primary motor cortex
(MI). Conversely, the cerebellar outflow, which was
thought to be directed exclusively to MI, also
352 BASAL GANGLIA
reaches PM and SMA cortical regions. It is
noteworthy that basal ganglia and cerebellar
projections to the ventral motor nuclei overlap much
more extensively in cats and rodents than in
primates.
Both cerebellar and basal ganglia–thalamic projec-
tions not only terminate in motor thalamic territories
but also reach major associative and limbic regions
of the primate thalamus that, in turn, innervate
various cortical areas in the frontal, parietal, and
temporal lobes involved in cognitive functions. These
projections provide a substrate by which basal
ganglia and cerebellar functions go beyond motor
control and involve complex cognitive and learning
processes.
Basal Ganglia Inputs to Intralaminar
Thalamic Nuclei
Most pallidal neurons that project to thalamic relay
nuclei send axon collaterals to the caudal intralami-
nar nuclei, where they follow a highly specific
pattern of distribution (Fig. 5). Pallidal axons arising
from the sensorimotor GPi terminate exclusively in
CM, where they form synapses with thalamostriatal
neurons projecting back to the sensorimotor terri-
tory of the striatum. In contrast, associative inputs
from the caudate-receiving territory of GPi termi-
nate massively in a dorsolateral extension of PF
(PFdl), which innervates preferentially the precom-
missural region of the putamen. Finally, the limbic
GPi innervates selectively the rostrodorsal part of PF
that, in turn, projects back to the nucleus accum-
bens. On the other hand, SNr projections are
confined to the PF, where they largely overlap with
thalamostriatal neurons projecting to the caudate
nucleus. Therefore, the CM/PF complex is part of
closed and open functional loops with the striato-
pallidal complex (Fig. 5). Although the functions of
these basal ganglia–thalamostriatal circuits are
largely unknown, there is evidence that thalamos-
triatal projections maintain a certain level of
vigilance and attention to incoming behaviorally
significant stimuli in striatal neurons. The CM/PF
are not the sole sources of thalamostriatal projec-
tions. Rostral intralaminar nuclei, midline nuclei,
and ventral motor nuclei also contribute signifi-
cantly to these projections. Projections from the
rostral intralaminar and midline thalamic nuclei are
mostly directed toward the ventral striatum,
whereas ventral motor nuclei send projections to
the sensorimotor striatum. Striatal projections from
interconnected ventral thalamic and cortical motor
areas converge in the monkey striatum. Based on
these data and previous findings showing that
thalamostriatal and thalamocortical neurons are
largely segregated in the caudal intralaminar nuclei,
we propose the existence of segregated basal gang-
lia–thalamostriatal loops that flow through the VA/
VL and CM/Pf in primates (Fig. 5).
The Pedunculopontine Nucleus:
An Additional Target of Basal
Ganglia Projections
In monkeys, more than 80% of GPi neurons that
project to the PPN send axon collaterals to the
ventral thalamus (Figs. 1 and 2). The noncholinergic
neurons of the pars diffusa of the PPN (PPNd) are the
main targets of GPi projections. The degree of
convergence of functionally segregated information
from GPi is much higher in PPNd than in the
thalamus (Fig. 6). The PPN is therefore in a position
to act as an interface between motivational, cogni-
tive, and motor information transmitted along the
pallidotegmental projection in primates. In contrast
to the VL, which largely conveys basal ganglia
information to the cerebral cortex, the PPN gives
rise to descending projections to the pons, medulla,
and spinal cord as well as prominent ascending
projections to the different structures of the basal
ganglia, the thalamus, and the basal forebrain
(Fig. 6). Acetylcholine, glutamate, and GABA are
used as neurotransmitters by PPN projection neu-
rons. The SNr also provides substantial inputs to
cholinergic and noncholinergic neurons of the PPN
in rats. The basal ganglia outputs to PPN may thus
be a route by which information can escape from the
basal ganglia–thalamocortical circuitry to reach
lower motor and autonomic centers.
The PPN sends massive cholinergic and noncholi-
nergic projections to various thalamic nuclei. These
projections play a major role in mediating cortical
desynchronization during waking and rapid eye
movement sleep. Cholinergic and glutamatergic
PPN inputs to thalamostriatal neurons in PF and
PFdl have been demonstrated. In contrast, the CM is
almost completely devoid of PPN inputs. These
observations raise the interesting possibility that
attention-related influences from PPN are mainly
transmitted to associative and limbic thalamostriatal
neurons. Interestingly, neurons in PF respond faster
to visual and auditory stimuli than do neurons in
CM, regardless of whether or not the stimuli are
associated with reward. Knowing the importance of
PPN in attention and arousal, the possibility that
 BASAL GANGLIA 353

Figure 5
Proposed basal ganglia–thalamocortical and thalamostriatal circuits flowing through the ventral motor thalamic nuclei and CM/Pf. The thick
and thin lines indicate massive and lighter axonal projections, respectively. The projection from Pfdl to the cortex is marked with a dashed
line because this pathway has not been established. See text for details.

the differential distribution of PPN inputs to CM and Additional Targets of Basal

PF underlies these physiological responses should
definitely be kept in mind while studying the role of
the thalamostriatal projection in the basal ganglia
circuitry. Thus, the PPN occupies a strategic position
that allows modulation of neuronal activity in
functional basal ganglia–thalamocortical and thala-
mostriatal loops. The facts that there is a significant
loss of PPN neurons in parkinsonians and that lesion
of PPN results in akinesia and postural instabilities
are further evidence that the PPN plays a major role
in basal ganglia circuitry in both normal and
pathological conditions.
Ganglia Outputs
The SNr sends a massive and topographically
organized GABAergic projection to the intermediate
layer of the superior colliculus. The nigral terminals
form distinctive clusters in the deep and intermediate
layers of the superior colliculus, where they innervate
neurons that project to the spinal cord, medulla, and
periabducens area. This projection plays an impor-
tant role in a variety of visual and auditory responses
and the control of saccadic eye movements orienting
the eyes toward a stimulus. This is consistent with
354 BASAL GANGLIA
Figure 6
Pattern of distribution of functionally segregated GPi inputs to the
PPN. Axonal projections from the associative, sensorimotor, and
limbic territories of GPi converge at a common region of the pars
diffusa of the PPN (PPNd). In turn, the PPNd provides
glutamatergic, GABAergic, and cholinergic inputs to various basal
ganglia nuclei (mostly SNc and STN), the thalamus, and several
nuclear groups in the pons, medulla, and spinal cord.
the fact that SNr receiving neurons of the inter-
mediate layer of the superior colliculus are targeted
by visual inputs from the cortex and project to
brainstem regions that control eye movements. The
medullary reticular formation is another target of
SNr outflow. This projection plays a role in the
control of orofacial movements. Finally, the lateral
habenular nucleus receives GABAergic inputs from
the GPi/EPN and ventral pallidum. Because of the
prominent connections between the lateral habenula
and various limbic structures, the pallidohebenular
projection is considered a functional interface
between the limbic system and basal ganglia.
CONCLUSION
Our knowledge of the basal ganglia anatomy has
increased tremendously during the past 10 years. In
this review, we briefly summarized the current view
of basal ganglia anatomy and highlighted recent data
that led to reconsideration of some aspects of the
functional circuitry of the basal ganglia. It is clear
that one of the major breakthroughs in our under-
standing of basal ganglia functions occurred with the
introduction of the model of direct and indirect
pathways in the late 1980s. This relatively simple
model served as a functional hypothesis for a
tremendous amount of work that has been done in
various fields of basal ganglia research during the
past 10 years. More important, it helped us under-
stand the pathophysiological processes that underlie
movement disorders related to basal ganglia dysfunc-
tions and set the stage for the resurgence of surgical
therapies for Parkinson’s disease. As discussed in this
review, it is clear that this model is an oversimplified
scheme of basal ganglia circuitry and does not
explain all aspects of normal and abnormal basal
ganglia functions. The existence of multiple indirect
pathways and changes in firing pattern of basal
ganglia neurons in Parkinson’s disease should defi-
nitely be considered as potential additions to this
model. However, despite these limitations, it is clear
that such a model must remain a major basis for both
basic and clinical research on basal ganglia.
Another important aspect of the basal ganglia
anatomy is the concept of parallel processing of
information flow. Since the introduction of this
concept in 1986, various anatomical techniques,
mostly based on anterograde and retrograde tracing
methods as well as transsynaptic virus transport,
have confirmed that a large component of the
information flowing through basal ganglia–thalamo-
cortical circuits is mostly processed in parallel
segregated channels, although a certain degree of
convergence must be considered. However, it appears
that the descending information from basal ganglia
output structures to the pedunculopontine tegmental
nucleus displays a much higher degree of functional
convergence than the information sent to the
thalamus. Although the role of the PPN in the basal
ganglia circuitry remains to be established, the fact
that it projects to all basal ganglia nuclei and receives
major inputs from GPi and SNr indicates that it
is tightly related to basal ganglia functions and
possibly serves as a major integrative center whereby
basal ganglia outflow may escape thalamocortical
circuits to reach lower brainstem structures and
spinal cord.
Finally, it has become clear during the past
few years that basal ganglia and cerebellar outflow

gains access not only to motor cortical regions
but also to large areas of the prefrontal cortex
involved in nonmotor learning and memory func-
tions. This is in line with evidence that a specific
population of striatal interneurons, namely the
TANs, acquire responsiveness to the sensory con-
ditioning stimuli during behavioral learning. The
fact that such a learning process is highly depen-
dent on the integrity of the nigrostriatal and
thalamostriatal systems highlights the importance
of these striatal inputs in normal basal ganglia
functions. Furthermore, recent evidence that neural
representations of habits are built in an ensemble
of striatal output neurons is another indication
that basal ganglia functions go far beyond motor
control.
—Yoland Smith and Mamadou Sidibe
See also–Basal Ganglia, Diseases of; Brain
Anatomy; Caudate Nucleus; Cerebral Cortex:
Architecture and Connections; Corpus Striatum;
Thalamus
Acknowledgments
We thank Jean-Francois Pare, Maney Mazloom, and James Weeks
for technical assistance. This research was supported by NIH
Grants R01 NS 37948 and RR 00165.
Further Reading
Gerfen, C. R., and Wilson, C. J. (1996). The basal ganglia. In
Handbook of Chemical Neuroanatomy. Vol. 12: Integrated
Systems of the CNS, Part III (A. Bjorklund, T. Hokfelt, and
L. Swanson, Eds.), pp. 369–466. Elsevier, Amsterdam.
Graybiel, A. M. (1998). The basal ganglia and chunking of
action repertoires. Neurobiol. Learn. Mem. 70, 119–136.
Houk, J. C., Davis, J. L., and Beiser, D. G. (1995). Models of
Information Processing in the Basal Ganglia. MIT Press,
Cambridge, MA.
Kultas-Ilinsky, K., and Ilinsky, I. A. (2001). Basal Ganglia and
Thalamus in Health and Movement Disorders. Kluwer Aca-
demic/Plenum, New York.
Matsumoto, N., Minamimoto, T., Graybiel, A. M., et al. M.
(2001). Neurons in the thalamic CM–Pf complex supply striatal
neurons with information about behaviorally significant sen-
sory events. J. Neurophysiol. 85, 960–976.
Mayberg, M. R., and Winn, H. R. (1998). Neurosurgery Clinics of
North America: Surgical Treatments of Movement Disorders.
Saunders, Philadelphia.
Ohye, C., Kimura, M., and McKenzie, J. S. (1996). The Basal
Ganglia V. Plenum, New York.
Olanow, C. W., Obeso, J. A., and Nutt, J. G., et al. (Eds.) (2000).
Basal ganglia, Parkinson’s disease and levodopa therapy. Trends
Neurosci. 23, S1–S126.
Watts, R. L., and Koller, W. C. (1997). Movement Disorders:
Neurologic Principles and Practice. McGraw-Hill, New York.
BASAL GANGLIA, DISEASES OF 355
Basal Ganglia, Diseases of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
DISEASE of the basal ganglia (BG) has traditionally
been equated with dysfunction of the ‘‘extrapyrami-
dal system,’’ giving rise to the ‘‘extrapyramidal
syndrome.’’ Both terms are quite inaccurate and
disappearing from the anatomical and clinical
literature. The BG are a group of nuclei located
subcortically. The term BG has no precise anatomical
definition and is used to designate the corpus
striatum (caudate nucleus and the lenticular nucleus,
which includes the putamen and the globus pallidus)
and other subcortical allied nuclei, such as the
subthalamic nucleus and the substantia nigra (SN)
(pars compacta and pars reticulata), and, recently,
the pedunculopontine tegmental nucleus. Currently,
the putamen and caudate are conjointly referred to as
the striatum.
Diseases of the BG (Table 1) are most often
characterized by disorders of movement, but there is
also a certain terminological confusion. Movement
disorders comprise a large variety of motor manifes-
tations not all of which necessarily originate in the
BG. In addition, BG dysfunction may be associated
with nonmotor manifestations, such as attention
deficit, depression, and mania. Thus, the labeling
‘‘extrapyramidal’’ has no anatomical basis and is
clinically inaccurate.
In a simplistic way, one can view the motor
manifestations of BG diseases as opposite poles of
normal movement. On the one hand are Parkinson’s
disease and related conditions (parkinsonian syn-
dromes), in which there is poverty and slowness of
movement. On the other hand, dyskinesias, such as
chorea–ballism or dystonia, are characterized by
excessive and inappropriate motor activity. The
former are thought to depend on increased inhibitory
activity of motor cortical and brainstem areas
induced by reduced nigrostriatal dopaminergic activ-
ity and the latter with abnormal neuronal signaling
from the BG to the thalamus and cortex. It must be
recognized, however, that the origin and pathophy-
siological basis of some movement disorders are
currently ill defined. For instance, the tics of Gilles de
la Tourette, the involuntary movements associated
with chronic neuroleptic treatments (tardive dyski-
nesias), or the restless legs syndrome, all of which are
sensitive to drugs acting on the dopaminergic system,
are usually assumed to have a BG origin, but such

gains access not only to motor cortical regions
but also to large areas of the prefrontal cortex
involved in nonmotor learning and memory func-
tions. This is in line with evidence that a specific
population of striatal interneurons, namely the
TANs, acquire responsiveness to the sensory con-
ditioning stimuli during behavioral learning. The
fact that such a learning process is highly depen-
dent on the integrity of the nigrostriatal and
thalamostriatal systems highlights the importance
of these striatal inputs in normal basal ganglia
functions. Furthermore, recent evidence that neural
representations of habits are built in an ensemble
of striatal output neurons is another indication
that basal ganglia functions go far beyond motor
control.
—Yoland Smith and Mamadou Sidibe
See also–Basal Ganglia, Diseases of; Brain
Anatomy; Caudate Nucleus; Cerebral Cortex:
Architecture and Connections; Corpus Striatum;
Thalamus
Acknowledgments
We thank Jean-Francois Pare, Maney Mazloom, and James Weeks
for technical assistance. This research was supported by NIH
Grants R01 NS 37948 and RR 00165.
Further Reading
Gerfen, C. R., and Wilson, C. J. (1996). The basal ganglia. In
Handbook of Chemical Neuroanatomy. Vol. 12: Integrated
Systems of the CNS, Part III (A. Bjorklund, T. Hokfelt, and
L. Swanson, Eds.), pp. 369–466. Elsevier, Amsterdam.
Graybiel, A. M. (1998). The basal ganglia and chunking of
action repertoires. Neurobiol. Learn. Mem. 70, 119–136.
Houk, J. C., Davis, J. L., and Beiser, D. G. (1995). Models of
Information Processing in the Basal Ganglia. MIT Press,
Cambridge, MA.
Kultas-Ilinsky, K., and Ilinsky, I. A. (2001). Basal Ganglia and
Thalamus in Health and Movement Disorders. Kluwer Aca-
demic/Plenum, New York.
Matsumoto, N., Minamimoto, T., Graybiel, A. M., et al. M.
(2001). Neurons in the thalamic CM–Pf complex supply striatal
neurons with information about behaviorally significant sen-
sory events. J. Neurophysiol. 85, 960–976.
Mayberg, M. R., and Winn, H. R. (1998). Neurosurgery Clinics of
North America: Surgical Treatments of Movement Disorders.
Saunders, Philadelphia.
Ohye, C., Kimura, M., and McKenzie, J. S. (1996). The Basal
Ganglia V. Plenum, New York.
Olanow, C. W., Obeso, J. A., and Nutt, J. G., et al. (Eds.) (2000).
Basal ganglia, Parkinson’s disease and levodopa therapy. Trends
Neurosci. 23, S1–S126.
Watts, R. L., and Koller, W. C. (1997). Movement Disorders:
Neurologic Principles and Practice. McGraw-Hill, New York.
BASAL GANGLIA, DISEASES OF 355
Basal Ganglia, Diseases of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
DISEASE of the basal ganglia (BG) has traditionally
been equated with dysfunction of the ‘‘extrapyrami-
dal system,’’ giving rise to the ‘‘extrapyramidal
syndrome.’’ Both terms are quite inaccurate and
disappearing from the anatomical and clinical
literature. The BG are a group of nuclei located
subcortically. The term BG has no precise anatomical
definition and is used to designate the corpus
striatum (caudate nucleus and the lenticular nucleus,
which includes the putamen and the globus pallidus)
and other subcortical allied nuclei, such as the
subthalamic nucleus and the substantia nigra (SN)
(pars compacta and pars reticulata), and, recently,
the pedunculopontine tegmental nucleus. Currently,
the putamen and caudate are conjointly referred to as
the striatum.
Diseases of the BG (Table 1) are most often
characterized by disorders of movement, but there is
also a certain terminological confusion. Movement
disorders comprise a large variety of motor manifes-
tations not all of which necessarily originate in the
BG. In addition, BG dysfunction may be associated
with nonmotor manifestations, such as attention
deficit, depression, and mania. Thus, the labeling
‘‘extrapyramidal’’ has no anatomical basis and is
clinically inaccurate.
In a simplistic way, one can view the motor
manifestations of BG diseases as opposite poles of
normal movement. On the one hand are Parkinson’s
disease and related conditions (parkinsonian syn-
dromes), in which there is poverty and slowness of
movement. On the other hand, dyskinesias, such as
chorea–ballism or dystonia, are characterized by
excessive and inappropriate motor activity. The
former are thought to depend on increased inhibitory
activity of motor cortical and brainstem areas
induced by reduced nigrostriatal dopaminergic activ-
ity and the latter with abnormal neuronal signaling
from the BG to the thalamus and cortex. It must be
recognized, however, that the origin and pathophy-
siological basis of some movement disorders are
currently ill defined. For instance, the tics of Gilles de
la Tourette, the involuntary movements associated
with chronic neuroleptic treatments (tardive dyski-
nesias), or the restless legs syndrome, all of which are
sensitive to drugs acting on the dopaminergic system,
are usually assumed to have a BG origin, but such
356 BASAL GANGLIA, DISEASES OF

Table 1 MAIN CATEGORIES OF BASAL GANGLIA DISEASESa

Disease Pathological basis Pathophysiological hallmark Main clinical features

Parkinson’s disease SNc cell loss STN/GPi hyperactivity Bradykinesia

DA depletion Rigidity/resting tremor
Huntington’s disease Loss of medium spiny GABA Decreased striatal Chorea and slowness of
striatal neurons enkephalinergic tone movement
Decreased GPe activity Cognitive deterioration
Hemichorea–ballism STN lesion Decresed STN GPi activity Large, proximal continuous
movements
Torsion dystonia Striatum/GPib Abnormal GPi patterns of Prolonged muscle spasms and
discharge fixed postures
a
Abbreviations used: SNc, substantia nigra pars compacta; GPi; globus pallidus pars interna; GPe, globus pallidus pars externa; STN,
subthalamic nucleus.
b
Inferred from monkeys and patients with focal lesions.

assertion has not been directly proven. Here, we
discuss only the major clinical conditions known to
occur as a consequence of BG dysfunction, namely
Parkinson’s disease (PD) and other frequent causes of
parkinsonism and dyskinesias such as chorea–ballism
and dystonia.
2/1000 of the general population and 1/100 after the
sixth decade of life. In the past few years, several
gene mutations have been associated with familial
forms of PD, but the genetic and/or environmental
origin of the most common sporadic presentation
remains elusive.

PARKINSONIAN SYNDROME Clinical Characteristics

The cardinal features of PD are reduction of
The most frequent conditions presenting with a
spontaneous motor activity (i.e., eye blinking, arm
parkinsonian syndrome as major clinical manifesta-
swinging, facial expression, etc.) and slowness of
tion are summarized in Table 2. Parkinson’s disease
movement initiation and execution (akinesia–brady-
(PD) is by far the most common cause of parkinson-
kinesia), cogwheel rigidity of the axial musculature
ism in clinical practice, with a prevalence of 1 or
and the limbs, and resting tremor (‘‘pill-rolling’’
tremor of the hands). The predominant age of onset
is approximately the 60s but there is a large range
Table 2 MAJOR CAUSES OF ADULT-ONSET PARKINSONISM
MIMICKING PARKINSON’S DISEASE IN CLINICAL PRACTICE
(20s–80s). Typically, PD first affects one body
segment. The classic triad may not be present at
Neurodegenerations onset. The most frequent presentations are tremor of
Multiple system atrophies (OPCA, Shy–Dragger, etc.)
a limb, slowness and clumsiness of one hand, and leg
Progressive supranuclear palsy
Corticobasalganglionic degeneration dragging on walking. In young-onset PD (i.e., o45
Drugs and toxins years old), foot dystonia is a fairly common
Neuroleptics (haloperidol, chlorpromazine, etc.) and dopamine presentation. Less often, the initial manifestation of
depletors (tetrabenazine and reserpine) PD may be depression, shoulder pain, hypophonia,
Calcium channel antagonists (cinnarizine and flunarizine) or jaw tremor.
Valproic acid
PD is characterized pathologically by loss of
MPTP
pigmented neurons in the substantia nigra and
Infections
Postencephalitic parkinsonism the presence of characteristic inclusion bodies
AIDS (Lewy bodies) in many of the remaining neurons.
Syphilis Degeneration of the SN pars compacta leads to
Metabolic dopamine (DA) depletion in the striatum and other
Mitochondrial encephalopathy regions of the brain. In the early stages of the
Wilson’s disease
disease, severe (480%) dopamine reduction is
Hypoparathyroidism
mainly confined to the posterolateral putamen,

giving rise to the cardinal motor features of PD. As
the neurodegenerative process evolves, neuronal loss
and DA depletion affect the overall striatum and
many other basal ganglia, brainstem, and cortical
regions. As a result, a number of additional
symptoms and signs ensue. Thus, after 15–20 years
of evolution, a high proportion of PD patients may
suffer a plethora of additional motor and nonmotor
problems. Among the former are gait and equili-
brium difficulties, depression, dysphagia, sialorrhea,
and severe hypophonia; the latter comprise penile
erection problems, urinary urgency, sleepiness and
decreased alertness, reduced attention and visuomo-
tor capacity, etc. Approximately 30% of PD patients
develop frank dementia, but a much larger percen-
tage show cognitive deficits if appropriately assessed.
It is currently believed that dementia in PD is mainly
related to the extension of the pathological process to
the cortex, but the nosological limits between ‘‘pure’’
PD, PD with dementia, and diffuse Lewy body
disease are not clear.
Treatment
The discovery that striatal dopamine deficiency is a
major biochemical characteristic of PD led to the
introduction of its precursor, levodopa, as a major
pharmacological strategy. In the early stages of PD,
the response to levodopa plus a dopa-decarboxylase
inhibitor (carbidopa or benserazide) is excellent.
Although there is a large interindividual variability,
doses ranging between 300 and 600 mg of levodopa
are commonly sufficient to provide marked motor
improvement. Tolerance is also fairly good. How-
ever, with disease progression, the benefit of each
levodopa dose wears off before the next dose, and
the motor state of the patient fluctuates between the
‘‘on’’ (improvement) and the ‘‘off’’ (parkinsonism)
situation. In addition, the antiparkinsonian effect of
levodopa may be associated with involuntary move-
ments or dyskinesias that impair voluntary motor
control. Between 5 and 10 years after initiation of
levodopa therapy, more than 90% of patients will
have developed motor fluctuations and dyskinesias
(referred to conjointly as motor complications). The
origin and pathophysiology of motor complications
are not completely understood. Disease severity,
duration and dose of the treatment with levodopa,
and its short half-life (o2 hr) are the factors that best
correlate with the development of motor complica-
tions. Several strategies have been attempted in order
to treat and prevent motor complications. The
concept of continuous dopaminergic stimulation,
BASAL GANGLIA, DISEASES OF 357
developed in the 1980s, aims to provide steady
correction of the striatal dopamine deficit. This is
currently achieved by using long-acting dopamine
agonists (e.g., cabergoline, pergolide, pramipexole,
and ropirinol), by prolonging the effect of levodopa
with a peripheral (blood) inhibitor of the catechol-O-
methyltransferase enzyme, or by subcutaneous ad-
ministration of the DA agonist apomorphine.
Patients who cannot be satisfactorily controlled with
any of these measures are treated surgically. Lesion
or blockade (by high-frequency stimulation) of the
subthalamic nucleus or globus pallidus pars interna is
associated with marked motor benefit in a large
proportion of correctly selected patients. In the near
future, it may be possible to directly replenish the
striatal DA deficit by delivering dopamine locally
through minipumps, polymers, or genetically engi-
neered cells.
Regarding treatment initiation, it has been con-
clusively shown by several controlled studies that
patients receiving a dopamine agonist had a sig-
nificant reduction in the frequency of motor compli-
cations after 5 years compared with those treated
with levodopa. This effect was seen even in those
patients who required levodopa as adjuvant (‘‘res-
cue’’) therapy. This important finding is now known
to be a class effect, common and similar to all DA
agonists currently utilized.
Differential Diagnosis
A focal presentation with resting tremor and positive
response to dopaminergic drugs is associated with a
95% diagnostic accuracy for PD. However, several
other conditions may manifest with dopaminergic
sensitivity (Table 2). Thus, the pharmacological
response cannot be used in isolation to separate PD
from other diseases. On the other hand, parkinsonian
syndromes unresponsive to dopaminergic drugs are
easier to recognize. The most common conditions are
progressive supranuclear palsy, striatonigral degen-
eration, and corticobasal degeneration. Pure parkin-
sonism of vascular origin is much rarer than
previously thought.
CHOREA–BALLISM
Chorea consists of a continuous flow of irregular,
jerky, unsustained, and explosive movements that flit
irregularly from one body portion to another. Many
of the choreic movements resemble fragments of
normal motor behavior but occur in a random,
358 BASAL GANGLIA, DISEASES OF
purposeless manner. Ballism is an exaggeration of
chorea, with a frank proximal limb predominance.
Huntington’s Disease
The prevalence of Huntington’s disease (HD) is
approximately 5/100,000. The disease is inherited
as an autosomal dominant trait with complete
penetrance. The defective gene has been located in
the short arm of chromosome 4. The mutation is an
expansion of an unstable cytosine–guanine (CAG)
trinucleotide repeat in a gene labeled the IT-15 gene
or huntingtin. Normally, the CAG repeat codified by
this gene consists of 35 or fewer repeats. All patients
with HD have expanded alleles with 36 CAG repeats
or more. It should be noted that alleles of 27–35
repeats may be expanded in offspring to cause HD.
The diagnosis of HD can now be made during the
presymptomatic period. This allows HD to be readily
distinguished from other conditions presenting with
generalized chorea, such as acantocytosis, spinocer-
ebellar atrophies, benign hereditary chorea, and
mitochondrial disorders.
The symptoms of HD usually begin in the 30s and
40s. HD is clinically characterized by the presence of
generalized chorea, cognitive deficits, postural in-
stability, and slowness of voluntary movement. The
patella reflex shows a characteristic ‘‘hung-up’’
property whereby the leg remains extended for
several hundred milliseconds following the tap. The
disease is relentlessly progressive, and the average
duration of life after diagnosis is approximately
15–20 years. Pathologically, there is gross neuronal
loss in the striatum and cortex. In the striatum, initial
damage appears to occur in the GABA spiny
projection neurons, particularly those expressing
the neuropeptide enkephalin. This may be the basis
for the origin of the choreic movements.
Treatment is merely symptomatic. Dopamine
blockers may control the chorea, but they often
aggravate gait and bradykinesia and result in no
improvement in quality of life. An animal model of
HD is currently being used to test several experi-
mental strategies aimed at stopping the progressive
nature of this terrible condition.
DYSTONIA
Dystonia is characterized by forceful and prolonged
muscle contractions of antagonist muscles twisting
the trunk and limbs into sustained postures. At-
tempted voluntary movement exacerbates the dysto-
nia producing an ‘‘overflow’’ of activity in distant
muscles. Torsion dystonia (TD) is a syndrome that
may be classified according to etiology into primary
and secondary forms. Idiopathic TD is considered
mainly an autosomal dominant disorder with re-
duced penetrance. Early onset dystonia (onset up to
12 years of age) is mostly due to a mutation of DYT-1
that consists of a deletion of a single GAC triplet
coding for an ATP-binding protein called Torsin A.
The Torsin A gene mutation is limited to the
early onset, generalized presentation. Adult-onset,
focal dystonia (torticollis, blepharospasm–oroman-
dibular dystonia, laryngeal dystonia, and writer’s
cramp) may appear sporadic on superficial analy-
sis. Various types of focal dystonia have been
associated with three other loci: DYT6 on chromo-
some 18, DYT7 (focal cervical dystonia), and
DYT13 (cranial–cervical and limb dystonia of mild
severity).
The list of secondary causes of TD is long, but
commonly recognized entities are few. For general-
ized, early onset TD, the differential diagnosis mainly
includes Wilson’s disease, mitochondrial encephalo-
pathy (Leigh’s disease), organic acidurias, juvenile
neuronal ceroid–lipofuscinosis, GM-1 and GM-2
gangliosidosis, and Hallervorden–Spatz disease. Ad-
vances in neuroimaging and biological markers have
made the diagnostic workup of TD much easier in
recent years. The most common causes of focal
secondary dystonia in our experience are trauma and
stroke. Neuroleptics can cause both focal and
generalized dystonia.
In childhood-onset, generalized dystonia, a very
important differential diagnosis is with dopa-respon-
sive dystonia (DRD). This condition is due to
mutations in the GTP cyclohydrolase 1 gene, an
enzyme that catalyzes the first step of the synthesis of
tetrahydrobiopterin, the natural factor of tyrosine
hydroxylase. As a result, there is a severe deficit of
dopamine synthesis and massive striatal dopamine
depletion with normal content of nigrostriatal
terminals. Clinically, DRD is characterized by
diurnal variations in the severity of limb dystonia
(particularly affecting gait), sleep benefit, and a
marked sensitivity to very low doses of levodopa
(25–100 mg per day). The long-term evolution of
DRD is rather benign, particularly compared to that
of juvenile PD.
Treatment
Botolinum toxin is well established as the treat-
ment of choice for focal dystonia, particularly
the cranial and cervical forms. The beneficial effect

is much more limited, or frequently absent, in
patients with focal, task-specific hand dystonia
such as writer’s cramp. In the latter presentation, a
recent study suggested that immobilization of the
affected limb may lead to substantial and prolonged
improvement.
Generalized and severe segmental dystonia are
more difficult to treat. Intrathecal baclofen infusions
have been associated with variable outcome. Func-
tional surgery of the globus pallidum pars interna has
been revitalized in recent years. However, there are
no prospective long-term series with a sufficiently
large number of patients to evaluate the benefit-to-
risk ratio of this approach.
—J. A. Obeso, M. C. Rodriguez-Oroz, and M. Rodrı´guez
See also–Ballism; Basal Ganglia; Botulism;
Chorea; Dyskinesias; Dystonia; Huntington’s
Disease; Parkinson’s Disease
Further Reading
Goetz, C. G., Leurgans, S., Pappert, E. J., et al. (2001). Prospective
longitudinal assessment of hallucinations in Parkinson’s disease.
Neurology 57, 2078–2082.
Hughes, A. J., Daniel, S. E., and Lees, A. J. (2001). Improved
accuracy of clinical diagnosis of Lewy boy Parkinson’s disease.
Neurology 57, 1497–1499.
McMurray, C. T. (2001). Huntington’s disease: New hope for
therapeutics. Trends Neurosci. 24, S32–S38.
Mouradian, M. M. (2002). Recent advances in the genetics
and pathogenesis of Parkinson’s disease. Neurology 58,
179–185.
Obeso, J. A., Olanow, C. W., Rodriguez-Oroz, M. C., et al. (2001).
Deep brain stimulation of the subthalamic nucleus or the globus
pallidus pars interna in advanced Parkinson’s disease. N. Engl.
J. Med. 345, 956–963.
Olanow, C. W., Obeso, J. A., and Nutt, J. G. (Eds.) (2000). Basal
ganglia, Parkinson’s disease and levodopa. Trends Neurosci. 23,
S1–S126.
Basilar Artery Thrombosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BASILAR ARTERY originates from the union of the
two intracranial vertebral arteries at or very near
the junction of the medulla oblongata and the pons.
The artery courses along the ventral aspect of the
pons and ends by bifurcating into the paired poster-
ior cerebral arteries at or near the junction of the
pons with the midbrain. The anterior inferior
BASILAR ARTERY THROMBOSIS 359
cerebellar artery, a vessel that supplies the lateral
pontine tegmentum and the pontine base and the
anterior inferior portion of the cerebellum, originates
from the proximal portion of the basilar artery. The
superior cerebellar artery, a vessel that supplies a
portion of the rostral pontine and midbrain tegmen-
tum and the superior surface of the cerebellum,
originates from the distal portion of the basilar
artery. Penetrating arteries to the medial and para-
medial portions of the pontine base and tegmentum
originate from the basilar artery at a number of
different levels. Penetrating arteries to the midbrain
and thalamus originate from the rostral basilar artery
and the proximal portion of the posterior cerebral
arteries.
PATHOLOGY
The most common and most important disease that
affects the basilar artery is atheroscerosis. In some
necropsy studies, the basilar artery is the earliest and
most severely affected intracranial artery. The ear-
liest atherosclerotic change in the basilar artery is an
increase in connective tissue especially in the intima
and media. Sometimes the predominant increase in
connective tissue is in the adventitia, with strands of
collagen spreading into the media causing medial
fibrosis. Thickening of the internal elastica and
splitting of the elastic membrane are common. The
intimal connective tissue increases in size and may
replace the internal elastic elements and become
hyalinized and fragmented, especially in its deeper
layers. Fatty deposits form within the intima
between connective tissue elements. Later, fibrous
plaques that are grossly elevated form and thickened
regions that are grossly visible along the basilar
artery form and gradually lead to stenosis of the
artery. As the basilar artery lumen becomes progres-
sively stenosed, cracks in plaques and mural thrombi
may appear. In most autopsied patients with fatal
basilar artery ischemia, superimposed thrombosis of
the vessel has developed. The atherosclerotic
changes are relatively evenly distributed in the
proximal, middle, and distal portions of the artery.
Thrombi can involve only a limited portion of the
artery or can be extensive.
Embolism is the second most important cause
of basilar artery occlusion. Emboli most often arise
from plaques and clots from the heart, aorta, and
the extracranial and intracranial vertebral arteries.
Emboli that reach the basilar artery often stop at
the rostral end of the artery. The basilar artery

is much more limited, or frequently absent, in
patients with focal, task-specific hand dystonia
such as writer’s cramp. In the latter presentation, a
recent study suggested that immobilization of the
affected limb may lead to substantial and prolonged
improvement.
Generalized and severe segmental dystonia are
more difficult to treat. Intrathecal baclofen infusions
have been associated with variable outcome. Func-
tional surgery of the globus pallidum pars interna has
been revitalized in recent years. However, there are
no prospective long-term series with a sufficiently
large number of patients to evaluate the benefit-to-
risk ratio of this approach.
—J. A. Obeso, M. C. Rodriguez-Oroz, and M. Rodrı´guez
See also–Ballism; Basal Ganglia; Botulism;
Chorea; Dyskinesias; Dystonia; Huntington’s
Disease; Parkinson’s Disease
Further Reading
Goetz, C. G., Leurgans, S., Pappert, E. J., et al. (2001). Prospective
longitudinal assessment of hallucinations in Parkinson’s disease.
Neurology 57, 2078–2082.
Hughes, A. J., Daniel, S. E., and Lees, A. J. (2001). Improved
accuracy of clinical diagnosis of Lewy boy Parkinson’s disease.
Neurology 57, 1497–1499.
McMurray, C. T. (2001). Huntington’s disease: New hope for
therapeutics. Trends Neurosci. 24, S32–S38.
Mouradian, M. M. (2002). Recent advances in the genetics
and pathogenesis of Parkinson’s disease. Neurology 58,
179–185.
Obeso, J. A., Olanow, C. W., Rodriguez-Oroz, M. C., et al. (2001).
Deep brain stimulation of the subthalamic nucleus or the globus
pallidus pars interna in advanced Parkinson’s disease. N. Engl.
J. Med. 345, 956–963.
Olanow, C. W., Obeso, J. A., and Nutt, J. G. (Eds.) (2000). Basal
ganglia, Parkinson’s disease and levodopa. Trends Neurosci. 23,
S1–S126.
Basilar Artery Thrombosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BASILAR ARTERY originates from the union of the
two intracranial vertebral arteries at or very near
the junction of the medulla oblongata and the pons.
The artery courses along the ventral aspect of the
pons and ends by bifurcating into the paired poster-
ior cerebral arteries at or near the junction of the
pons with the midbrain. The anterior inferior
BASILAR ARTERY THROMBOSIS 359
cerebellar artery, a vessel that supplies the lateral
pontine tegmentum and the pontine base and the
anterior inferior portion of the cerebellum, originates
from the proximal portion of the basilar artery. The
superior cerebellar artery, a vessel that supplies a
portion of the rostral pontine and midbrain tegmen-
tum and the superior surface of the cerebellum,
originates from the distal portion of the basilar
artery. Penetrating arteries to the medial and para-
medial portions of the pontine base and tegmentum
originate from the basilar artery at a number of
different levels. Penetrating arteries to the midbrain
and thalamus originate from the rostral basilar artery
and the proximal portion of the posterior cerebral
arteries.
PATHOLOGY
The most common and most important disease that
affects the basilar artery is atheroscerosis. In some
necropsy studies, the basilar artery is the earliest and
most severely affected intracranial artery. The ear-
liest atherosclerotic change in the basilar artery is an
increase in connective tissue especially in the intima
and media. Sometimes the predominant increase in
connective tissue is in the adventitia, with strands of
collagen spreading into the media causing medial
fibrosis. Thickening of the internal elastica and
splitting of the elastic membrane are common. The
intimal connective tissue increases in size and may
replace the internal elastic elements and become
hyalinized and fragmented, especially in its deeper
layers. Fatty deposits form within the intima
between connective tissue elements. Later, fibrous
plaques that are grossly elevated form and thickened
regions that are grossly visible along the basilar
artery form and gradually lead to stenosis of the
artery. As the basilar artery lumen becomes progres-
sively stenosed, cracks in plaques and mural thrombi
may appear. In most autopsied patients with fatal
basilar artery ischemia, superimposed thrombosis of
the vessel has developed. The atherosclerotic
changes are relatively evenly distributed in the
proximal, middle, and distal portions of the artery.
Thrombi can involve only a limited portion of the
artery or can be extensive.
Embolism is the second most important cause
of basilar artery occlusion. Emboli most often arise
from plaques and clots from the heart, aorta, and
the extracranial and intracranial vertebral arteries.
Emboli that reach the basilar artery often stop at
the rostral end of the artery. The basilar artery
360 BASILAR ARTERY THROMBOSIS
diameter becomes smaller as the artery courses
rostrally. Clots that are small enough to travel
through the intracranial vertebral arteries are usually
too small to obstruct the wider proximal portion of
the basilar artery but travel rostrally to the termina-
tion of the artery.
Other important disorders that affect the basilar
artery are dissection, fusiform dilatation (often
called dolichoectasia), and trauma. Occasionally,
infection, especially by fungi, leads to basilar artery
thrombosis.
CLINICAL SYMPTOMS AND SIGNS
Most patients with atherosclerosis and basilar artery
occlusion have transient ischemic attacks that pre-
cede strokes. The most common symptoms and signs
in patients with basilar artery thrombosis involve the
motor and ocular motor systems. The corticospinal
tracts in the basis pontis are the most frequently
involved structures. Most patients with symptomatic
basilar artery occlusive disease and pontine ischemia
have some degree of paresis and corticospinal tract
abnormalities either as part of their stroke or as a
component of transient ischemic attacks. The
abnormality might consist of slight weakness, hy-
per-reflexia, or an extensor plantar reflex or abnor-
mal spontaneous movements, such as shivering,
twitching, shaking, or jerking on the relatively spared
side. The weakness is often asymmetric, but usually
there are some abnormalities on the nonparetic side.
Ataxia or incoordination of limb movements is
another common motor abnormality. The incoordi-
nation is usually worse in the legs. Toe-to-object and
heel-to-shin testing usually shows that there is a
rhythmic cerebellar-type component to the dysfunc-
tion. The ataxia is almost always bilateral
but may be asymmetric and more severe on the
weaker side.
Weakness of bulbar muscles is also very common
and a very important cause of morbidity and
mortality. The face, pharynx, larynx, and tongue
are most often involved. The pattern may be that of
crossed motor loss (e.g., one side of the face and the
contralateral body), but more often the bulbar
muscle weakness is bilateral. The bilateral involve-
ment is usually due to involvement of corticobulbar
fibers in the dorsal part of the basis pontis near
the central tegmental tracts. Bulbar symptoms
include facial weakness, dysphonia, dysarthria,
dysphagia, and limited jaw movements. Some
patients become unable to speak, open their mouth,
protrude their tongue, swallow, or move parts of
their face at will or on command. Secretions pool in
the pharynx and aspiration is an important and
serious complication.
Ocular motor abnormalities are also promi-
nent and are due to involvement of the abducens
nuclei, medial longitudinal fasciculi, and the
paramedian pontine reticular formation (often
called the pontine gaze center) structures loca-
ted in the medial pontine tegmentum. Double
vision, internuclear ophthalmoplegia (loss of ad-
duction of the ipsilateral eye and abducting
nystagmus of the contralateral eye), sixth nerve
palsy, and conjugate lateral gaze palsy are the
clinical findings.
Coma and a reduced level of consciousness are due
to involvement of the reticular formation nuclei in
the medial tegmentum of the pons. Coma is a very
serious adverse prognostic sign. Although some
patients with basilar artery occlusion report par-
esthesias, sensory abnormalities are usually not a
prominent part of the clinical picture.
OUTCOME AND TREATMENT
When the rostral part of the basilar artery becomes
occluded causing bilateral rostral pontine and mid-
brain ischemia, the prognosis is very poor. These
patients usually have stupor and quadriparesis. In
other patients, basilar artery occlusion can cause
only minor transient neurological abnormalities.
Although there have been no randomized trials of
treatment in patients with basilar artery occlusion,
coumadin anticoagulation is often given in an
attempt to diminish propagation and embolization
of the basilar artery thrombus. Maintenance of blood
pressure and blood volume helps to maintain blood
flow to the brainstem.
—Louis R. Caplan
See also–Arterial Thrombosis, Cerebral; Cerebral
Blood Vessels: Arteries; Cerebral Venous
Thrombosis
Further Reading
Caplan, L. R. (1996). Posterior Circulation Disease. Clinical
Findings, Diagnosis, and Management. Blackwell, Cambridge,
MA.
Kubik, C., and Adams, R. D. (1946). Occlusion of the basilar
artery—A clinical and pathological study. Brain 69, 6–121.
LaBauge, R., Pages, C., Marty-Double, J. M., et al. (1981).
Occlusion du tronc basilaire. Rev. Neurol. 137, 545–571.

Basilar Migraine
see Migraine with Aura
Bassen-Kornzweig Disease
see Lipoprotein Disorders
Bastian, Henry Charlton
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
HENRY CHARLTON BASTIAN (1837–1915) was a
physician in Victorian London who made important
early observations on aphasia and paralysis. He
championed the concept that afferent muscular
impulses play a part in coordinated movements.
Early in life he made a celebrated study of
nematodes, and he was a forceful proponent of
spontaneous generation of bacteria. Along with his
colleagues John Hughlings Jackson and William
Gowers, Bastian established the National Hospital,
Queen Square, as an international center for clinical
and experimental neurology.
Bastian received a B.A. and M.A. from University
College London and took his M.B. in 1863. He was a
house physician in neurology at the State Asylum for
Criminal Lunatics, Broadmoor, in 1865. He was then
appointed assistant physician and lecturer in pathol-
ogy at St. Mary’s Hospital, London. In 1866, he
received an M.D. degree and the next year was
appointed professor of pathological anatomy in the
University College London. In 1868, he was
appointed physician to the Hospital for the Epileptic
and Paralysed, later called the National Hospital,
Queen Square, London. He became the protégé of
John Russell Reynolds and wrote a number of
articles on neurology for Reynolds’ A System of
Medicine. He was professor of the principles and
practice of medicine at the University of London
from 1887 to 1898. He was a fellow of the Royal
Society and of the Royal College of Physicians of
London and an honorary fellow of the Royal College
of Physicians in Ireland. In 1915, he was awarded a
civil list pension for services to medicine. He died in
Chesham Bois, England, in 1915.
BASTIAN, HENRY CHARLTON 361
Bastian’s first scientific work, done while working
on his M.D., was a study of the class of nematodes
called Anguillulidae, in which he described many
new species. This work earned him election as a
fellow of the Royal Society at the age of 31, although
he gave up his work on nematology when he
developed an allergic reaction to them. Shortly
thereafter, he began his long and productive neuro-
logical career with a series of articles on the
controversial topic of aphasia. He described patients
with focal brain pathology who had circumscribed
inability to read, to write, or to understand spoken
language, leading him to propose discrete brain
centers for each of these functions. Bastian used
patients with ‘‘word blindness’’ and ‘‘word deafness’’
to argue that aphasia results from damage to word
centers or to the connections between them, which he
represented in a famous diagram. Henry Head later
criticized Bastian as a diagram maker who ignored
pathology in service of a predetermined idea,
although Head accorded Bastian priority for the
discovery of isolated word deafness and word
blindness. Modern views of language do not support
fully Bastian’s precise anatomical localizations, but
his concept of disconnection of language centers has
enjoyed a remarkable longevity.
Bastian was a key participant in the debate on the
concept that sensory organs in muscles send in-
formation about movement to the brain. He coined
the term ‘‘kinaesthesis’’ to describe sensory informa-
tion derived from movement, which he thought
could be conscious or unconscious. He thought that
this muscular sense projects to the prerolandic
cortex, which is therefore intrinsically sensory rather
than motor, and that some type of cortical sensory
event initiates all movement. The nature and cortical
localization of Bastian’s muscular sense were the
subject of an 1886 debate at the Neurological Society
of London. Many of the leaders of British neurology
disagreed with Bastian’s formulation, but it played
an important role in Charles Scott Sherrington’s
concept of proprioception.
Bastian was an astute neurologist, one of the first
to practice scientific bedside localization. His interest
in sensory anatomy and physiology led him to
describe the anterior spinocerebellar tract, which
became known as the Gowers’ tract after William
Gowers’ later but more extensive description. Bas-
tian showed that complete section of the cord
produces hypotonia and areflexia below the level of
the section, a phenomenon that has been called
Bastian’s law. His books on the localization of
362 BATTEN, FREDERICK EUSTACE

paralysis, and his clinical lectures on the same Strick, J. (1999). Darwinism and the origin of life: The role of
subject, established his reputation as a teacher of H. C. Bastian in the British spontaneous generation debates,
1868–1873. J. Hist. Biol. 32, 51–92.
scientific neurology. He also wrote a treatise on
hysterical and functional paralysis, in which he
firmly distinguished between the two.
Bastian was an outstanding clinical neurologist
and an inspiring teacher, but his true scientific
interest was the origin of life. He was a strong
Batten, Frederick Eustace
Encyclopedia of the Neurological Sciences
adherent of Darwinian evolution, which implied that Copyright 2003, Elsevier Science (USA). All rights reserved.

organic life could proceed from inorganic starting

material. Unlike most of his contemporaries, how-
ever, he believed that such a process was common in
modern times, particularly in the generation of
bacteria. He denied that living beings always arise
from other living beings, a doctrine of Omne vivum
ex vivo. On the contrary, he believed in heterogen-
esis—the idea that bacteria can arise from a mixture
of inorganic precursors. This put him in direct
conflict with T. H. Huxley, Louis Pasteur, and
William Lister, among others. He pursued this theory
with experimental rigor and inventiveness, publish-
ing an extensive series of bacteriological studies in
which he claimed that certain inorganic chemical
conditions could produce microorganisms. His views
evoked vigorous opposition from the pioneering
bacteriologists of his time, but this did not deter
Bastian from his ideas. He famously defended his
thesis at the 1881 International Medical Congress in
London, at which he preceded Pasteur to the podium
at a session chaired by Lister. His single-minded
adherence to theories of spontaneous generation long
after mainstream scientists had dismissed them made
others see a certain pathos in his later life. His friends
saw him in a different light. To them, Bastian’s
qualities of moral courage, tenacity, and burning
intellect made pathos impossible.
—George K. York
See also–Aphasia; Gowers, William Richard;
Jackson, John Hughlings (see Index entry
Biography for complete list of biographical
entries)
Further Reading
Bastian, H. C. (1880). The Brain as an Organ of Mind. Kegan
Paul, London.
Bastian, H. C. (1888). The ‘‘muscular sense’’; Its nature and
cortical localization. Brain 10, 1–137.
Bastian, H. C. (1898). A Treatise on Aphasia and Other Speech
Defects. Lewis, London.
Jones, E. G. (1972). The development of the ‘‘muscular sense’’
concept during the nineteenth century and the work of H.
Charlton Bastian. J. Hist. Med. Allied Sci. 27, 298–311.
FREDERICK EUSTACE BATTEN (1865–1918) was one of
the most important neurologists of the 19th and 20th
centuries. His reputation was based on his clinical
and, to a lesser extent, his investigative skills. Batten
was one of the first clinicians who specialized in the
neurological problems of infants and children, and
he is rightfully considered one of the founding fathers
of the subspecialty of child neurology.
Batten was born in Plymouth, England. Batten’s
early schooling was at the Westminster School.
Batten subsequently attended Trinity College in
Cambridge and received a second-class degree in
natural science in 1887. He then began study at St.
Bartholomew’s Hospital and, in 1891, qualified for
the M.B. degree (the equivalent of the M.D. in the
United States). Batten became a member of the Royal
College of Physicians in 1894 and received the British
M.D. degree in 1895. He served as a medical
registrar at the Hospital for Sick Children in Great
Ormond Street in London. Later, he became an
assistant physician and finally a full physician at this
hospital, which remained his primary professional
location for the rest of his life. In 1899, he was
appointed pathologist at the National Hospital for
Neurology and Neurosurgery located at Queen’s
Square and soon after was appointed to this
hospital’s honorary staff. He functioned as an out-
patient physician for both the National Hospital and
the King George Hospital.
362 BATTEN, FREDERICK EUSTACE

paralysis, and his clinical lectures on the same Strick, J. (1999). Darwinism and the origin of life: The role of
subject, established his reputation as a teacher of H. C. Bastian in the British spontaneous generation debates,
1868–1873. J. Hist. Biol. 32, 51–92.
scientific neurology. He also wrote a treatise on
hysterical and functional paralysis, in which he
firmly distinguished between the two.
Bastian was an outstanding clinical neurologist
and an inspiring teacher, but his true scientific
interest was the origin of life. He was a strong
Batten, Frederick Eustace
Encyclopedia of the Neurological Sciences
adherent of Darwinian evolution, which implied that Copyright 2003, Elsevier Science (USA). All rights reserved.

organic life could proceed from inorganic starting

material. Unlike most of his contemporaries, how-
ever, he believed that such a process was common in
modern times, particularly in the generation of
bacteria. He denied that living beings always arise
from other living beings, a doctrine of Omne vivum
ex vivo. On the contrary, he believed in heterogen-
esis—the idea that bacteria can arise from a mixture
of inorganic precursors. This put him in direct
conflict with T. H. Huxley, Louis Pasteur, and
William Lister, among others. He pursued this theory
with experimental rigor and inventiveness, publish-
ing an extensive series of bacteriological studies in
which he claimed that certain inorganic chemical
conditions could produce microorganisms. His views
evoked vigorous opposition from the pioneering
bacteriologists of his time, but this did not deter
Bastian from his ideas. He famously defended his
thesis at the 1881 International Medical Congress in
London, at which he preceded Pasteur to the podium
at a session chaired by Lister. His single-minded
adherence to theories of spontaneous generation long
after mainstream scientists had dismissed them made
others see a certain pathos in his later life. His friends
saw him in a different light. To them, Bastian’s
qualities of moral courage, tenacity, and burning
intellect made pathos impossible.
—George K. York
See also–Aphasia; Gowers, William Richard;
Jackson, John Hughlings (see Index entry
Biography for complete list of biographical
entries)
Further Reading
Bastian, H. C. (1880). The Brain as an Organ of Mind. Kegan
Paul, London.
Bastian, H. C. (1888). The ‘‘muscular sense’’; Its nature and
cortical localization. Brain 10, 1–137.
Bastian, H. C. (1898). A Treatise on Aphasia and Other Speech
Defects. Lewis, London.
Jones, E. G. (1972). The development of the ‘‘muscular sense’’
concept during the nineteenth century and the work of H.
Charlton Bastian. J. Hist. Med. Allied Sci. 27, 298–311.
FREDERICK EUSTACE BATTEN (1865–1918) was one of
the most important neurologists of the 19th and 20th
centuries. His reputation was based on his clinical
and, to a lesser extent, his investigative skills. Batten
was one of the first clinicians who specialized in the
neurological problems of infants and children, and
he is rightfully considered one of the founding fathers
of the subspecialty of child neurology.
Batten was born in Plymouth, England. Batten’s
early schooling was at the Westminster School.
Batten subsequently attended Trinity College in
Cambridge and received a second-class degree in
natural science in 1887. He then began study at St.
Bartholomew’s Hospital and, in 1891, qualified for
the M.B. degree (the equivalent of the M.D. in the
United States). Batten became a member of the Royal
College of Physicians in 1894 and received the British
M.D. degree in 1895. He served as a medical
registrar at the Hospital for Sick Children in Great
Ormond Street in London. Later, he became an
assistant physician and finally a full physician at this
hospital, which remained his primary professional
location for the rest of his life. In 1899, he was
appointed pathologist at the National Hospital for
Neurology and Neurosurgery located at Queen’s
Square and soon after was appointed to this
hospital’s honorary staff. He functioned as an out-
patient physician for both the National Hospital and
the King George Hospital.

Batten had interests that extended beyond child
neurology. For example, Batten wrote about infec-
tious diarrhea, empyema, tuberculosis, diphtheria,
cholera, thyroid disease, and the rehabilitation of
patients with poliomyelitis and other chronic debil-
itating disorders. Batten’s neurological contributions
encompassed both adult and pediatric neurology.
Examples of his contributions to adult neurology
include an article on combined degeneration of the
spinal cord (with J. S. Risien Russell and James
Collier, 1900). This was probably the first paper
on the spinal cord complications of vitamin B12
deficiency associated with pernicious anemia.
Batten was the senior author of a paper that is
probably the first description of myotonic dystrophy,
which he called myotonia atrophica. He also wrote
several articles about the pathology of multiple
sclerosis.
Batten’s publications in the field of pediatric
neurology were extensive. In a commemorative
review, Higgins was able to identify 106 articles
written by Batten. Batten’s greatest contribution to
child neurology was his description of the chronic
juvenile form of neuronal ceroid lipofuscinosis
(NCL-1). NCL-1 represents one of the most common
neurodegenerative disorders recognized by child
neurologists. In 1903, Batten described a familial
neurodegenerative disease that was characterized by
blindness, a granular-type degeneration of the
macula lutae, slowly progressive neurological failure,
progressive dementia, and later epileptic seizures.
Batten clearly separated this disease from Tay–Sachs
disease. Batten later described other forms of ‘‘his’’
disease with different age of onset and clinical
characteristics.
Batten made many other contributions to pediatric
neurology. He served as an editor of Garrod’s
Textbook on Diseases of Children (1913) and wrote
two extensive chapters on ‘‘Organic Nervous Dis-
eases’’ and ‘‘Diseases of Muscle.’’ Batten was one of
the first to describe progressive spinal muscular
atrophy, his paper appearing a year after the
description by Werdnig (1891) but before the more
complete publication by Hoffmann (1893). Batten
supplemented this early report with more detailed
descriptions in a series of articles that appeared in
Brain in 1897, 1903 (with H. M. Fletcher), and
1911. His last paper on the subject, coauthored with
Gordon Holmes in 1912, described a 14-month-old
child who died of this disorder. He included carefully
performed neuropathological examinations, compar-
ing the spinal cord of the child with spinal muscular
BATTEN, FREDERICK EUSTACE 363
atrophy to normal spinal cords. Batten’s interest in
muscle disease was also reflected in several publica-
tions on the muscle spindle, early degenerative
changes in the sensory end organ of muscles, and
the effect that Marchi fluid staining had on the
nervous system.
Batten’s other pediatric neurological publications
covered a wide range of topics, including arrested
neural development, cerebral diplegia, cerebellar
diplegia, cerebellar ataxia, poliomyelitis, polioence-
phalitis, myopathies, Moebius syndrome, partial
epilepsy, spinal cord tumors, diffuse neural sarcoma-
tosis, myasthenia gravis, ophthalmoplegia, muscular
dystrophy, meningitis, acute myelitis, functional
astasia, dystrophia adiposogenitalis, epilepsy, Peli-
zaeus–Merzbacher’s disease, post-traumatic encepha-
lopathies, and even Tay–Sachs disease. The breadth
of his interests is reflected in the diseases that
eponymously bear his name: myotonic muscular
dystrophy, neuronal ceroid lipofuscinoses, cerebellar
diplegia or congenital cerebellar ataxia, progressive
spinal muscular atrophy (Werdnig–Batten–Hoff-
mann’s disease), subacute combined degeneration of
the spinal cord (Russell–Batten–Collier’s disease),
and acute ophthalmoplegia externa with fever and
weakness (probably an early description of the
Miller–Fisher syndrome).
After conversations with many confederates who
either worked with Batten or were educated by
him, Higgins eloquently described Batten as a ‘‘brisk
lithe figure with the conspicuous domed head and
lively eye.’’ He possessed a ‘‘bubbling humor,’’ was
‘‘able, enthusiastic, indefatigable,’’ and had an
‘‘unflinching honesty of purpose [and] no trace of
arrogance or egotism.’’ He was ‘‘practical and
purposeful [and] children loved him.’’ Batten was a
perfectionist, and he insisted on accurate, up-to-date,
type-written notes. Such rules, Higgins states, meant
many a late hour for the poor, suffering house
officers who were required to work-up his patients.
However, Batten was held in high esteem by his
students, registrars, and colleagues. It was said that
he consulted with others frequently and was known
to carry on long and spirited arguments with all of
his Queen’s Square colleagues, including Gordon
Holmes and S. Kinnier Wilson. His adversaries in
discussion ‘‘always found him a tough, though
scrupulously fair and courteous antagonist’’ (Obit-
uary, 1918). In 1918, at the height of his powers at
the age of 53, he died from complications following a
prostatectomy.
—Paul Richard Dyken
364 BEHAVIOR, NEURAL BASIS OF
See also–Child Neurology, History of; Spinal
Muscular Atrophy (see Index entry Biography
for complete list of biographical entries)
Further Reading
Dyken, P. R. (1990). Frederick Batten. The Founders of Child
Neurology, pp. 415–420. Norman, San Francisco.
Higgins, T. T. (1962). F. E. Batten. Dev. Med. Child Neurol. 4,
1–29.
Obituary (1918). Frederick Batten. Lancet 2, 157.
Becker’s Dystrophy
see Muscular Dystrophy: Limb-Girdle,
Becker’s, and Duchenne’s
Behavior, Neural Basis of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BEHAVIOR is generally defined as the sum of actions
and psychomotor reactions that can be objectively
observed and interpreted and that interfere with the
subject’s environment. In its broader interpretation,
this term includes functions as diverse as motor
activity, language, socially oriented actions, and
affectivity expression. Some types of behavior are
considered goal oriented because their sensory,
psychomotor, emotional, and cognitive components
contribute harmoniously to the individual’s specific
plans. They represent the more hierarchical form of
action.
Some behaviors are exhibited only in specific
situations in reaction to a type of stimulus (e.g., an
impulsive or violent reaction to frustration). A
behavioral pathology will reflect cognitive failure,
abnormal personality traits, and/or a neurobiological
dysfunction. One of the main purposes of cognitive
neuroscience is to assess normal and disturbed
behaviors and to highlight their probable relation-
ship with normal and abnormal brain functioning
(i.e., to link mind and brain).
The history of the presumed relationships between
brain function and behavior has involved two
opposing views. The first maintains that most motor,
perceptive, and cognitive functions can be attributed
to specific areas of the brain. This position was born
with the phrenology doctrine, which tried to
correlate the shapes of the skull with the underlying
cortical areas and, to some extent, with the traits of
character that these cortical areas were supposed to
serve. Although now considered spurious, phrenol-
ogy largely influenced emerging neurology, whose
first solid conclusions were based on the established
link between a localized lesion and a particular
deficit. One of the first such links was established by
Paul Broca, a French anthropologist and surgeon
who, in the 19th century, discovered the existence of
a brain region dedicated to language. A lesion in this
particular cortical area consistently induced a form
of aphasia. In keeping with this localization concept,
it was assumed that the larger the lesion, the more
severe the subsequent deficit. This is particularly
relevant to certain instrumental functions, such as
language, primary sensory perceptions, and motor
components of action.
In the second point of view, the pioneers of
neurology suspected that complex or subtle cognitive
functions required collaboration between multiple
brain regions. The concept of distributed processing
still dominates the neural basis of cognition and
behavior. This view, which is similar to the concept
of plasticity, suggests that the brain can compensate
for local dysfunction by activating alternative path-
ways or systems.
Phylogenesis provides information on the func-
tional organization of the brain. The relationships
between the anatomy and function of the brain
derive from specific phylogenetic development. The
brain can be divided anatomically into three main
cores that appeared successively during evolution,
giving rise to the concept of the ‘‘triune brain.’’ The
inner layer emerged in reptiles, and it contains
neuronal groups serving consciousness, metabolism,
and the main vegetative functions, namely the
reticular core, the cranial nerves, and the hypotha-
lamus. This corresponds in primates and humans to
the brainstem and part of the basal diencephalic
structures. These structures are crucial in arousal
mechanisms and biological (e.g., metabolic) motiva-
tion processes.
The paramedian layer is essentially composed of
the basal ganglia, limbic structures (hippocampus,
amygdala, and emerging tracts), and olfactory
cortex. It is involved in mnemonic and emotional
aspects of motivation, motor coordination, and
affective components of action and thought.
The most highly evolved outer layer developed in
late mammals but has only achieved its particular
364 BEHAVIOR, NEURAL BASIS OF
See also–Child Neurology, History of; Spinal
Muscular Atrophy (see Index entry Biography
for complete list of biographical entries)
Further Reading
Dyken, P. R. (1990). Frederick Batten. The Founders of Child
Neurology, pp. 415–420. Norman, San Francisco.
Higgins, T. T. (1962). F. E. Batten. Dev. Med. Child Neurol. 4,
1–29.
Obituary (1918). Frederick Batten. Lancet 2, 157.
Becker’s Dystrophy
see Muscular Dystrophy: Limb-Girdle,
Becker’s, and Duchenne’s
Behavior, Neural Basis of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BEHAVIOR is generally defined as the sum of actions
and psychomotor reactions that can be objectively
observed and interpreted and that interfere with the
subject’s environment. In its broader interpretation,
this term includes functions as diverse as motor
activity, language, socially oriented actions, and
affectivity expression. Some types of behavior are
considered goal oriented because their sensory,
psychomotor, emotional, and cognitive components
contribute harmoniously to the individual’s specific
plans. They represent the more hierarchical form of
action.
Some behaviors are exhibited only in specific
situations in reaction to a type of stimulus (e.g., an
impulsive or violent reaction to frustration). A
behavioral pathology will reflect cognitive failure,
abnormal personality traits, and/or a neurobiological
dysfunction. One of the main purposes of cognitive
neuroscience is to assess normal and disturbed
behaviors and to highlight their probable relation-
ship with normal and abnormal brain functioning
(i.e., to link mind and brain).
The history of the presumed relationships between
brain function and behavior has involved two
opposing views. The first maintains that most motor,
perceptive, and cognitive functions can be attributed
to specific areas of the brain. This position was born
with the phrenology doctrine, which tried to
correlate the shapes of the skull with the underlying
cortical areas and, to some extent, with the traits of
character that these cortical areas were supposed to
serve. Although now considered spurious, phrenol-
ogy largely influenced emerging neurology, whose
first solid conclusions were based on the established
link between a localized lesion and a particular
deficit. One of the first such links was established by
Paul Broca, a French anthropologist and surgeon
who, in the 19th century, discovered the existence of
a brain region dedicated to language. A lesion in this
particular cortical area consistently induced a form
of aphasia. In keeping with this localization concept,
it was assumed that the larger the lesion, the more
severe the subsequent deficit. This is particularly
relevant to certain instrumental functions, such as
language, primary sensory perceptions, and motor
components of action.
In the second point of view, the pioneers of
neurology suspected that complex or subtle cognitive
functions required collaboration between multiple
brain regions. The concept of distributed processing
still dominates the neural basis of cognition and
behavior. This view, which is similar to the concept
of plasticity, suggests that the brain can compensate
for local dysfunction by activating alternative path-
ways or systems.
Phylogenesis provides information on the func-
tional organization of the brain. The relationships
between the anatomy and function of the brain
derive from specific phylogenetic development. The
brain can be divided anatomically into three main
cores that appeared successively during evolution,
giving rise to the concept of the ‘‘triune brain.’’ The
inner layer emerged in reptiles, and it contains
neuronal groups serving consciousness, metabolism,
and the main vegetative functions, namely the
reticular core, the cranial nerves, and the hypotha-
lamus. This corresponds in primates and humans to
the brainstem and part of the basal diencephalic
structures. These structures are crucial in arousal
mechanisms and biological (e.g., metabolic) motiva-
tion processes.
The paramedian layer is essentially composed of
the basal ganglia, limbic structures (hippocampus,
amygdala, and emerging tracts), and olfactory
cortex. It is involved in mnemonic and emotional
aspects of motivation, motor coordination, and
affective components of action and thought.
The most highly evolved outer layer developed in
late mammals but has only achieved its particular

predominance and organization in humans. It is
mainly composed of the neocortex, which is differ-
entiated into the primary sensorimotor cortex and
associative regions, with the latter occupying the
larger part of the cortex. Behavior results from
synergistic interactions between these three main
cores of the brain.
The hierarchical nature of brain organization
confers a high degree of coherence on information
processing. Some cortical association areas are
considered as unimodal (i.e., process information
arising from specific perceptual modalities; Fig. 1).
Dysfunction of these regions will induce specific or
behavioral deficits. For example, damage to Wer-
nicke’s area situated at the posterior part of the
temporal lobe is responsible for relatively pure fluent
aphasia.
Conversely, a second type of association cortex
processes information in a heteromodal way and thus
in a more integrated mode. For instance, the
parietoparietal associative cortex integrates informa-
tion from all primary and secondary sensory cortices,
and its dysfunction may reduce or abolish the ‘‘sense
of meaning’’ of the incoming sensory information.
This may produce alexia (deficit of word meaning),
anomia (e.g., deficit of naming objects or colors),
agnosia (loss of recognition of objects or living
things) when left-sided, whereas right-sided lesions
will affect visuospatial construction and orientation.
Brain functioning can be understood in the form of
structured neural networks, which run from the top
Figure 1
Hierarchical conception of the cortex (adapted from Mesulam,
1985).
BEHAVIOR, NEURAL BASIS OF 365
to the bottom of the central nervous system and vice
versa, but that also run within specific brain cores
that will be systematically organized (e.g., the limbic
system, basal ganglia group, and prefrontal lobe
circuits). Because of the complexity of neuronal
circuitry, it appears that behavioral abnormalities
may arise from lesions or dysfunction in specific
crucial areas (e.g., amnesia after bihippocampal
damage) and from abnormalities in one or several
sites of a large network. Generally, behavior depends
on neural parallel distributed processing, which
means that most cognitive and behavioral functions
are served by not only multiple serial but also parallel
neural pathways.
The brain structures and circuits that play a key
role in complex behaviors (i.e., frontal subcortical
circuits and the limbic system) are discussed next.
Then, examples of dysfunction in these circuits and
their clinical consequences are presented. There is
compelling anatomical evidence that most complex
behaviors are based on the functioning of cortical–
subcortical circuits, particularly involving the frontal
lobes.
FRONTAL SUBCORTICAL CIRCUITS
Alexander et al. introduced the concept of parallel
and segregated frontal–subcortical circuits. These
authors described five circuits that unite specific
regions of the frontal cortex with the basal ganglia
and the thalamus via circuits that mediate motor
activity and behavior. Two circuits are involved in
motor activity and eye movements, which respec-
tively originate in the supplementary motor area and
the frontal eye fields. The remaining three circuits
originate in the dorsolateral prefrontal (Brodmann’s
areas A9 and A10), lateral orbitofrontal (A10 and
A11), and anterior cingulate cortex (A24) (Fig. 2).
Each of these three circuits circumnavigates the
same member structures, including the frontal lobe,
striatum (caudate and putamen), globus pallidus,
substantia nigra, and thalamus, but the relative
anatomical positions of the circuits are preserved as
they pass through different parts of the subcortical
area. For instance, the dorsolateral frontal cortex
projects to the dorsolateral region of the caudate
nucleus, the orbital frontal regions to the ventral
caudate, and the anterior cingulate to the medial
striatum. In parallel to a principal direct loop, each
of these circuits has an indirect pathway that includes
the subthalamic nucleus (Fig. 3).
366 BEHAVIOR, NEURAL BASIS OF
Figure 2
Functional subdivisions of the prefrontal lobe. (Top) In this brain
lateral view, dorsolateral prefrontal cortex (horizontal lines) covers
areas A9 and A10. The shaded region is the external part of the
lateral orbitofrontal cortex. (Middle) This inferior view shows the
median (A11) and lateral (A10, A11, and A45) divisions of the
orbitofrontal cortex. (Bottom) Medial view. The cingulate gyrus
(squares) has four functional subdivisions. (A) Visceral motor
region, mainly subcallosal. (B) Cognitive effector region (anterior
cingulate). (C) Motor effector region. These three regions process
information from visceral, attentional, and motor systems to adapt
the motivation to the necessary implication in the external
environment. (D) Sensory-processing region or posterior cingulate
involved in sensory and memory processes (adapted from Mega
and Cummings, 1997).
Figure 3
General anatomical and biochemical organization of frontal–
subcortical circuits. S.N. pr, substantia nigra pars reticulata.
The effect of the direct loop is to activate the
thalamus, which in turn activates the original cortical
area as the indirect subthalamic pathway inhibits the
thalamus. This organization contributes to modulat-
ing the activity of each circuit, which will depend on
the relative activity of each loop.
The three nonmotor frontal circuits can be func-
tionally dissociated. The dorsolateral prefrontal sub-
cortical circuit mediates executive functions (i.e.,
functions permitting the adaptation of many beha-
vioral responses to environmental constraints or
changes), cognitive strategies and their behavioral
responses when solving complex problems, and
generation and monitoring of complex motor or
behavioral programs. The role of this system in the
control and planning of actions over time is pre-
ponderant and is crucial for the relative independence
of the subject from environmental contingencies.
The orbitofrontal cortex is functionally divided
into lateral and medial parts, from which derive two
overlapping circuits. The lateral orbitofrontal cortex
mediates the emotional aspects of behavior. By
linking appropriate behavioral and emotional re-
sponses to external and social cues, it plays an
essential role in emotional adaptation to the envir-
onment and in sociability. It exerts some control over
visual and auditory sensory processing (external flow
of information) through its direct input from
auditory (A22) and visual (A20 and A21) associative
temporal areas.
Conversely, the medial orbitofrontal cortex, also
called the paralimbic cortex because of its major
connections with other limbic structures, integrates

more information about the visceral and emotional
state of the body, by which its controls motivational
input. It receives input from the amygdala, entorh-
inal cortex, anterior cingulate, and temporal pole.
Because these orbitofrontal circuits receive emo-
tional experiences from different origins (i.e., from
the external and internal milieu), they are involved in
emotionally and socially appropriate behavior.
The anterior cingulate subcortical circuit serves
motivated behavior and is tightly connected to the
limbic system, of which it is considered to be a part.
Afferents come from the hippocampus, associative
limbic cortex in the parahippocampal gyrus, and the
amygdala, which provide the anterior cingulate with
emotional aspects of the experience and internal
motivation. It appears that the anterior cingulate
cortex, located at the intersection of the prefrontal
cortex with the limbic system and basal ganglia, is an
important node linking attention, motivation, affect,
and consciousness of the experience. The principal
behavioral disorder associated with anterior cingu-
late dysfunction is apathy.
LIMBIC SYSTEM
The limbic system includes a group of midbrain
structures particularly involved in emotion, memory,
and motivation processes. In neomammals and
primates, the limbic structures (Fig. 4) form an
intermediate level between the internal layers (re-
ticulated area and hypothalamus) and the external
Figure 4
Limbic circuit. The inner loop corresponds to Papez’s circuit,
involved in memory processes. The outer loop is centered by
amygdala and processes emotional patterns linked with experience
coming from the association cortex.
BEHAVIOR, NEURAL BASIS OF 367
layers (sensorimotor and associative cortices and
corpus callosum). The limbic system components,
especially those located in the medial temporal
regions (hippocampus and immediately adjacent
structures, parahippocampal cortices, and mammil-
lary bodies), were long thought to be involved only in
memory processes. The amygdala has been asso-
ciated with affective and emotional components of
memory.
It is now clear that the limbic system is a necessary
pathway in the processing of behavior through two
superimposed circuits:
*
A hippocampus-centered circuit, originating in
the primary sensory cortex and projecting to the
prefrontal cortex (dorsolateral and cingulate) but
also to the hypothalamus. It comprises the loop
described by Papez that contributes to conscious
encoding of experiences in suitable attentional
conditions, which is the first step of memorization.
It is involved in explicit cognitive processes and
motivation, in relation with memorized experiences.
*
An amygdala circuit that more specifically serves
information processing with emotional patterns. The
amygdala receives information about internal moti-
vation and the visceral state of the organism but also
receives information on the external milieu because
of multiple afferents from all the unimodal associa-
tive areas. Its interaction with hippocampal forma-
tion will determine the motivational significance of
the current internal and external state and play a role
in the learning of new experiences with emotional
coloration. Through its main connections with the
prefrontal cortex (medial orbitofrontal), this subsys-
tem computes current information and compares it
with remote experience. The result of this comparison
and its relevance to the presumed result will control
the response by activation or inhibition. The amyg-
dala has been viewed as a ‘‘motivational rheostat.’’ It
appears that most behaviors are to some extent
dependent on this type of comparison and on perma-
nent access to emotionally charged memorized data.
These two circuits share certain pathways and
structures but work in synergy. As the amygdala–
prefrontal circuit assesses how relevant sensory
stimuli are to the organism, the hippocampal–
cingulate division participates in episodic encoding,
intentional selection, and habituation. They form
part of the frontal–subcortical circuits, and dysfunc-
tion of limbic systems will share some features with
described prefrontal syndromes.
368 BEHAVIOR, NEURAL BASIS OF
Damage to the hippocampal division (e.g., after
extensive medial temporal lobe ablation) will cause
severe anterograde amnesia. Deficient conscious
encoding of the experience will interfere with
behavior. Lesions of the amygdala are responsible
for Kluver–Bucy syndrome, which in humans is
associated with placidity, elimination of previous
aggressiveness, and lack of association with implicit
visceral or affective information.
With the basal ganglia, this limbic system forms a
system involved in goal-directed behavior. The
hippocampal and amygdala structures are tightly
connected to the ventral striatopallidal complex
(nucleus accumbens, olfactory tubercle, and ventral
pallidum)—a system thought to play an important
role in conditioned behaviors. It is assumed that these
basal ganglia are crucial in controlling drive-related
action. These stimuli can be generated internally
through the hypothalamus or externally through the
limbic system and neocortex.
The frontal and limbic circuits form closed loops
but are also interconnected at the cortical limb or in
the basal ganglia (especially the substantia nigra pars
reticulata and globus pallidus interna). These links
are functionally crucial. For instance, motor cortex
projections to the substantia nigra relay information
to the associative prefrontal cortex about current
motor processes. Reciprocally, projections from the
associative prefrontal cortex to the globus pallidus
interna may activate the closed motor circuit (e.g., for
the execution of learned motor programs). The
associative prefrontal cortex is also informed by the
limbic prefrontal cortex, through the substantia
nigra, on the global motivational state and will
therefore control the execution of motor programs by
its direct or indirect projections to the motor cortex.
NEUROCHEMISTRY
Frontal–subcortical structures are linked by excita-
tory pathways (glutamatergic) and inhibitory path-
ways (mainly GABAergic), organized in a closed loop
to which a secondary subthalamic loop is connected.
Other intrinsic and extrinsic pathways exert neuro-
modulation of these circuits.
Dopamine projections enhance frontal cortical
activity, mainly through three distinct pathways.
One pathway arises from the substantia nigra pars
compacta, innervating the striatum and contributing
to thalamocortical activation. This nigrostriatal
system is involved in movement control and is
affected in Parkinson’s disease, but it is also involved
in motivation and cognition. Two circuits originate
from the ventral tegmental area and project to the
mesial limbic system (nucleus accumbens, amygdala,
and hippocampus) and the entire prefrontal cortex.
They play a determining role in emotional expression
and motivation. For example, a reduction in the
activity of the mesocortical pathway will result in a
paucity of affect and loss of motivation and
planning, whereas secondary overactivity of the
mesolimbic system will produce disturbances of
thought and perceptions (generally delusions and
hallucinations). These radically opposing disorders
may coexist in schizophrenia, a frequent and
disabling psychosis in which dopaminergic dysfunc-
tion is thought to be a core biological disturbance.
Acetylcholine exerts its activation effect from two
cholinergic systems: the basal forebrain system
(Meynert’s nucleus basalis and septum median
nuclei) and the pedunculopontotegmental complex.
The first system projects to the major part of
neocortex and the hippocampus, and it plays a role
in the modulation of brain excitability, learning, and
memory. The deficit of this system present in
Alzheimer’s disease is at least partly responsible for
many of the memory and behavioral disturbances.
Serotonin pathways, arising from the raphe nuclei
in the brainstem, project to the entire cortex and are
primarily involved in the regulation of the sleep–wake
cycle. They are also important in mood regulation
and, to some extent, in affective behaviors because
they reduce aggressive and impulsive tendencies.
CLINICAL SYNDROMES
Focal lesions, in particular cortical or subcortical
areas, may induce behavioral or thought disorders
that depend on the degree of specialization of the
affected zone, the extension and rapidity of the
lesion, and compensation by other linked structures.
Behavioral symptoms can also occur in dysfunctions
not associated with detectable anatomical lesions,
such as in psychiatric disorders. Different types of
disorders are shown in Table 1.
CONCLUSION
In summary, the links between brain and behavior
derive from a hierarchical organization in which
some areas are important for specialized functions,
and their lesions are responsible for circumscribed
neurological disorders. In contrast, higher cognitive
functions and complex actions depend more on

Table 1 NEUROPSYCHIATRIC CLINICAL SYNDROMES
Affected circuit Distributed functions
Dorsolateral prefrontal Executive dysfunction
Affective disorders
Lateral orbitoprefrontal Personality disorders
Mood disorders
Anterior cingulate Behavioral and affective disorders
Subcortical syndromes Motor function
Behavioral and cognitive disorders
Limbic syndromes Behavioral and cognitive disorders
Mood disorders
parallel and superimposed circuits than on limited
areas, accounting for the unlimited diversity of
normal and abnormal thought and behavior.
—M. Benoit and P. H. Robert
See also–Behavior, Neuropathology of; Broca,
Pierre-Paul; Cognitive Behavioral
Psychotherapy; Emotion, Neural Mechanisms of;
Instinct; Learning, Overview; Limbic System;
Neuropsychology, Overview
Further Reading
Alexander, G. E., DeLong, M. R., and Strick, P. L. (1986). Parallel
organization of functionally segregation circuits linking basal
ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381.
Chow, T. W., and Cummings, J. L. (1998). Frontal–subcortical
circuits. In The Human Frontal Lobes (B. L. Miller and J. L.
Cummings, Eds.), pp. 3–26. Guilford, New York.
Cummings, J. L. (1993). Frontal–subcortical circuits and human
behavior. Arch. Neurol. 50, 873–880.
Devinsky, O., Morrell, M., and Vogt, B. (1995). Contributions of
anterior cingulate cortex to behaviour. Brain 118, 279–306.
Duffy, J. D. (1997). The neural substrates of motivation.
Psychiatric Ann. 27, 24–29.
Joel, D., and Weiner, I. (1994). The organization of the basal
ganglia–thalamocortical circuits: Open interconnected rather
than closed segregated. Neuroscience 63, 363–379.
BEHAVIOR, NEUROPATHOLOGY OF 369
Disorders
Deficit of search and organizational strategies (memory, drawing, speech)
Environmental dependency (utilization behavior)
Perseverations, difficulties in cognitive shifting
Depression, anxiety
Lack of insight and shelf-care
Familiarity, lack of social adaptation
Disinhibition, impulsivity
Euphoria or mood lability
Apathy, slowness, akinetic mutism
Lack of motivation
Indifference to painful stimuli
Akinesia, rigidity (Parkinson’s disease)
Involuntary movements (tremor, dystonia, dyskinesia)
Lack of motivation, psychomotor poverty
Progressive dementia
Delusions, hallucinations (schizophrenia)
Apathy (anterior cingulate)
Memory deficits (hippocampal complex)
Kluver–Bucy syndrome (amygdala)
Delusions (mesolimbic pathway)
Obsessive–compulsive disorder (mesial orbitofrontal)
Depression, mania, anxiety
MacLean, P. D. (1970). The triune brain, emotion and scientific
bias. In The Neurosciences: Second Study Program (F. O.
Schmitt, Ed.), pp. 336–349. Rockefeller Univ. Press, New York.
Mega, M. S., Cummings, J. L., Salloway, S., and Malloy, P. (1997).
The limbic system: An anatomic, phylogenetic, and clinical
perspective. J. Neuropsychiatry Clin. Neurosci. 9, 315–330.
Mesulam, M. M. (1985). Patterns in behavioral neuroanatomy:
association areas, the limbic system, and hemispheric speciali-
zation. In Behavioral Neurology (M. M. Mésulam, Ed.), pp.
1–70. Davis, Philadelphia.
Mesulam, M. M. (1995). The cholinergic contribution to
neuromodulation in the cerebral cortex. Semin. Neurosci. 9,
23–28.
Nieuwenhuys, R. (1995). Chemoarchitecture of brain. In Che-
moarchitecture of Brain. Springer-Verlag, New York.
Behavior, Neuropathology of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE NEUROPATHOLOGY of behavior concerns those
brain lesions that underlie the human cognitive
dysfunctions (e.g., language impairment, memory
loss, and dementia) in addition to the neuropatho-
logical changes that accompany human aging.

Table 1 NEUROPSYCHIATRIC CLINICAL SYNDROMES
Affected circuit Distributed functions
Dorsolateral prefrontal Executive dysfunction
Affective disorders
Lateral orbitoprefrontal Personality disorders
Mood disorders
Anterior cingulate Behavioral and affective disorders
Subcortical syndromes Motor function
Behavioral and cognitive disorders
Limbic syndromes Behavioral and cognitive disorders
Mood disorders
parallel and superimposed circuits than on limited
areas, accounting for the unlimited diversity of
normal and abnormal thought and behavior.
—M. Benoit and P. H. Robert
See also–Behavior, Neuropathology of; Broca,
Pierre-Paul; Cognitive Behavioral
Psychotherapy; Emotion, Neural Mechanisms of;
Instinct; Learning, Overview; Limbic System;
Neuropsychology, Overview
Further Reading
Alexander, G. E., DeLong, M. R., and Strick, P. L. (1986). Parallel
organization of functionally segregation circuits linking basal
ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381.
Chow, T. W., and Cummings, J. L. (1998). Frontal–subcortical
circuits. In The Human Frontal Lobes (B. L. Miller and J. L.
Cummings, Eds.), pp. 3–26. Guilford, New York.
Cummings, J. L. (1993). Frontal–subcortical circuits and human
behavior. Arch. Neurol. 50, 873–880.
Devinsky, O., Morrell, M., and Vogt, B. (1995). Contributions of
anterior cingulate cortex to behaviour. Brain 118, 279–306.
Duffy, J. D. (1997). The neural substrates of motivation.
Psychiatric Ann. 27, 24–29.
Joel, D., and Weiner, I. (1994). The organization of the basal
ganglia–thalamocortical circuits: Open interconnected rather
than closed segregated. Neuroscience 63, 363–379.
BEHAVIOR, NEUROPATHOLOGY OF 369
Disorders
Deficit of search and organizational strategies (memory, drawing, speech)
Environmental dependency (utilization behavior)
Perseverations, difficulties in cognitive shifting
Depression, anxiety
Lack of insight and shelf-care
Familiarity, lack of social adaptation
Disinhibition, impulsivity
Euphoria or mood lability
Apathy, slowness, akinetic mutism
Lack of motivation
Indifference to painful stimuli
Akinesia, rigidity (Parkinson’s disease)
Involuntary movements (tremor, dystonia, dyskinesia)
Lack of motivation, psychomotor poverty
Progressive dementia
Delusions, hallucinations (schizophrenia)
Apathy (anterior cingulate)
Memory deficits (hippocampal complex)
Kluver–Bucy syndrome (amygdala)
Delusions (mesolimbic pathway)
Obsessive–compulsive disorder (mesial orbitofrontal)
Depression, mania, anxiety
MacLean, P. D. (1970). The triune brain, emotion and scientific
bias. In The Neurosciences: Second Study Program (F. O.
Schmitt, Ed.), pp. 336–349. Rockefeller Univ. Press, New York.
Mega, M. S., Cummings, J. L., Salloway, S., and Malloy, P. (1997).
The limbic system: An anatomic, phylogenetic, and clinical
perspective. J. Neuropsychiatry Clin. Neurosci. 9, 315–330.
Mesulam, M. M. (1985). Patterns in behavioral neuroanatomy:
association areas, the limbic system, and hemispheric speciali-
zation. In Behavioral Neurology (M. M. Mésulam, Ed.), pp.
1–70. Davis, Philadelphia.
Mesulam, M. M. (1995). The cholinergic contribution to
neuromodulation in the cerebral cortex. Semin. Neurosci. 9,
23–28.
Nieuwenhuys, R. (1995). Chemoarchitecture of brain. In Che-
moarchitecture of Brain. Springer-Verlag, New York.
Behavior, Neuropathology of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE NEUROPATHOLOGY of behavior concerns those
brain lesions that underlie the human cognitive
dysfunctions (e.g., language impairment, memory
loss, and dementia) in addition to the neuropatho-
logical changes that accompany human aging.
370 BEHAVIOR, NEUROPATHOLOGY OF
The actions of the human brain subserve not only
relatively simple behaviors, such as eating, smiling,
and walking, but also complex behaviors, such as
learning, memory, thinking, and feeling. The in-
tellectual and emotional human behaviors are so
elaborate and diverse that attempts to relate the
impairment of specific cognitive abilities to lesions in
discrete parts of the brain have only been partially
successful. For example, language dysfunction is
closely associated with diseases involving the domi-
nant cerebral hemisphere, particularly the perisylvian
regions of the frontal, temporal, and parietal lobes.
Loss of capacity for reading and calculation is related
to lesions in the left posterior hemisphere. Impair-
ment in drawing or constructing simple and complex
figures is observed with parietal lobe lesions, more
often in the nondominant than dominant hemi-
spheres. Disinhibition, impairment in planning and
executing multistepped processes, and loss of social
graces are associated with pathology of the frontal
lobe.
Dementia involves acquired cognitive impairment
and behavioral alterations of multiple domains.
Adult-onset dementing disorders are one of the
major medical problems of modern society. Until
the past decade, neurodegenerative diseases, includ-
ing Alzheimer’s disease, were considered to be among
the most obscure and intractable disorders in
medicine. In many neurodegenerative diseases, it is
still the neuropathologist who makes the definitive
diagnosis at biopsy or autopsy. There have been
considerable advances in neuropathology that,
coupled with clinical–pathological correlation, mo-
lecular genetics, cellular and molecular biological
techniques, and elucidation of neurotransmitters and
their receptors, have contributed to the understand-
ing of dementing disorders.
NEUROPATHOLOGICAL CHANGES IN THE
ELDERLY HUMAN BRAIN
A realistic definition of normal aging acknowledges
that structural alterations, although present, are not
necessarily associated with detectable clinical mani-
festations. At autopsy, the brains of elderly persons
often show a number of changes—shrinkage of the
overlying folds (gyri) and widening of the sulci,
thickening of the arachnoid, an increase in size of the
arachnoid granulations, and enlargement of the
cerebral ventricles. Brain weights in apparently
mentally normal individuals start to decline at
40–50 years of age at a rate of approximately
2 or 3% per decade and eventually reach a value of
approximately 10% below maximum by the ninth
decade of life. It is unclear what contributes to the
brain atrophy—decreasing neuron numbers and/or
size or alterations in nonneuronal elements. Changes
in neuron numbers, dendrites, axons, cell bodies, and
synapses have been described.
Neuron Numbers
Whether there is neuronal loss associated with
normal aging remains controversial. Although the
majority of early studies indicated a substantial
age-related decline in neuron number in the cerebral
cortex, recent studies reveal only neuron shrinkage
accompanied by an overall preservation of, or
perhaps only a slight decrease in, cell number.
Dendritic Changes
Dendrites comprise approximately 95% of the total
receptive surface that neurons offer for contact with
one another; therefore, maintenance of the size and
integrity of the dendritic tree is paramount to ensure
that the integrative capacity of individual nerve cells,
brain regions, or the system as a whole remains
effective. Studies of the extent of dendritic changes in
human aging have yielded widely differing results by
different investigators. Early work suggested that a
reduction in the size of dendritic trees occurred with
aging in both the cerebral cortex and the hippocam-
pus. However, recent studies demonstrate a net
dendritic growth in pyramidal cells that may reflect
a compensatory response on the part of surviving
cells to the loss of their neighbors.
Axonal and Synaptic Changes
Less is known concerning changes in axons and
synapses with aging. Several studies have revealed an
age-related decrease in synaptic density and a
compensatory increase in the contact length of
residual synapses.
Cell Body Changes
Several investigations have shown a reduction in the
size of cell bodies with aging, although the structural
and molecular counterparts of this neuronal atrophy
are unknown. Other cell body changes include the
formation and accumulation of inclusions, such as
Lewy bodies and neurofibrillary tangles (NFTs), and
increases in the amount of neuropigments. In
addition, diffuse amyloid plaques are frequently
seen, although usually to a mild extent, in the brains
of normal elderly persons.

ALZHEIMER’S DISEASE
By far the most common dementing disorder in the
elderly is Alzheimer’s disease (AD). This progressive
dementing syndrome is characterized clinically by
early and prominent memory loss, visuospatial
impairment, disorientation, and language dysfunc-
tion. A definitive diagnosis of AD can only be made
by biopsy or autopsy. In AD, macroscopic examina-
tion of the brain shows cortical atrophy that is much
more severe than in age-matched controls and often
most evident in the temporal and, to a lesser degree,
frontal lobes. The brain is reduced in weight, and
there is accompanying ventricular dilatation. The
basal ganglia may also appear atrophied. Micro-
scopic examination of the brain shows extensive
neuronal loss that is most evident in the hippocam-
pus and frontal and temporal cortex and is accom-
panied by astrocytosis. These changes involve other
cortical areas and subcortical gray matter structures,
such as the amygdala and nucleus basalis. The major
neuropathological features of AD are neocortical,
hippocampal, and entorhinal NFTs and neuritic
plaques. Other abnormalities found in AD include
synaptic changes, granulovacuolar bodies, and
Hirano bodies:
NFTs
NFTs are intracytoplasmic neuronal inclusions that
are most numerous in the hippocampus and temporal
cortex. Tangles are elongated, flame-shaped struc-
tures composed of paired helical filaments. Their
precise chemical composition is unknown; however,
a hyperphosphorylated form of tau (a microtubule-
associated protein) and neurofilament protein are
present. NFTs also contain ubiquitin, a polypeptide
of 76 amino acids, whose function is to label effete or
redundant proteins for proteolysis.
Amyloid Plaques
These are complex extracellular structures that occur
most frequently in the hippocampus and cerebral
cortex but are also present in deep gray matter
structures (e.g., the nucleus basalis and amygdala).
Two types of plaques can be identified morphologi-
cally: neuritic (or senile) and diffuse plaques. The
neuritic plaque is a relatively large and complex
structure. There is an amyloid core, formed from b-
amyloid protein (Ab protein, a cleaved product of b-
amyloid precursor protein), surrounded by an
accumulation of irregular neuritic processes derived
from degenerating axons and dendrites. Activated
BEHAVIOR, NEUROPATHOLOGY OF 371
microglia and, less frequently, reactive astrocytes are
present at the periphery of the plaque. Diffuse
plaques consist of a loose accumulation of Ab
protein, but these accumulations are not accompa-
nied by dystrophic neurites. The amyloid deposition
in the diffuse plaque does not have a dense central
core. Diffuse plaques are now recognized to be an
age-related phenomenon.
Synaptic Changes
One of the neuropathological features of AD is a
major loss of synapses in the cerebral cortex. This
synapse loss outweighs that of neuronal loss and
leads to a decline in the ratio between neuronal and
synaptic densities.
Granulovacuolar Bodies
Granulovacuolar bodies are enlarged lysosome-like
structures within which a central dot-like inclusion is
identifiable. Their precise nature and mechanism of
formation are unknown.
Hirano Bodies
Hirano bodies are brightly stained eosinophilic
inclusions with a rod-shaped structure that are found
within the cytoplasm of hippocampal neurons. These
inclusions are composed predominately of a-actinin,
but their mechanism of formation is unknown.
FRONTOTEMPORAL LOBAR DEGENERATION
Frontotemporal lobar degeneration (FTLD) consists
of a group of dementing disorders that cause frontal
and anterior temporal lobe degeneration. At least
three prototypic neurobehavioral syndromes have
been described: frontotemporal dementia (FTD; also
called frontal type of FTLD), progressive nonfluent
aphasia (PA), and semantic dementia (SD). Clinical
features of the most common form, FTD, include
relatively early onset (mean age of onset is 54 years);
striking behavioral and personality changes (includ-
ing disinhibition, distractibility, emotional blunting,
and lack of insight and judgment); language dysfunc-
tion; impairments in attention, abstraction, planning,
and problem solving; memory decline; and often
family histories of dementia. The clinical features of
PA include nonfluent, hesitant, distorted spontaneous
speech, impaired repetition, and relatively preserved
comprehension. Fluent anomic aphasia with im-
paired comprehension and loss of knowledge are
core features of SD. Although each of these
syndromes has a characteristic clinical profile,
372 BEHAVIOR, NEUROPATHOLOGY OF
pathologically each may be accompanied by a
number of non-AD, and even AD, neuropathological
changes. There is no good clinical–pathological
correlation between the clinical syndrome and
subtype of FTLD pathology.
At least five distinct neuropathological patterns
are associated with the clinical features of FTLD.
The most common pattern is microvacuolar degen-
eration and gliosis lacking distinctive inclusions.
It is characterized by neuronal loss and spongiform
changes, accompanied by varying degrees of astro-
cytosis affecting mainly laminae I–III of the anterior
cingulated gyrus and the frontal and anterior
temporal lobes. There is a paucity of neuritic plaques
and NFTs. There are no Pick bodies, cortical
Lewy bodies, or inflated neurons. A second type,
a pattern of Pick’s disease histology, is characterized
by intense astrocytic gliosis in the presence of
intraneuronal Pick inclusion bodies and inflated
neurons in all layers of the hippocampal dentate
gyrus and frontotemporal cortex. Pick bodies are
rounded, well-circumscribed, basophilic, cytoplas-
mic intraneuronal inclusions. They are argyrophilic
and, on immunocytochemistry, give a positive stain-
ing reaction for tau and ubiquitin. Pick cells are
distended neurons with a characteristic ballooned
shape. A third pattern consists of motor neuron
degeneration at the cervical and thoracic levels in
addition to ubiquitin-positive inclusions in cortical
layer II and hippocampal dentate granule cells. A
fourth pattern includes familial FTD with character-
istic tau-positive inclusion in neurons and glial
cells. The final pattern consists of corticobasal
degeneration in the presence of tau-positive but
ubiquitin-negative inclusions in cortical layer II and
the substantia nigra, with ballooned achromatic
neurons and astrocytosis.
DEMENTIA WITH PARKINSONISM
Some neurodegenerative disorders with dementia
have prominent parkinsonian symptoms. Many
patients with AD, for example, develop signs of
parkinsonism as the disease progresses; conversely,
many patients with idiopathic Parkinson’s disease
(PD) become demented at later stages. Numerous
neuropathological studies have demonstrated an
overlap between the histopathological findings of
AD and PD (the hallmark of which is the subcortical
Lewy body). In fact, there is a spectrum of
neurodegenerative disorders with Lewy bodies,
comprising idiopathic PD, diffuse Lewy body dis-
ease, and the Lewy body variant (LBV) of AD. In
addition, some neurodegenerative diseases (e.g.,
progressive supranuclear palsy, corticobasal degen-
eration, and dementia pugilistica) have prominent
parkinsonism but lack Lewy body pathology.
Lewy bodies are rounded intracytoplasmic inclu-
sions, usually circular in outline, with a brightly
eosinophilic, hyaline core surrounded by a pale halo.
Their precise chemical composition is unknown, but
they are composed of filamentous structures and give
a positive reaction for neurofilament protein, ubiqui-
tin, and a-synuclein.
Parkinson’s Disease with Dementia
Dementia is commonly associated with PD as the
illness progresses, often 10 years after disease onset.
The dementia associated with PD is generally
characterized by impairment of executive functions,
visuospatial skills, free-recall memory, and verbal
fluency, consistent with a pattern of frontal/subcor-
tical dementia. The neuropathological hallmark of
PD is the presence of Lewy bodies in the substantia
nigra, locus ceruleus, and other brainstem and
diencephalic nuclei. There is also evidence of
neuronal loss accompanied by gliosis. Neocortical
Lewy bodies are distinctly uncommon.
Diffuse Lewy Body Disease
The clinical presentation of dementia with Lewy
bodies includes a fluctuating course, visual hallucina-
tions and other psychotic symptoms, and parkinso-
nian signs. In diffuse Lewy body disease (DLBD), the
memory loss is usually less severe. Neuropathologi-
cally, DLBD is characterized by the presence of Lewy
bodies not only in the pigmented nuclei in the
brainstem and diencephalon but also widely distrib-
uted throughout the cerebral cortex. Neuropatholo-
gical findings of AD are usually absent.
Lewy Body Variant of AD
The clinical presentation of LBV is often indistin-
guishable from that of DLBD, although patients may
have evidence of a greater memory deficit. The
neuropathological features of LBV are abundant
neocortical and brainstem Lewy bodies accompanied
by sufficient pathological findings of AD, including
senile plaques and NFTs.
Progressive Supranuclear Palsy
Progressive supranuclear palsy is a neurodegenera-
tive disease involving the brainstem, basal ganglia,
and cerebellum with gradually progressive vertical

supranuclear gaze palsy; parkinsonism (characterized
by bradykinesia, gait disorder, postural instability
with falls, axial rigidity, and neck dystonia); cogni-
tive decline (especially frontal lobe dysfunction); and
pseudobulbar palsy, including dysarthria and dys-
phagia. The neuropathological features are numer-
ous NFTs in selected structures of the basal ganglia
and brainstem, granulovacuolar degeneration, and
neuronal loss and fibrillary gliosis associated with the
degeneration of various fiber tracts.
Corticobasal Degeneration
This uncommon disorder is characterized clinically
by parkinsonism and signs of cortical dysfunction,
including apraxia, alien hand syndrome, cortical
sensory loss, and dementia. The neuropathological
features are cortical atrophy, neuronal loss, and
astrocytosis in the cerebral cortical layer II and
substantia nigra, with variable numbers of ballooned
achromatic neurons that are tau positive but
ubiquitin negative.
Dementia Pugilistica
Dementia pugilistica is a clinical–pathological entity
occurring in boxers who have experienced repeated
head injury. The neuropathological features include a
large and fenestrated septum cavum; degeneration of
the substantia nigra and basal ganglia; numerous
NFTs in the hippocampus, parahippocampal gyrus,
amygdala, and temporal neocortex; b-amyloid de-
posits in the form of diffuse plaques widely
distributed throughout the cerebral cortex; and
marked loss of Purkinje cells, accompanied by
astrocytosis, in the cerebellum.
VASCULAR DEMENTIA
Cerebrovascular disease is a common cause of
morbidity in the elderly. Vascular dementia, espe-
cially in association with AD (mixed dementia),
accounts for approximately 10–15% of all cases of
dementia. A broad spectrum of heterogeneous
vascular lesions can be associated with a decline in
cognitive functioning.
Multi-infarct Dementia
Multi-infarct dementia is characterized clinically by
a progressive stepwise impairment in cognitive
functions accompanied by focal neurological symp-
toms and signs. Unlike AD, memory loss is not
usually predominant over other cognitive impair-
ments. The neuropathological features include nu-
BEHAVIOR, NEUROPATHOLOGY OF 373
merous infarcts in the brain, although the extent and
distribution of the infarcts demonstrate considerable
variability from case to case.
Binswanger’s Disease
This uncommon form of vascular dementia occurs
most frequently in the elderly and in patients with
poorly controlled hypertension and diabetes mel-
litus. Dementia, apathy, lack of drive, mild depres-
sion, pseudobulbar state, and gait disorder are
common clinical characteristics. The neuropatholo-
gical features include extensive ischemic damage in
the subcortical white matter. Such lesions produce
widespread loss of axons and demyelinization
accompanied by astrocytosis, with relative sparing
of the overlying cerebral cortex. Hyalination and
intimal fibrosis of the proximal middle cerebral
artery and lenticulostriate perforating arteries are
also observed.
Lacunar State
The clinical features of lacunar state are dementia,
lack of volition, akinetic mutism, hemiparesis,
dysarthria, pseudobulbar palsy, small-stepped gait,
and urinary incontinence. The neuropathological
features are multiple lacunar infarcts in the basal
ganglia, thalamus, internal capsule, corona radiata,
and frontal subcortical white matter. The ischemic
lesions affect especially the prefrontal subcortical
circuit, which explains the cognitive, behavioral, and
clinical features.
CADASIL
CADASIL is an acronym for cereberal autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy. An autosomal dominant dis-
ease resulting from mutations in the notch 3 gene,
CADASIL is characterized by recurrent small
strokes, often beginning in early adulthood, and
subcortical dementia. The neuropathological features
include numerous partially cavitated infarctions in
the white matter and basal ganglia, with loss of
axons and myelin. The media of the small vessels in
the regions of infarction contain basophilic granular
deposits accompanied by degenerating smooth mus-
cle fibers.
—G. Tong and Jody Corey-Bloom
See also–Aging, Overview; Alzheimer’s Disease;
Behavior, Neural Basis of; CADASIL; Dementia;
Neuropsychology, Overview; Parkinsonism
374 BELL, CHARLES
Further Reading
Feinberg, T. E., and Farah, M. J. (Eds.) (1997). Behavioral
Neurology and Neuropsychology, pp. 497–638. McGraw-Hill,
New York.
Graham, D. I., and Lantos, P. L. (Eds.) (1997). Greenfield’s
Neuropathology, 6th ed. Oxford Univ. Press, New York.
Hodges, J. R., and Miller, R. (2001). The classification, genetics
and neuropathology of frontotemporal dementia. Introduction
to the special topic papers: Part I. Neurocase 7, 31–35.
Jellinger, K. A., and Bancher, C. (1998). Neuropathology of
Alzheimer’s disease: A critical update. J. Neural Transm. 54,
S77–S95.
Markesbery, W. R. (Ed.) (1998). Neuropathology of Dementing
Disorders, pp. 121–143. Arnold, London.
Bell, Charles
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHARLES BELL (1774–1842) was the son of an
Episcopalian minister who, with his second wife,
had six children. He qualified as a doctor from the
University of Edinburgh but, because of his brother’s
unpopularity as a surgeon, he was advised to further
his career in London. On arrival there in 1804, he
made a living by lecturing in anatomy and art. His
reputation had preceded him because he had
published as a student in 1798 a System of
Dissections. He was therefore received by such
well-known personalities as Sir Astley Cooper, Sir
Joseph Banks, and Mathew Baillie. Two years after
arriving in London, he published An Essay of the
Anatomy of Expression in Painting. He had been
helped in his artistic expression by a painter, Charles
Allan, known as the ‘‘Hogarth of Scotland.’’
In 1811, at the age of 37, he married and moved to
Soho Square. He became a member of the Royal
College of Surgeons of England in 1813 and in the
following year was elected surgeon to the Middlesex
Hospital. In 1815, he went to Waterloo to minister to
the wounded after the battle, operating all day but
continuing to paint and sketch. He was appointed
professor of anatomy and surgery to the Royal
College of Surgeons of England in 1824, serving on
its council, and he helped found the University of
London. At the age of 61, he returned to Edinburgh
to become professor of surgery at the University of
Edinburgh and died 6 years later from heart disease.
Bell classified nerve roots into two types: The
anterior root (in front), which is motor and supplies
muscles, and the posterior root (in back), which
conveys sensation and possesses a ganglion (an
enlargement of the nerve). He also described, for
the first time, several nerves he called ‘‘respiratory’’;
these included the vagus (10th cranial nerve),
accessory (11th cranial nerve), and the long nerve
of Bell. In addition, he defined the action of the facial
(seventh cranial) nerve. He attempted to distinguish
the function of the trigeminal nerve, which is the
nerve of taste, salivary glands, and muscles of the
face and jaws, from ordinary facial sensation. The
facial nerve supplies the muscles of facial expression,
but he mistakenly thought the trigeminal nerve was
also involved in this but corrected himself in later
publications.
He published several books, such as The Anatomy
of Brain (1802), which includes 12 of his own
engravings, and his original plates were published in
The Course of the Nerves (1803) and A System of
Operative Surgery (1807). His New Anatomy (1811)
was published privately and was not therefore widely
known; in this book, he indicated the different
functions of the cerebrum and the cerebellum. He
is best known for Bell’s palsy, which he reported in a
paper to the Royal Society in 1821.
In The Nervous System of the Human Body
(1830), he described what has come to be known
as Bell’s phenomenon: ‘‘a very remarkable upturning
of the cornea in an attempt to close the eyelids.’’
In June 1822, Magendie in France published his
work with the unequivocal statement that anterior
roots were motor and posterior roots were sensory
but failed to refer to Bell’s work. This was the cause
of much discussion regarding priority, but the
compromise was to call the theory of motor and
sensory roots the Bell–Magendie rule.
—F. Clifford Rose
374 BELL, CHARLES
Further Reading
Feinberg, T. E., and Farah, M. J. (Eds.) (1997). Behavioral
Neurology and Neuropsychology, pp. 497–638. McGraw-Hill,
New York.
Graham, D. I., and Lantos, P. L. (Eds.) (1997). Greenfield’s
Neuropathology, 6th ed. Oxford Univ. Press, New York.
Hodges, J. R., and Miller, R. (2001). The classification, genetics
and neuropathology of frontotemporal dementia. Introduction
to the special topic papers: Part I. Neurocase 7, 31–35.
Jellinger, K. A., and Bancher, C. (1998). Neuropathology of
Alzheimer’s disease: A critical update. J. Neural Transm. 54,
S77–S95.
Markesbery, W. R. (Ed.) (1998). Neuropathology of Dementing
Disorders, pp. 121–143. Arnold, London.
Bell, Charles
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHARLES BELL (1774–1842) was the son of an
Episcopalian minister who, with his second wife,
had six children. He qualified as a doctor from the
University of Edinburgh but, because of his brother’s
unpopularity as a surgeon, he was advised to further
his career in London. On arrival there in 1804, he
made a living by lecturing in anatomy and art. His
reputation had preceded him because he had
published as a student in 1798 a System of
Dissections. He was therefore received by such
well-known personalities as Sir Astley Cooper, Sir
Joseph Banks, and Mathew Baillie. Two years after
arriving in London, he published An Essay of the
Anatomy of Expression in Painting. He had been
helped in his artistic expression by a painter, Charles
Allan, known as the ‘‘Hogarth of Scotland.’’
In 1811, at the age of 37, he married and moved to
Soho Square. He became a member of the Royal
College of Surgeons of England in 1813 and in the
following year was elected surgeon to the Middlesex
Hospital. In 1815, he went to Waterloo to minister to
the wounded after the battle, operating all day but
continuing to paint and sketch. He was appointed
professor of anatomy and surgery to the Royal
College of Surgeons of England in 1824, serving on
its council, and he helped found the University of
London. At the age of 61, he returned to Edinburgh
to become professor of surgery at the University of
Edinburgh and died 6 years later from heart disease.
Bell classified nerve roots into two types: The
anterior root (in front), which is motor and supplies
muscles, and the posterior root (in back), which
conveys sensation and possesses a ganglion (an
enlargement of the nerve). He also described, for
the first time, several nerves he called ‘‘respiratory’’;
these included the vagus (10th cranial nerve),
accessory (11th cranial nerve), and the long nerve
of Bell. In addition, he defined the action of the facial
(seventh cranial) nerve. He attempted to distinguish
the function of the trigeminal nerve, which is the
nerve of taste, salivary glands, and muscles of the
face and jaws, from ordinary facial sensation. The
facial nerve supplies the muscles of facial expression,
but he mistakenly thought the trigeminal nerve was
also involved in this but corrected himself in later
publications.
He published several books, such as The Anatomy
of Brain (1802), which includes 12 of his own
engravings, and his original plates were published in
The Course of the Nerves (1803) and A System of
Operative Surgery (1807). His New Anatomy (1811)
was published privately and was not therefore widely
known; in this book, he indicated the different
functions of the cerebrum and the cerebellum. He
is best known for Bell’s palsy, which he reported in a
paper to the Royal Society in 1821.
In The Nervous System of the Human Body
(1830), he described what has come to be known
as Bell’s phenomenon: ‘‘a very remarkable upturning
of the cornea in an attempt to close the eyelids.’’
In June 1822, Magendie in France published his
work with the unequivocal statement that anterior
roots were motor and posterior roots were sensory
but failed to refer to Bell’s work. This was the cause
of much discussion regarding priority, but the
compromise was to call the theory of motor and
sensory roots the Bell–Magendie rule.
—F. Clifford Rose

See also–Accessory Nerve (Cranial Nerve XI);
Facial Nerve (Cranial Nerve VII); Magendie,
Franc¸ois; Thoracic Nerve, Long; Vagus Nerve
(Cranial Nerve X) (see Index entry Biography for
complete list of biographical entries)
Further Reading
Gardner-Thorpe, C. (2002). The art of the surgeon: Sir Charles
Bell (1774–1842). In Neurology of the Arts (F. C. Rose, Ed.).
Thomas, Evanston, IL.
Rose, F. C. (1999). Charles Bell: ‘‘The Nervous System of the
Human Body (1830).’’ In A Short History of Neurology: The
British Contribution, 1660–1910 (F. C. Rose, Ed.), pp. 122–
128. Butterworth-Heinemann, Oxford.
Bell’s Palsy
see Facial Nerve (Cranial Nerve VII)
Benign Intracranial
Hypertension
see Pseudotumor Cerebri
Benign Paroxysmal
Positional Vertigo
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BENIGN PAROXYSMAL positional vertigo (BPPV),
initially defined by Bárány in 1921, is the most
common cause of vertigo, particularly in the elderly.
By age 70, approximately 30% of all elderly subjects
have experienced this disorder at least once. This
condition is characterized by brief attacks of rotatory
vertigo and concomitant positional torsional–vertical
nystagmus that are elicited by rapid changes in head
position. It is a mechanical disorder of the inner
ear in which the precipitating positioning of the
head causes abnormal stimulation, usually of the
posterior semicircular canal of the undermost ear
and less frequently of the horizontal or the anterior
semicircular canal.
It is now generally accepted that debris floating
freely within the endolymph fluid of the canal
BENIGN PAROXYSMAL POSITIONAL VERTIGO 375
(canalolithiasis) cause BPPV. The debris, possibly
particles detached from the otoliths, congeal to form
a free-floating clot (plug). Because the clot is heavier
than the endolymph, it will always gravitate to the
most dependent part of the canal during changes in
head position that alter the angle of the canal relative
to gravity. Like a plunger, the clot induces bidirec-
tional (pushing or pulling) forces on the cupula,
thereby triggering the vertiginous attack. Canalo-
lithiasis explains all the features of the disorder:
Figure 1
Schematic drawing of the Semont liberatory maneuver in a patient
with typical BPPV of the left ear. Left to right: position of body and
head, position of labyrinth in space, position and movement of the
clot in the posterior canal and resulting cupula deflection, and
direction of the torsional nystagmus. The clot is depicted as an
open circle within the canal; a solid circle represents the final
resting position of the clot. (1) In the sitting position, the head is
turned horizontally 451 toward the unaffected ear. The clot, which
is heavier than endolymph, settles at the base of the left posterior
semicircular canal. (2) The patient is tilted approximately 1051
toward the left (affected) ear. The change in head position relative
to gravity causes the clot to settle in the lowermost part of the
canal and the cupula to deflect downward, inducing BPPV with
rotatory nystagmus beating toward the undermost ear. The patient
maintains this position for 1 min. (3) The patient is turned
approximately 1951 with the nose down, causing the clot to move
toward the exit of the canal. The endolymphatic flow again
deflects the cupula so that the nystagmus beats toward the left ear,
now uppermost. The patient remains in this position for 1 min. (4)
The patient is slowly moved to the sitting position; this causes the
clot to enter the utricular cavity. A, P, and H, anterior, posterior,
and horizontal semicircular canals, respectively; Cup, cupula; UT,
utricular cavity; RE, right eye; LE, left eye (reproduced with
permission from Brandt et al., 1994).

See also–Accessory Nerve (Cranial Nerve XI);
Facial Nerve (Cranial Nerve VII); Magendie,
Franc¸ois; Thoracic Nerve, Long; Vagus Nerve
(Cranial Nerve X) (see Index entry Biography for
complete list of biographical entries)
Further Reading
Gardner-Thorpe, C. (2002). The art of the surgeon: Sir Charles
Bell (1774–1842). In Neurology of the Arts (F. C. Rose, Ed.).
Thomas, Evanston, IL.
Rose, F. C. (1999). Charles Bell: ‘‘The Nervous System of the
Human Body (1830).’’ In A Short History of Neurology: The
British Contribution, 1660–1910 (F. C. Rose, Ed.), pp. 122–
128. Butterworth-Heinemann, Oxford.
Bell’s Palsy
see Facial Nerve (Cranial Nerve VII)
Benign Intracranial
Hypertension
see Pseudotumor Cerebri
Benign Paroxysmal
Positional Vertigo
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BENIGN PAROXYSMAL positional vertigo (BPPV),
initially defined by Bárány in 1921, is the most
common cause of vertigo, particularly in the elderly.
By age 70, approximately 30% of all elderly subjects
have experienced this disorder at least once. This
condition is characterized by brief attacks of rotatory
vertigo and concomitant positional torsional–vertical
nystagmus that are elicited by rapid changes in head
position. It is a mechanical disorder of the inner
ear in which the precipitating positioning of the
head causes abnormal stimulation, usually of the
posterior semicircular canal of the undermost ear
and less frequently of the horizontal or the anterior
semicircular canal.
It is now generally accepted that debris floating
freely within the endolymph fluid of the canal
BENIGN PAROXYSMAL POSITIONAL VERTIGO 375
(canalolithiasis) cause BPPV. The debris, possibly
particles detached from the otoliths, congeal to form
a free-floating clot (plug). Because the clot is heavier
than the endolymph, it will always gravitate to the
most dependent part of the canal during changes in
head position that alter the angle of the canal relative
to gravity. Like a plunger, the clot induces bidirec-
tional (pushing or pulling) forces on the cupula,
thereby triggering the vertiginous attack. Canalo-
lithiasis explains all the features of the disorder:
Figure 1
Schematic drawing of the Semont liberatory maneuver in a patient
with typical BPPV of the left ear. Left to right: position of body and
head, position of labyrinth in space, position and movement of the
clot in the posterior canal and resulting cupula deflection, and
direction of the torsional nystagmus. The clot is depicted as an
open circle within the canal; a solid circle represents the final
resting position of the clot. (1) In the sitting position, the head is
turned horizontally 451 toward the unaffected ear. The clot, which
is heavier than endolymph, settles at the base of the left posterior
semicircular canal. (2) The patient is tilted approximately 1051
toward the left (affected) ear. The change in head position relative
to gravity causes the clot to settle in the lowermost part of the
canal and the cupula to deflect downward, inducing BPPV with
rotatory nystagmus beating toward the undermost ear. The patient
maintains this position for 1 min. (3) The patient is turned
approximately 1951 with the nose down, causing the clot to move
toward the exit of the canal. The endolymphatic flow again
deflects the cupula so that the nystagmus beats toward the left ear,
now uppermost. The patient remains in this position for 1 min. (4)
The patient is slowly moved to the sitting position; this causes the
clot to enter the utricular cavity. A, P, and H, anterior, posterior,
and horizontal semicircular canals, respectively; Cup, cupula; UT,
utricular cavity; RE, right eye; LE, left eye (reproduced with
permission from Brandt et al., 1994).
376 BENZODIAZEPINES
latency, short duration, fatigability (diminution with
repeated positioning), changes in the direction of
nystagmus with changes in head position, and the
efficacy of physical therapy (Fig. 1).
Approximately 5–10% of BPPV patients suffer
from abnormal stimulation of the horizontal
semicircular canal, which is elicited when the supine
head is turned from side to side around the long-
itudinal axis. Combinations of types are possible,
and transitions from involvement of the posterior to
horizontal canal occur if the clot moves from one to
the other semicircular canal. Transitions from
canalolithiasis to cupulolithiasis in the horizontal
canal have been described. Most cases are idiopathic,
with incidence increasing with advancing age.
Prolonged bed rest facilitates their occurrence. Other
cases arise due to trauma, vestibular neuritis, or inner
ear infections.
The diagnosis of typical BPPV is simple and safe.
Differential diagnosis includes central vestibular
vertigo or nystagmus, perilymph fistula, drug or
alcohol intoxication, vertebrobasilar ischemia, Me-
nière’s disease, and psychogenic vertigo.
—Thomas Brandt
See also–Balance; Bárány, Robert; Nystagmus
and Saccadic Intrusions and Oscillations; Vertigo
and Dizziness; Vestibular System
Further Reading
Baloh, R. W., and Halmagyi, G. M. (Eds.) (1996). Disorders of the
Vestibular System. Oxford Univ. Press, Oxford.
Brandt, T., Steddin, S., and Daroff, R. B. (1994). Therapy for
benign paroxysmal positioning vertigo, revisited. Neurology 44,
796–800.
Benzodiazepines
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BENZODIAZEPINES are a class of medications with
anxiolytic and sedative–hypnotic properties. The first
benzodiazepine to be marketed was chlordiazepox-
ide (Librium) in 1960. Since then, numerous other
benzodiazepines have been developed, and they are
now the most widely prescribed antianxiety agents in
the world. Benzodiazepines have become popular
because of their efficacy as anxiolytic and sedative–
hypnotic agents, and because they have a higher
therapeutic index and lower abuse potential than
older sedative–hypnotics such as barbiturates.
Benzodiazepines bind to receptors that allow for
the increased activity of the inhibitory neurotrans-
mitter g-aminobutyric acid (GABA). The GABA
system is the principal mediator of synaptic inhibi-
tion in the brain, and the major postsynaptic GABA
receptor is known as GABAA. The ion channel
associated with the GABAA receptor is selective for
anions, particularly that of chloride; when GABA
binds to the GABAA receptor, the chloride channel is
opened, allowing chloride ions to move into the cell.
Benzodiazepines are known to bind to the GABAA
receptor and potentiate GABA binding, which
increases the frequency and number of openings of
the chloride channel, thus decreasing cellular excit-
ability. Although not conclusively shown, it is
thought by many that benzodiazepines exert their
properties via this mechanism. Studies have shown
that benzodiazepine receptors, sometimes known as
GABA-BZ receptors, are associated with five differ-
ent subunits, which mix in a heterogeneous manner
to produce a wide range of receptors with differing
pharmacological properties. Thus, there remains a
great potential for research to further elucidate the
variants of receptors and to develop drugs that may
take advantage of this heterogeneity.
Drugs that bind to benzodiazepine receptors may
have direct agonist, inverse agonist, or antagonist
effects. Direct agonists act on the GABA-BZ receptor
to increase the frequency and number of openings of
the chloride channel. These drugs may have anxio-
lytic, sedating, muscle relaxant, or anticonvulsant
properties and, besides benzodiazepines, include
zolpidem and zaleplon. Inverse agonists decrease
the frequency of chloride channel openings and have
been demonstrated to produce anxiety and convul-
sions in humans; one such compound used in
research is the diazepam-binding inhibitor (DBI).
Antagonists block the effects of agonists or inverse
agonists. Flumazenil is the most widely studied
antagonist, and it reverses the physiological effects
of benzodiazepine agonists. Patients may be given
flumazenil to reverse the sedative effects of benzo-
diazepines that have been used for clinical indica-
tions or taken in overdose. Partial benzodiazepine
agonists have also been developed but are not
available for clinical use.
Although all benzodiazepines share a similar
mechanism of action, they differ with regard to rate
of onset of action, distribution and elimination half-
life, and potency (Table 1). These differences may
376 BENZODIAZEPINES
latency, short duration, fatigability (diminution with
repeated positioning), changes in the direction of
nystagmus with changes in head position, and the
efficacy of physical therapy (Fig. 1).
Approximately 5–10% of BPPV patients suffer
from abnormal stimulation of the horizontal
semicircular canal, which is elicited when the supine
head is turned from side to side around the long-
itudinal axis. Combinations of types are possible,
and transitions from involvement of the posterior to
horizontal canal occur if the clot moves from one to
the other semicircular canal. Transitions from
canalolithiasis to cupulolithiasis in the horizontal
canal have been described. Most cases are idiopathic,
with incidence increasing with advancing age.
Prolonged bed rest facilitates their occurrence. Other
cases arise due to trauma, vestibular neuritis, or inner
ear infections.
The diagnosis of typical BPPV is simple and safe.
Differential diagnosis includes central vestibular
vertigo or nystagmus, perilymph fistula, drug or
alcohol intoxication, vertebrobasilar ischemia, Me-
nière’s disease, and psychogenic vertigo.
—Thomas Brandt
See also–Balance; Bárány, Robert; Nystagmus
and Saccadic Intrusions and Oscillations; Vertigo
and Dizziness; Vestibular System
Further Reading
Baloh, R. W., and Halmagyi, G. M. (Eds.) (1996). Disorders of the
Vestibular System. Oxford Univ. Press, Oxford.
Brandt, T., Steddin, S., and Daroff, R. B. (1994). Therapy for
benign paroxysmal positioning vertigo, revisited. Neurology 44,
796–800.
Benzodiazepines
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BENZODIAZEPINES are a class of medications with
anxiolytic and sedative–hypnotic properties. The first
benzodiazepine to be marketed was chlordiazepox-
ide (Librium) in 1960. Since then, numerous other
benzodiazepines have been developed, and they are
now the most widely prescribed antianxiety agents in
the world. Benzodiazepines have become popular
because of their efficacy as anxiolytic and sedative–
hypnotic agents, and because they have a higher
therapeutic index and lower abuse potential than
older sedative–hypnotics such as barbiturates.
Benzodiazepines bind to receptors that allow for
the increased activity of the inhibitory neurotrans-
mitter g-aminobutyric acid (GABA). The GABA
system is the principal mediator of synaptic inhibi-
tion in the brain, and the major postsynaptic GABA
receptor is known as GABAA. The ion channel
associated with the GABAA receptor is selective for
anions, particularly that of chloride; when GABA
binds to the GABAA receptor, the chloride channel is
opened, allowing chloride ions to move into the cell.
Benzodiazepines are known to bind to the GABAA
receptor and potentiate GABA binding, which
increases the frequency and number of openings of
the chloride channel, thus decreasing cellular excit-
ability. Although not conclusively shown, it is
thought by many that benzodiazepines exert their
properties via this mechanism. Studies have shown
that benzodiazepine receptors, sometimes known as
GABA-BZ receptors, are associated with five differ-
ent subunits, which mix in a heterogeneous manner
to produce a wide range of receptors with differing
pharmacological properties. Thus, there remains a
great potential for research to further elucidate the
variants of receptors and to develop drugs that may
take advantage of this heterogeneity.
Drugs that bind to benzodiazepine receptors may
have direct agonist, inverse agonist, or antagonist
effects. Direct agonists act on the GABA-BZ receptor
to increase the frequency and number of openings of
the chloride channel. These drugs may have anxio-
lytic, sedating, muscle relaxant, or anticonvulsant
properties and, besides benzodiazepines, include
zolpidem and zaleplon. Inverse agonists decrease
the frequency of chloride channel openings and have
been demonstrated to produce anxiety and convul-
sions in humans; one such compound used in
research is the diazepam-binding inhibitor (DBI).
Antagonists block the effects of agonists or inverse
agonists. Flumazenil is the most widely studied
antagonist, and it reverses the physiological effects
of benzodiazepine agonists. Patients may be given
flumazenil to reverse the sedative effects of benzo-
diazepines that have been used for clinical indica-
tions or taken in overdose. Partial benzodiazepine
agonists have also been developed but are not
available for clinical use.
Although all benzodiazepines share a similar
mechanism of action, they differ with regard to rate
of onset of action, distribution and elimination half-
life, and potency (Table 1). These differences may
 BENZODIAZEPINES 377

Table 1 BENZODIAZEPINES AVAILABLE IN THE UNITED STATES

Elimination
half-life of
Equivalent Onset of action Distribution active
Name dose (mg) (oral route) half-life metabolites (hr) Usual dosage forms

Alprazolam (Xanax) 0.5 Intermediate Intermediate Short (6–20) 0.25-, 0.5-, 1-, 2-mg tablets; oral
solution
Chlordiazepoxide 10 Intermediate Slow Long (30–100) 5-, 10-, 25-mg capsules;
(Librium) injectable form
Clonazepam 0.25 Intermediate Intermediate Long (18–50) 0.5-, 1-, 2- mg tablets
(Klonopin)
Clorazepate 7.5 Rapid Rapid Long (30–100) 3.75-, 7.5-, 11.25-, 15-, 22.5-mg
(Tranxene) tablets; 3.75-, 7.5-, 15-mg
capsules
Diazepam (Valium) 5 Rapid Rapid Long (30–100) 2-, 5-, 10-mg tablets; oral
solution; injectable form;
rectal gel
Estazolam (ProSom) 1 Rapid Rapid Short (10–24) 1-, 2-mg tablets
Flurazepam (Dalmane) 15 Rapid Rapid Long (50–160) 15-, 30-mg capsules
Halazepam (Paxipam) 20 Intermediate–slow Intermediate Long (30–100) 20-, 40-mg tablets
Lorazepam (Ativan) 1 Intermediate Intermediate Short (10–20) 0.5-, 1-, 2-mg tablets; oral
solution; injectable form
Midazolam (Versed) N/A Rapid Rapid Short (2–3) 2 mg/ml oral syrup for pediatrics;
injectable form
Oxazepam (Serax) 15 Slow Intermediate Short (8–12) 10-, 15-, 30-mg capsules; 15-mg
tablets
Quazepam (Doral) 15 Rapid–intermediate Intermediate Long (50–160) 7.5-, 15-mg tablets
Temazepam (Restoril) 15 Intermediate Rapid Short (8–15) 7.5-, 15-, 30-mg capsules
Triazolam (Halcion) 0.25 Rapid Rapid Short (1.5–5) 0.125-, 0.25-mg capsules

lead to the choice of a particular benzodiazepine for
a given clinical situation. For example, a benzodia-
zepine with a quick onset of action may be preferred
when emergency sedation is needed, whereas a drug
with a long half-life may be avoided in patients with
a higher susceptibility to adverse side effects.
Benzodiazepines with higher potency require a lower
dose to achieve efficacy. The rate of onset of
benzodiazepine action is related to absorption in
the gastrointestinal system. Benzodiazepines have
different durations of efficacy, based on (i) distribu-
tion half-life, which characterizes the length of time
that the drug is redistributed into peripheral tissues
such as fat, and (ii) elimination half-life, which
characterizes the time course of elimination by the
liver and kidneys. In most cases, redistribution
occurs more quickly than elimination, so duration
of efficacy for a single or occasional dose is related
mainly to redistribution half-life. With repeated
dosing, the peripheral tissues become saturated, so
elimination half-life plays a greater role in the
duration of efficacy. Benzodiazepines with active
metabolites that are slowly biotransformed have
longer elimination half-lives. Because these benzo-
diazepines undergo metabolism by the liver, caution
should be taken when using them in patients with
hepatic disease. Benzodiazepines that are directly
biotransformed and develop no active metabolites
have shorter elimination half-lives. The advantages
of benzodiazepines with long half-lives include less
frequent dosing, less severe withdrawal syndromes,
and less variation in plasma concentration, whereas
the advantages of drugs with short half-lives include
lack of drug accumulation and less daytime sedation.
Benzodiazepines may be administered via oral,
sublingual, intramuscular, and intravenous routes.
Most benzodiazepines are well absorbed following
oral administration, with maximal intensity reached
in 1–3 hr. The sublingual route may give a slightly
quicker onset of action than the oral route. Absorp-
tion of benzodiazepines via the intramuscular route
is erratic and varies depending on the drug and the
378 BENZODIAZEPINES
site of administration. Intravenous administration is
useful in patients requiring immediate effect, such as
those in status epilepticus or with severe agitation.
Benzodiazepines are less likely to stimulate hepatic
microsomal enzymes than most barbiturates and
therefore interact with relatively few other medica-
tions in comparison. However, all benzodiazepines
may enhance central nervous system (CNS) depres-
sant effects with other sedative agents, including
alcohol. Benzodiazepines may increase blood levels
of phenytoin and digoxin. Cimetidine, disulfiram,
and serotonin-selective reuptake inhibitors can in-
crease the plasma concentrations of long-acting
benzodiazepines, although the clinical significance
of such interactions is unclear. Food and antacids
may decrease the absorption of benzodiazepines.
Benzodiazepines are highly useful in the treatment
of anxiety. They may be used to treat patients with
social phobia, generalized anxiety disorder, and
panic disorder with or without agoraphobia; these
patients may require maintenance usage of benzo-
diazepines. Patients with panic disorder do not
appear to develop tolerance to the anxiolytic effects
of benzodiazepines when used long-term, but it is less
clear whether or not patients with social phobia and
generalized anxiety disorder develop tolerance.
Short-term or episodic use may be indicated in
patients with anxiety associated with situational
stress or in patients who confront a specific phobic
situation infrequently (e.g., air travel in a patient
with fear of flying). In some studies, clonazepam has
been shown to be effective in the management of
acute mania. The use of benzodiazepines in patients
with posttraumatic stress disorder is controversial
and may even cause negative effects upon with-
drawal of the drug.
Benzodiazepines may also be used to treat
insomnia. In general, benzodiazepines have seda-
tive–hypnotic effects at higher doses and antianxiety
effects at relatively low doses. For short-term
insomnia, benzodiazepines may be beneficial when
prescribed in conjunction with nonpharmacological
recommendations about sleep hygiene. For long-term
insomnia, benzodiazepines may also help, but their
benefits must be weighed against the risk of side
effects and dependence with long-term use. In the
long-term, patients may develop tolerance to some of
the sedative–hypnotic effects of benzodiazepines.
Because benzodiazepines have a cross-tolerance
with alcohol (as well as with other sedative–
hypnotics such as barbiturates), these medications
are effective in the treatment of alcohol withdrawal.
Dosages vary depending on the severity of the
withdrawal symptoms. If the patient develops
delirium tremens, aggressive use of benzodiazepines
is indicated because of the high mortality associated
with the condition.
Benzodiazepines have anticonvulsant properties,
and the intravenous forms of lorazepam and
diazepam are widely used as first-line agents in the
treatment of status epilepticus; intravenous midazo-
lam may also be effective. Although benzodiazepines
may be useful for the acute control of seizures, their
long-term use has been associated with undesirable
sedation and development of tolerance to their
antiepileptic effect. However, benzodiazepines may
play a role in treating and prophylaxing against
specific types of seizures. Examples include diaze-
pam administered rectally for febrile seizures,
midazolam for neonatal seizures, and clonazepam
for myoclonic seizures. Clonazepam may also be
beneficial in treating myoclonus not associated with
epilepsy.
Other indications for which benzodiazepines
have been used include neuroleptic-induced akathi-
sia, catatonia, nausea, and conscious sedation.
Although beta-adrenergic antagonists appear to be
most consistently effective in treating akathisia,
benzodiazepines may be helpful as a second-line
agent. Lorazepam, particularly in intravenous or
intramuscular form, has been reported to reverse
catatonic states. Parenteral, including sublingual,
forms of lorazepam have also been used to treat
nausea and vomiting, particularly when associated
with chemotherapy, although the data are largely
anecdotal. Because of their sedating effects, benzo-
diazepines may be used not only for conscious
sedation prior to procedures but also for agitation.
If the agitated patient is delirious or demented,
benzodiazepines should be used with caution because
the elderly and medically ill can be more vulnerable
to side effects.
The most common adverse side effect of benzo-
diazepines is drowsiness, which is often transient.
Marked sedation can occur with higher doses, in
combination with other CNS depressants, or in
patients who are older or have impaired hepatic
metabolism. Other adverse effects include dizziness
and dose-dependent ataxia. Relatively rare reactions
include nausea, vomiting, headache, cutaneous aller-
gic reaction, and weight gain. A paradoxical disin-
hibition of behavior, manifested as increased hostility
and aggression, has also been reported as a reaction.
Anterograde amnesia has been associated with

benzodiazepines, particularly high-potency, short-
acting drugs; this effect can also be worsened by
concomitant ingestion of alcohol. Patients on benzo-
diazepines may experience impairment in attention,
reaction time, and motor performance. An emer-
gence or worsening of depressed mood has also been
associated with benzodiazepines. In the elderly, the
use of benzodiazepines, particularly at high doses, is
a major independent risk factor for falls, although it
is not entirely clear how much a longer half-life
contributes to the risk. In patients with chronic
obstructive pulmonary disease or sleep apnea,
benzodiazepines have been reported to cause impair-
ments in respiration.
The data on benzodiazepine use in pregnancy
remain inconclusive. However, since some reports
have suggested that this class of drugs is teratogenic,
and there is no convincing evidence that benzodia-
zepines are entirely safe during pregnancy, their use
in pregnant women should be avoided. The use of
benzodiazepines during the first trimester of preg-
nancy has been associated with cleft lip or palate, but
these data are not well substantiated. When used in
the third trimester, benzodiazepines may cause
marked withdrawal symptoms in the newborn;
sedation, apneic spells, reluctance to suck, and
hyptonia have been observed. Benzodiazepines are
secreted in breast milk, and their use late in
pregnancy or during nursing has been associated
with a ‘‘floppy infant syndrome.’’
Benzodiazepines have been shown to be remark-
ably safe in overdose and alone almost never cause
fatalities. However, when ingested with other CNS
depressants, such as alcohol, barbiturates, or opiates,
they may contribute to the lethality of the combi-
nation.
When benzodiazepines are discontinued after a
course of treatment for anxiety, the patient may
develop a recurrence of the original symptoms. After
discontinuation, patients may also develop rebound
symptoms, experienced as a temporary return of the
original symptoms with greater intensity. All benzo-
diazepines may cause dependence and withdrawal,
the risk of which varies with potency, half-life, and
the length of time a patient has taken the drug.
Dependence and withdrawal symptoms are more
likely with higher dosages and longer term use. High-
potency, short-acting benzodiazepines pose the great-
est risk, and abrupt discontinuation of these medica-
tions, particularly alprazolam, may cause severe
withdrawal symptoms. Severe withdrawal may also
be seen in patients who have taken high dosages of
BENZODIAZEPINES 379
any of the benzodiazepines for a sustained period of
time. Therefore, in these cases, the drug should be
tapered gradually. Withdrawal symptoms include
insomnia, irritability, anxiety, fatigue, headache,
tremulousness, dizziness, anorexia, nausea, and
sweating; some of these symptoms may represent a
rebound or recurrence of the original anxiety. A
patient in severe withdrawal may present with
seizures, paranoia, dysphoria, and delirium. The
onset of withdrawal is generally 1 or 2 days after
discontinuation of short-acting drugs but may be as
long as 1 or 2 weeks after stopping long-acting
agents.
Although benzodiazepines may be sought out to
produce a euphoric or intentionally apathetic state,
abuse is unusual among patients with an anxiety
disorder. However, risk of benzodiazepine abuse may
be increased in patients with a history of alcohol,
sedative–hypnotic, or other psychoactive substance
abuse. Thus, with the exception of medical detox-
ification from alcohol or sedative–hypnotics, use of
benzodiazepines should be avoided in these patients.
Compared with older sedative–hypnotic agents,
benzodiazepines have a superior safety profile and
more established efficacy as an anxiolytic and thus
offer much potential benefit to patients. In addition,
benzodiazepines may be useful for other clinical
indications, including insomnia, alcohol withdrawal,
and seizures. However, the clinical decision to use
benzodiazepines should be carefully considered
because of the side effects and dependence that can
develop. All patients being started on benzodiaze-
pines should be clearly educated about the risks and
anticipated benefits of the medication, the rationale
for treatment, the estimated dose and duration of
therapy, and the potential for abuse, dependence, and
withdrawal. Patients should be advised of the risks of
sudden discontinuation, of driving or engaging in
other possibly dangerous activities (especially when
initiating treatment) and of potentiation by conco-
mitant use of alcohol and other sedative–hypnotics.
If the benzodiazepine is meant to be used as short-
term or episodic treatment, clinicians should make
their patients aware of this fact. Because of the
problems associated with long-term use, the clinician
should continuously re-evaluate the overall risk-to-
benefit ratio of treatment during the course of
therapy. If a decision is made to discontinue the
medication after a period of chronic, regular use,
slow tapering is necessary to avoid rebound or
withdrawal.
—Kewchang Lee
380 BERI-BERI
See also–Antianxiety Pharmacology; Anxiety
Disorders, Overview; Endozepines and Coma;
Gamma Aminobutyric Acid (GABA); Insomnia
Further Reading
Adams, R. D., Victor, M., and Ropper, A. H. (1997). Epilepsy and
other seizure disorders. Principles of Neurology—Sixth Edition,
pp. 313–343. McGraw-Hill, New York.
Ballenger, J. C. (2000). Benzodiazepine receptor agonists and
antagonists. In Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry VII (B. J. Sadock and V. A. Sadock, Eds.), pp. 2317–
2324. Lippincott Williams & Wilkins, Philadelphia.
Hyman, S. E., Arana, G. W., and Rosenbaum, J. F. (1995).
Handbook of Psychiatric Drug Therapy. Little, Brown, Boston.
Kaplan, H. I., and Sadock, B. J. (1996). Pocket Handbook of
Psychiatric Drug Treatment. Williams & Wilkins, Baltimore.
Nordli, D. R., Jr., and Pedley, T. A. (2000). Febrile seizures/
neonatal seizures. In Merritt’s Neurology—Tenth Edition (L. P.
Rowland, Ed.), pp. 833–836. Lippincott Williams & Wilkins,
Philadelphia.
Reiman, E. M. (1997). Anxiety. In The Practitioner’s Guide to
Psychoactive Drugs (A. J. Gelenberg and E. L. Bassuk, Eds.),
pp. 229–242. Plenum, New York.
Waxham, M. N. (1999). Neurotransmitter receptors. In Funda-
mental Neuroscience (M. J. Zigmond and F. E. Bloom, et al.,
Eds.), pp. 235–263. Academic Press, San Diego.
Beri-Beri
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN OLDER CHILDREN and adults, thiamine deficiency
in its fully blown form results in beri-beri, a serious
illness that includes severe and sometimes fatal
cardiovascular and/or neurological manifestations.
Traditionally, this disease has been categorized as
wet beri-beri, in which cardiovascular symptoms and
signs predominate, or dry beri-beri, in which
neurological symptoms and signs predominate. In
reality, most patients have involvement of both
systems, so the wet/dry terminology is no longer
widely used. Beri-beri heart disease leads to high-
output cardiac failure, with low peripheral resis-
tance; cerebral blood flow may be decreased,
however. There is also an acute fulminant form in
which cardiovascular collapse can occur, with death
occurring within hours to days. Administration of
thiamine typically restores peripheral vascular resis-
tance more rapidly than myocardial contractility, so
high-output failure may be converted to low-output
failure before resolution occurs.
Neurological manifestations have been variously
termed cerebral beri-beri or, more commonly, Wer-
nicke’s encephalopathy. Although Wernicke’s ence-
phalopathy has been classically described in adult
alcoholics, there is increasing awareness that the
encephalopathy can occur in children and other
populations, such as pregnant women with hyper-
emesis gravidarum.
Wernicke’s encephalopathy often occurs in con-
junction with a characteristic amnestic psychosis,
Korsakoff’s syndrome. Indeed, the two are believed
not to represent distinct clinical events but distinct
parts of a complex neuropsychiatric syndrome
termed Wernicke–Korsakoff syndrome. Wernicke’s
encephalopathy features a characteristic progression
of neurological symptoms and signs that may aid in
its recognition, including vomiting and nystagmus
(often horizontal but sometimes vertical), followed
by unilateral or bilateral ophthalmoplegia and
subsequent improvement of nystagmus. Ataxia and
progressive mental deterioration follow, culminating
in coma and death. Intertwined with these neurolo-
gical signs and symptoms is a dramatic amnestic–
confabulatory mental state known as the Korsakoff
syndrome; these patients have a remarkable inability
to lay down new memory. The Wernicke–Korsakoff
syndrome is much more widely described in adults,
especially alcoholics, than children, but several
clinical scenarios might predispose an older child to
this serious condition, including malignancy, anor-
exia nervosa, and hemodialysis. Treatment consists
of the parenteral administration of 50–100 mg of
thiamine followed by glucose. It has been a
consistent observation that administration of glucose
to thiamine-depleted patients, even those asympto-
matic, results in a worsening in clinical state. Despite
treatment, residual neurological symptoms and signs
may remain in the majority of patients.
—Rosario R. Trifiletti
See also–Thiamine (Vitamin B1); Neuropathies,
Nutritional; Wernicke’s Encephalopathy
Further Reading
Decker, M. J., and Isaacman, D. J. (2000). A common cause of
altered mental status occurring at an uncommon age. Pediatr.
Emerg. Care 16, 94–96.
Gardian, G. (1999). Wernicke’s encephalopathy induced by
hyperemesis gravidarum. Acta Neurol. Scand. 99, 196–198.
Heridas, L. (1947). Infantile berri-berri in Singapore. Arch. Dis.
Child. 22, 23.
Linden, M. C. (1991). Nutritional Biochemistry and Metabolism.
Elsevier, New York.
McCandless, D. W., and Schenker, S. (1968). Encephalopathy of
thiamine deficiency: Studies of intracerebral mechanisms.
J. Clin. Invest. 47, 2268.
380 BERI-BERI
See also–Antianxiety Pharmacology; Anxiety
Disorders, Overview; Endozepines and Coma;
Gamma Aminobutyric Acid (GABA); Insomnia
Further Reading
Adams, R. D., Victor, M., and Ropper, A. H. (1997). Epilepsy and
other seizure disorders. Principles of Neurology—Sixth Edition,
pp. 313–343. McGraw-Hill, New York.
Ballenger, J. C. (2000). Benzodiazepine receptor agonists and
antagonists. In Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry VII (B. J. Sadock and V. A. Sadock, Eds.), pp. 2317–
2324. Lippincott Williams & Wilkins, Philadelphia.
Hyman, S. E., Arana, G. W., and Rosenbaum, J. F. (1995).
Handbook of Psychiatric Drug Therapy. Little, Brown, Boston.
Kaplan, H. I., and Sadock, B. J. (1996). Pocket Handbook of
Psychiatric Drug Treatment. Williams & Wilkins, Baltimore.
Nordli, D. R., Jr., and Pedley, T. A. (2000). Febrile seizures/
neonatal seizures. In Merritt’s Neurology—Tenth Edition (L. P.
Rowland, Ed.), pp. 833–836. Lippincott Williams & Wilkins,
Philadelphia.
Reiman, E. M. (1997). Anxiety. In The Practitioner’s Guide to
Psychoactive Drugs (A. J. Gelenberg and E. L. Bassuk, Eds.),
pp. 229–242. Plenum, New York.
Waxham, M. N. (1999). Neurotransmitter receptors. In Funda-
mental Neuroscience (M. J. Zigmond and F. E. Bloom, et al.,
Eds.), pp. 235–263. Academic Press, San Diego.
Beri-Beri
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN OLDER CHILDREN and adults, thiamine deficiency
in its fully blown form results in beri-beri, a serious
illness that includes severe and sometimes fatal
cardiovascular and/or neurological manifestations.
Traditionally, this disease has been categorized as
wet beri-beri, in which cardiovascular symptoms and
signs predominate, or dry beri-beri, in which
neurological symptoms and signs predominate. In
reality, most patients have involvement of both
systems, so the wet/dry terminology is no longer
widely used. Beri-beri heart disease leads to high-
output cardiac failure, with low peripheral resis-
tance; cerebral blood flow may be decreased,
however. There is also an acute fulminant form in
which cardiovascular collapse can occur, with death
occurring within hours to days. Administration of
thiamine typically restores peripheral vascular resis-
tance more rapidly than myocardial contractility, so
high-output failure may be converted to low-output
failure before resolution occurs.
Neurological manifestations have been variously
termed cerebral beri-beri or, more commonly, Wer-
nicke’s encephalopathy. Although Wernicke’s ence-
phalopathy has been classically described in adult
alcoholics, there is increasing awareness that the
encephalopathy can occur in children and other
populations, such as pregnant women with hyper-
emesis gravidarum.
Wernicke’s encephalopathy often occurs in con-
junction with a characteristic amnestic psychosis,
Korsakoff’s syndrome. Indeed, the two are believed
not to represent distinct clinical events but distinct
parts of a complex neuropsychiatric syndrome
termed Wernicke–Korsakoff syndrome. Wernicke’s
encephalopathy features a characteristic progression
of neurological symptoms and signs that may aid in
its recognition, including vomiting and nystagmus
(often horizontal but sometimes vertical), followed
by unilateral or bilateral ophthalmoplegia and
subsequent improvement of nystagmus. Ataxia and
progressive mental deterioration follow, culminating
in coma and death. Intertwined with these neurolo-
gical signs and symptoms is a dramatic amnestic–
confabulatory mental state known as the Korsakoff
syndrome; these patients have a remarkable inability
to lay down new memory. The Wernicke–Korsakoff
syndrome is much more widely described in adults,
especially alcoholics, than children, but several
clinical scenarios might predispose an older child to
this serious condition, including malignancy, anor-
exia nervosa, and hemodialysis. Treatment consists
of the parenteral administration of 50–100 mg of
thiamine followed by glucose. It has been a
consistent observation that administration of glucose
to thiamine-depleted patients, even those asympto-
matic, results in a worsening in clinical state. Despite
treatment, residual neurological symptoms and signs
may remain in the majority of patients.
—Rosario R. Trifiletti
See also–Thiamine (Vitamin B1); Neuropathies,
Nutritional; Wernicke’s Encephalopathy
Further Reading
Decker, M. J., and Isaacman, D. J. (2000). A common cause of
altered mental status occurring at an uncommon age. Pediatr.
Emerg. Care 16, 94–96.
Gardian, G. (1999). Wernicke’s encephalopathy induced by
hyperemesis gravidarum. Acta Neurol. Scand. 99, 196–198.
Heridas, L. (1947). Infantile berri-berri in Singapore. Arch. Dis.
Child. 22, 23.
Linden, M. C. (1991). Nutritional Biochemistry and Metabolism.
Elsevier, New York.
McCandless, D. W., and Schenker, S. (1968). Encephalopathy of
thiamine deficiency: Studies of intracerebral mechanisms.
J. Clin. Invest. 47, 2268.
 BETZ CELLS 381

Meyers, C. C., Schochet, S. S., Jr., and McCormick, W. F. (1978).

Wernicke’s encephalopathy in infancy: Development during
parenteral nutrition. Acta Neuropathol. 43, 267.
Miyajima, Y., Fukuda, M., and Kojima, S. (1993). Wernicke’s
encephalopathy in a child with acute lymphoblastic leukemia.
Am. J. Pediatr. Hematol. Oncol. 15, 331.
Seear, M. D., and Norman, M. G. (1988). Two cases of Wernicke’s
encephalopathy in children: An under-diagnosed complication
of poor nutrition. Ann. Neurol. 24, 85.
Valyasevi, A. (1978). Infantile berri-berri. In Diseases of Children
in the Sub-tropics and Tropics (D. V. Jeliffe and J. P. Sternfield,
Eds.). Arnold, London.
Vasconcelos, M. M. (1999). Early diagnosis of pediatric Wer-
nicke’s encephalopathy. Pediatr. Neurol. 20, 289–294.
Victor, M. (1990). MR in the diagnosis of Wernicke–Korsakoff
syndrome. AJR Am. J. Roentgenol. 155, 1315–1316.

Bethlem Myopathy
see Muscular Dystrophy: Emery-Dreifuss,
Facioscapulohumeral, Scapuloperoneal, and
Bethlem Myopathy

Betz Cells
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

THE GIANT pyramidal neurons of Betz, first described

in 1874, are unique to the primary motor cortex and
define Brodmann’s cytoarchitectonic area 4, located
on the precentral gyrus. They are characterized by
their extraordinary size (up to 120 mm in height) and
thus are easily recognizable in Nissl-stained sections
(Fig. 1). Betz cells are located in layer V; they do not
form a compact layer but are rather isolated or
arranged in small clusters. The axons of Betz cells
form part of the pyramidal tract; however, the
approximately 25,000 Betz cells in the human motor
cortex are not the only source of pyramidal tract
fibers, although certainly they are the most conspic-
uous one. Somatosensory input from area 2 is
relayed to Betz cells through corticocortical fibers
from layers II and III of the motor cortex.
In addition to their outstanding size, Betz cells are
characterized by their peculiar basal dendrites, also
termed circumferential dendrites because they arise
along the entire circumference of the soma (Fig. 2).
Circumferential dendrites are extremely long; they
extend over several hundred micrometers in a
horizontal or obliquely descending direction and
Figure 1
Layer V of human primary motor cortex with giant Betz cells
(Nissl stain).
may even reach up to 1 or 2 mm. Atypical
morphological varieties are not uncommon. Exam-
ples are bipolar Betz cells, which are particularly
numerous at the crown of the precentral gyrus; in
addition to several circumferential dendrites, they
have a long, thick, root-like basal dendrite that enters
the white matter. Since the apical dendrite extends
into layer I, the dendritic territory of Betz cells spans
the entire cortical width. The density of dendritic
spines of Betz cells is extraordinary variable, and
Betz cells may display in this aspect a larger degree of
individuality than other pyramidal cells. The pleo-
morphism of Betz cells is a factor to be taken into
account when examining pathological tissue because
deviations from a standard morphology may express
the wide range of normal variations rather than a
pathological alteration.
 BETZ CELLS 381

Meyers, C. C., Schochet, S. S., Jr., and McCormick, W. F. (1978).

Wernicke’s encephalopathy in infancy: Development during
parenteral nutrition. Acta Neuropathol. 43, 267.
Miyajima, Y., Fukuda, M., and Kojima, S. (1993). Wernicke’s
encephalopathy in a child with acute lymphoblastic leukemia.
Am. J. Pediatr. Hematol. Oncol. 15, 331.
Seear, M. D., and Norman, M. G. (1988). Two cases of Wernicke’s
encephalopathy in children: An under-diagnosed complication
of poor nutrition. Ann. Neurol. 24, 85.
Valyasevi, A. (1978). Infantile berri-berri. In Diseases of Children
in the Sub-tropics and Tropics (D. V. Jeliffe and J. P. Sternfield,
Eds.). Arnold, London.
Vasconcelos, M. M. (1999). Early diagnosis of pediatric Wer-
nicke’s encephalopathy. Pediatr. Neurol. 20, 289–294.
Victor, M. (1990). MR in the diagnosis of Wernicke–Korsakoff
syndrome. AJR Am. J. Roentgenol. 155, 1315–1316.

Bethlem Myopathy
see Muscular Dystrophy: Emery-Dreifuss,
Facioscapulohumeral, Scapuloperoneal, and
Bethlem Myopathy

Betz Cells
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

THE GIANT pyramidal neurons of Betz, first described

in 1874, are unique to the primary motor cortex and
define Brodmann’s cytoarchitectonic area 4, located
on the precentral gyrus. They are characterized by
their extraordinary size (up to 120 mm in height) and
thus are easily recognizable in Nissl-stained sections
(Fig. 1). Betz cells are located in layer V; they do not
form a compact layer but are rather isolated or
arranged in small clusters. The axons of Betz cells
form part of the pyramidal tract; however, the
approximately 25,000 Betz cells in the human motor
cortex are not the only source of pyramidal tract
fibers, although certainly they are the most conspic-
uous one. Somatosensory input from area 2 is
relayed to Betz cells through corticocortical fibers
from layers II and III of the motor cortex.
In addition to their outstanding size, Betz cells are
characterized by their peculiar basal dendrites, also
termed circumferential dendrites because they arise
along the entire circumference of the soma (Fig. 2).
Circumferential dendrites are extremely long; they
extend over several hundred micrometers in a
horizontal or obliquely descending direction and
Figure 1
Layer V of human primary motor cortex with giant Betz cells
(Nissl stain).
may even reach up to 1 or 2 mm. Atypical
morphological varieties are not uncommon. Exam-
ples are bipolar Betz cells, which are particularly
numerous at the crown of the precentral gyrus; in
addition to several circumferential dendrites, they
have a long, thick, root-like basal dendrite that enters
the white matter. Since the apical dendrite extends
into layer I, the dendritic territory of Betz cells spans
the entire cortical width. The density of dendritic
spines of Betz cells is extraordinary variable, and
Betz cells may display in this aspect a larger degree of
individuality than other pyramidal cells. The pleo-
morphism of Betz cells is a factor to be taken into
account when examining pathological tissue because
deviations from a standard morphology may express
the wide range of normal variations rather than a
pathological alteration.
382 BETZ CELLS
Figure 2
Betz cell and medium-sized pyramidal neurons (asterisks) of layer
V (Golgi method). Scale bar ¼ 50 mm.
Betz cells are not uniformly distributed throughout
area 4 but are more abundant in its dorsal region,
which contains the motor representation of the lower
part of the body. They are particularly numerous and
arranged in large clusters in the paracentral lobule.
More laterally, they disappear from the surface of the
precentral gyrus and become restricted to the
anterior wall and the bottom of the central sulcus.
NEUROCHEMISTRY OF BETZ CELLS
A large proportion of Betz cells and some smaller
pyramidal neurons in layers V and VI were reported
to express low to moderate levels of nitric oxide
synthase, which may have a neuroprotective role
and is normally not present in pyramidal cells.
Furthermore, Betz cells in primate motor cortex
express parvalbumin, a calcium-binding protein
usually described in interneurons. Almost all Betz
cells express acetylcholinesterase, which is also found
in many other pyramidal cells of layers III and V, and
they may thus represent a subgroup of cholinoceptive
cortical neurons. Another characteristic feature of
Betz cells is densely aggregated lipofuscin deposits
that increase with age.
BETZ CELLS IN MOTOR NEURON DISEASE
Betz cells are affected in a variety of motor neuron
diseases, such as primary lateral sclerosis, amyo-
trophic lateral sclerosis, multiple system atrophy,
lathyrism, and neurocassavism (Konzo), all of which
are characterized by the degeneration of descending
motor pathways. Although most forms of motor
neuron disease also involve the non-giant pyramidal
cell population of the motor cortex, pathological
changes are more readily detected in Betz cells. The
relationship between Betz cells and motor neuron
disease is particularly evident in the case of amyo-
trophic lateral sclerosis (ALS). In ALS, Betz cells
present ultrastructural signs of degeneration, such as
changes of presynaptic vesicles, conglomerates of dark
mitochondria, and fragmentation of the Golgi appa-
ratus. Most significant, in ALS inclusions of mutant
copper–zinc superoxide dismutase are found in the
perikarya, dendrites, and axons of both lower and
upper motor neurons, including Betz cells. Further
manifestations of ALS are aggregations in Betz cells of
nonphosphorylated neurofilaments and the presence
of Bunina bodies. Loss of Betz cells seems to be more
consistent in primary lateral sclerosis than in ALS.
The observations described previously not only are
important for understanding the pathomechanism of
ALS but also are essential for the proper evaluation
of experimental animal models of motor neuron
diseases.
—Gundela Meyer and Francisco Javier Carrillo-Padilla
See also–Amyotrophic Lateral Sclerosis (ALS);
Brodmann’s Areas; Motor Cortex
Further Reading
Economo, C. V., and Koskinas, G. N. (1925). Die Cytoarchitek-
tonik der Hirnrinde des erwachsenen Menschen. Springer-
Verlag, Berlin.
Kaneko, T., Caria, M. A., and Asanuma, H. (1994). Information
processing within the motor cortex. II. Intracortical connections
between neurons receiving somatosensory cortical input and
motor output neurons of the cortex. J. Comp. Neurol. 345,
172–184.
Meyer, G. (1987). Forms and spatial arrangement of neurons in the
primary motor cortex of man. J. Comp. Neurol. 262, 402–428.

Bilirubin
see Kernicterus
Bipolar Disorder
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BIPOLAR DISORDER, formerly called manic–depres-
sive disorder, is a chronic illness characterized by
impaired regulation of mood, including episodic
shifts into major depression, hypomania, mania,
and mixed mood states that dramatically impact
behavior and the capacity to function. Patients can
shift directly from one pole to another or have
extended periods of normal mood between episodes.
Bipolar disorder has a lifetime prevalence of 1.5%.
Patients with bipolar disorder have a lifetime suicide
attempt rate of 25–50% and a completed suicide rate
of 10–15%. Individual patients can present with a
predictable or unpredictable frequency and pattern
of cycling, often with psychiatric comorbidities that
complicate and delay diagnosis and impact treatment
algorithms. Many patients with bipolar disorder can
be very successful, driven by increased energy and
creativity that can be a prelude to frank mania and
major depression. The pathology, pathophysiology,
and etiology of bipolar disorder remain unknown.
Notably, the individual symptoms of the illness are
not unique to this syndrome. Familial associations
and overlap in symptoms between bipolar disorder
and other psychiatric disorders have led to extensive
research into hypothesized etiological links between
these disorders and ongoing debate about how best
to conceptualize bipolar disorder.
CLASSIFICATION
Diagnostic and Statistical Manual IV
The Diagnostic and Statistical Manual IV (DSM-IV)
organizes bipolar disorder in its various manifesta-
tions under the rubric of two distinct subtypes,
bipolar I and bipolar II disorder, as well as bipolar
disorder not otherwise specified and cyclothymic
disorder. A first manic episode or mixed mood state
not accounted for by another diagnosis and lasting at
least 1 week or leading to hospitalization is sufficient
criterion for a diagnosis of bipolar I disorder,
BIPOLAR DISORDER 383
regardless of the number of episodes of major
depression. Bipolar II disorder is characterized by
at least one hypomanic episode and one episode of
major depression but the absence of a history of
frank mania or a mixed mood episode. Rapid cycling
is a longitudinal specifier for either subtype referring
to a frequency of at least four shifts in mood polarity
in 1 year with either a 2-month interepisode recovery
or a clear shift to the opposite pole. Other long-
itudinal specifiers in the DSM-IV include a seasonal
component to the major depressive episodes and
whether or not there is interepisode recovery. Bipolar
disorder not otherwise specified refers to (i) those
patients who exhibit mood dysregulation in a pattern
not consistent with the previously mentioned sub-
types, such as recurrent hypomania without inter-
episode symptoms of depression; (ii) very rapid
alteration in mood from depressive to manic-like
symptoms that do not meet criteria for either mood
state; and (iii) episodic mood shifts in the setting of a
primary psychotic disorder such as schizophrenia.
Each mood state is characterized by a set of
symptoms. Patients with a major depressive episode
present with depressed mood and/or anhedonia as
well as vegetative symptoms, such as change in sleep
behavior, change in appetite, loss of energy, impaired
libido, and poor concentration. Patients with bipolar
disorder are more likely to develop symptoms of
hyperphagia and hypersomina during a major
depression, in contrast to the insomnia and loss of
appetite associated with unipolar, melancholic de-
pression. Debilitating feelings of worthlessness, ex-
cessive guilt, and suicidal thoughts are common.
Patients may notably withdraw from family and
friends and become irritable and rejection sensitive.
Psychosis can be a complicating factor. Severe
depression can lead to significant loss of functioning,
hopelessness, and suicide.
At the opposite pole, classic mania is characterized
by an elevated mood, increased energy and produc-
tivity, less need for sleep, pressured speech, rapid
shifts from one subject to another and back again
called ‘‘track jumping’’ (or flight of ideas), distract-
ibility, and increased engagement in pleasurable
activities irrespective of the dangers involved and
often out of character for the euthymic patient.
Although the elation and high energy of patients with
mania can be attractive to others initially, patients
suffering a loss of judgment, hypersexuality, and
impulsivity progressing to irritability, paranoia, and
aggression can drive away family and other social
supports and can engage in disastrous behaviors,
384 BIPOLAR DISORDER
such as incurring a large financial debt, engaging in
unprotected sex, and marrying impulsively. In its
severest form, manic episodes can include grandios-
ity, delusions, paranoid ideation, and auditory
hallucinations. Manic episodes can occur suddenly
and may be precipitated by psychosocial stressors. A
hypomanic episode is similar to a manic episode, but
it is less severe and without psychosis, a loss of social
functioning, or need for hospitalization. Finally, a
mixed episode refers to a mood state that meets
criteria for both mania and major depression daily
for at least 1 week, either at one time or alternating
over the course of a day. A mixed episode may be a
distinct entity or it may represent a transitional state
from mania to major depression or vice versa.
Although patients with bipolar depression are at
highest risk for suicide, the irritability, depressed
mood, and high energy in combination in a mixed
mood state are significant risk factors.
Reconceptualizing Bipolar Disorder
There is much discussion and debate on the issue of
reconceptualizing bipolar disorder and broadening
the diagnostic criteria to include subtler forms of
affective dysregulation and cyclical mood states. The
extension of bipolar disorder to include bipolar II
disorder is part of the decades-long trend to expand
the diagnosis. Proponents suggest that a too restric-
tive classification of bipolar disorder will lead to
missed diagnoses in patients with subtler presenta-
tions, such as patients with apparent unipolar
depression who are at high risk for bipolarity
because of a family history of bipolar disorder or
an early onset of depression as well as patients with
subtle signs of elevated mood who do not meet the
criteria for hypomania. The recent concern that
antidepressants may worsen the course of bipolar
disorder in the absence of prophylaxis with a mood
stabilizer has made this discussion more clinically
apropos. Others suggest that expanding the diag-
nostic criteria of bipolar disorder will dilute its
usefulness in research.
There does appear to be a growing consensus that
the DSM-IV criteria for a mixed episode are too
restrictive since symptoms of dysphoria, short of
meeting criteria for major depressive episode, are
often seen in mania. The presence of two symptoms
of depression during a manic episode has been
proposed as a distinct entity called dysphoric mania,
as contrasted with ‘‘euphoric mania.’’ Dysphoric
mania is often seen in the literature side by side with
mixed mood, and both are characterized by resis-
tance to treatment with lithium monotherapy.
EPIDEMIOLOGY
Bipolar I disorder has a lifetime prevalence of 0.8%,
and bipolar II disorder has a lifetime prevalence of
0.5%. The literature is variable about whether
women are more predisposed than men to develop
bipolar II disorder or are just more represented in
patient samples. A history of bipolar disorder in a
first-degree relative increases the risk of having the
disease. Other risk factors for bipolar disorder
include early onset of major depression and anti-
depressant-induced mania or hypomania. Age of
onset of the disease is usually before 25 years, often
in late adolescence and associated with a psychoso-
cial stressor. A first manic episode in later life is
usually secondary to other medical causes, such as
neurological disease, medication side effects, and
substance use.
DIAGNOSTIC ISSUES AND COMORBIDITY
Bipolar disorder is diagnosed on the basis of the
clinical presentation and history, including history of
frequency and pattern of mood disturbances, family
history, social history, medical history, psychiatric
history, and history of current and past substance
use. It is important in evaluating the patient to rule
out medical and substance-induced factors that may
secondarily present as any of the mood states
described. This includes doing appropriate blood
work and imaging, depending on the presentation.
Dramatic shifts in mood from one polarity to the
other can be seen in patients with substance use and
personality disorders, notably borderline personality
disorder. The impulsivity of mania is shared by those
disorders as well as the impulse control disorders and
attention deficit hyperactivity disorder (ADHD).
Notably, bipolar disorder is very difficult to diagnose
in childhood because it can appear to be ADHD,
conduct disorder, and depression in this population.
Psychosis and agitation of bipolar mania are
consistent with substance abuse, schizophrenia,
delusional disorders, and psychosis not otherwise
specified. Similarly, a mixed mood state may need to
be differentiated from an agitated depression.
The lifetime prevalence of substance abuse is 60%
in patients with bipolar disorder, higher in men than
in women, and predominantly takes the form of
alcohol abuse. Patients with substance abuse can be

impulsive, agitated, manic appearing, psychotic, and
depressed either under the influence of the substance
or in withdrawal. A history of bipolar disorder
symptoms during an extended period of sobriety or
an extended period of abstinence after the initial
presentation may be needed to make a clear
diagnosis. A structured substance abuse history can
help elucidate which disorder is primary. The CAGE
questionnaire can be a valuable office screen, both as
a diagnostic tool and as a vehicle for discussing
substance abuse with a patient. A positive response
to two of the four questions about alcohol use is
strongly suggestive of an alcohol problem. Substance
abuse is associated with poor adherence to treat-
ment, poor response to treatment, a more severe
course of illness, and greater likelihood of mixed
mood states or dysphoric mania.
Reasons for the high rate of comorbidity with
substance abuse are not clear. It has been theorized
that both bipolar disorder and substance abuse are
based on a common etiological element. For exam-
ple, poor impulse control is a common trait,
suggestive of a common genetic link. Another
possibility is that patients with substance abuse are
susceptible to receiving the diagnosis of bipolar
disorder based on recurring symptoms of mood
dysregulation under the influence of the substances.
Alternatively, substance abuse may be a complication
of bipolar disorder. Certainly, patients with bipolar
disorder may be more susceptible to substance use in
episodic mood states, for example, when feeling more
impulsive and exhibiting uncharacteristic behavior. It
is not uncommon for patients with mood disorders to
attempt to treat their symptoms with illicit sub-
stances. In some patients, treatment of the bipolar
disorder may lead to significant reduction in sub-
stance abuse. Patients with primary substance abuse
may need specialized substance abuse treatment.
There is an increased frequency of obsessive–
compulsive disorder (OCD) and panic disorder in
patients with bipolar disorder. There is an increased
incidence of OCD in families of patients with bipolar
disorder. For patients with comorbid anxiety, pre-
scribing an antidepressant can be contraindicated,
given the possibility of destabilizing mood. Never-
theless, comorbid diagnoses need to be aggressively
treated concomitant with treatment for the bipolar
disorder. Treatment with a mood stabilizer prior to
prescribing an SSRI may be indicated. Valproic acid
is a treatment for panic disorder that is also
efficacious for the mood disturbance. An overlap in
symptoms and an increased rate of ADHD in
BIPOLAR DISORDER 385
patients with bipolar disorder has led to interest in
the possibility of a genetic relationship between the
two disorders and raises complex diagnostic and
treatment issues. Nevertheless, ADHD is often
diagnostically elusive. Further genetic and diagnos-
tically acute measures may be required to confidently
characterize the disorders with respect to each other
and determine the effects of comorbidity on disease
course and treatment.
PRECIPITANTS AND DISEASE COURSE
Precipitants of an episode of bipolar disorder include
stressful life events, anniversaries of stressful events,
poor compliance with treatment, sudden withdrawal
of mood-stabilizing drugs, substance abuse, antide-
pressants in the absence of mood-stabilizing medica-
tions, and changes in sleep habits. Typical onset of
bipolar disorder occurs in late adolescence or early
adulthood. Childhood or adolescent onset is asso-
ciated with a more severe course and more episodes
of mood disturbance. Men are more likely than
women to present with mania as a first expression of
bipolar I disorder and to have more manic episodes
during the course of the disease. Patients with a
manic episode have a 90% chance of recurrence. Up
to 70% of episodes of mania occur in close
association with a depressive episode. Early episodes
of bipolar disorder tend to occur less frequently than
later episodes, often 3 or 4 years apart. Patients who
are well treated can continue for several years
without recurrence. Theories regarding the tendency
for increasing frequency of episodes over the course
of the illness range from neurological kindling to
undertreatment of early episodes leading to a more
severe disease process. Kindling refers to the low-
ering of the threshold of response to a stimulus
through repeated subthreshold stimulation. Accord-
ing to the kindling theory, early episodes of bipolar
disorder may be triggered by environmental factors;
however, later episodes may be spontaneous. Un-
treated, manic and hypomanic episodes may last for
days to months. Major depressive episodes can last
from weeks to years. Alternatively, rapid and
ultrarapid cycling can include a frequency of mood
shifts from weeks to days. Patients who exhibit a
pattern of mania followed by depression may be
more treatable. Patients with bipolar II disorder who
exhibit a depression to hypomania pattern tend to
experience more depression.
Rapid cycling is more common in women and
occurs more frequently in bipolar II disorder. It has a
386 BIPOLAR DISORDER
high rate of morbidity, can lead to significant loss of
functioning, and is distinguished by relative refrac-
toriness to treatment with lithium (36 vs 70–80%).
Rapid cycling may be a transient feature of bipolar
illness in a patient or represent a more severe form of
the illness. It can develop early or late in the disease
process. Its etiology is unknown; however, low levels
of thyroid hormone have been posited as a possible
factor. Evidence includes a finding that patients with
rapid cycling are more likely to have clinical or
subclinical hypothyroidism. Antidepressant use may
have a role in inducing a rapid cycling course.
TREATMENT
The treatment of bipolar disorder is complicated by
the multiplicity of presentations and comorbid
diagnoses. Recent efforts in the field have resulted
in algorithms for psychopharmacological treatment
based on evidence in the literature and expert
opinion. Nonmedical treatments have an important
adjuvant role in the treatment of bipolar disorder.
Pharmacological
The first-line treatment of acute mania is a mood
stabilizer, either lithium or divalproex sodium.
Divalproex can be more rapidly titrated than lithium,
which may be an advantage in acute mania.
Divalproex is better tolerated than valproic acid.
For mixed mood and rapid cycling with mania,
characterized by resistance to treatment by lithium,
divalproex remains the treatment of choice. Adju-
vant treatment may be utilized to help calm patients
and provide necessary sleep and containment.
Benzodiazepines, particularly clonazepam, have anti-
manic properties. Additionally, typical antipsycho-
tics, such as haldoperidol, in low doses have been
shown to have efficacy acutely for both psychotic
symptoms of mania and acute agitation. Atypical
antipsychotics, most notably olanzapine, have
recently been shown to have mood-stabilizing
properties and are preferable to the typical anti-
psychotics because of decreased risk of extrapyrami-
dal and other side effects. In acute mania, alternative
second-line treatment may include combining mood
stabilizers, lithium and divalproex, or, as an alter-
native, a combination of either with carbamazepine.
Among the new anticonvulsants, there is evidence of
good efficacy for lamotrigine in treating bipolar
depression. Lamotrigine is associated with Stephens–
Johnson syndrome, and slow titration of lamotrigine
is indicated to minimize risk of a rash. Topiramate is
less well-studied at this time, but may have some
efficacy in bipolar disorder. In treating depression in
a patient with rapid cycling, the use of two mood
stabilizers prior to using an antidepressant may be
indicated given the potential etiological link between
antidepressant use and this form of the disease.
Exogenous thyroid hormone, either T3 or T4, at a
dose sufficient to produce supranormal blood levels
of T3 has been examined as a treatment for
refractory bipolar disorder, rapid cycling.
Electroconvulsive therapy remains a relatively safe
and effective mainstay of treatment of bipolar
disorder in pregnant patients, patients who cannot
tolerate the side effects of medications, and those
refractory to medication treatment.
Nonpharmacological
Education is the mainstay of nonmedical, supportive
treatment of patients with bipolar disorder. Ensuring
a stable sleep pattern, abstinence from substance use,
and medication adherence is of primary importance.
Helping patients understand their disease processes
and teaching patients to appreciate early signs of a
mood shift, such as a reduced need for sleep and
increased goal-directed activity, can help prevent
recurrence. In addition, specific, manualized treat-
ments for bipolar disorder, such as cognitive–
behavioral therapies and a variant of interpersonal
therapy called interpersonal and social rhythm
therapy, may help patients identify behaviors and
situations that might predispose them to recurrence
and implement behavioral and coping strategies to
better manage these stresses.
—Jonathan E. Lichtmacher
See also–Borderline Personality Disorder;
Depression; Lithium Carbonate; Mania; Mood
Disorders, Biology; Mood Disorders, Treatment;
Mood Stabilizer Pharmacology; Obsessive-
Compulsive Disorders; Panic Disorders
Acknowledgments
I thank L. Alison McInnes, M.D., M.S., Assistant Adjunct
Professor of Psychiatry, University of California, San Francisco,
for her assistance in the preparation of this entry.
Further Reading
Akiskal, H. S. (1996). The prevalent clinical spectrum of bipolar
disorders: beyond DSM IV. J. Clin. Psychpharmocol. 16,
4S–14S.

Feske, U., Frank, E., Mallinger, A. G., et al. (2000). Anxiety as a
correlate of response to the acute treatment of bipolar I
disorder. Am. J. Psychiatry 157, 956–962.
Ghaemi, S. N., Sachs, G. S., Chiou, A. M., et al. (1999). Is bipolar
disorder still underdiagnosed? Are antidepressants overutilized?
J. Affect. Disord. 52, 135–144.
Jamison, K. R. (1995). An Unquiet Mind. Vintage Books, New York.
Leibenluft, E., and Suppes, T. (1999). Treating bipolar illness:
Focus on treatment algorithms and management of the sleep
wake cycle. Am. J. Psychiatry 156, 1976–1979.
Malkoff-Schwartz, S., Frank, E., Anderson, B., et al. (1998).
Stressful life events and social rhythm disruption in the onset of
manic and depressive bipolar episodes: A preliminary investiga-
tion. Arch. Gen. Psychiatry 55, 702–707.
Sachs, G. S., Printz, D. J., Kahn, D. A., et al. (2000). The expert
consensus guideline series: Medication treatment of bipolar
disorder [Special report]. Postgrad. Med., 1–104.
Sonne, S. C., and Brady, K. T. (1999). Substance abuse and bipolar
comorbidity. Psychiatry Clin. North Am. 22, 609–627.
Bladder Control
see Micturation
Bladder Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
LOWER urinary tract dysfunction is very common in
neurological disease and can manifest as urinary
frequency, urgency, incontinence (stress, urge, over-
flow, and total), hesitancy initiating urination,
nocturia, incomplete bladder emptying, and urinary
retention. Urodynamic testing, a procedure combin-
ing cystometry, fluoroscopy, and urethral sphincter
electromyography, can reveal various bladder dis-
orders that may or may not correspond with the
patient’s symptomatology. For a given individual
with a particular neuropathic process, any combina-
tion of the following urodynamic findings can occur:
1. Decreased sensation: With neurological dis-
eases of the peripheral nerves or spinal cord, there
can be a resultant loss of sensation from the bladder.
As a result, there is inadequate afferent input to the
supraspinal centers regulating bladder function to
initiate a strong detrusor contraction. The patient
may not be aware of the sensory loss, and there may
be a gradual increase in post-void residual volumes
until the patient reaches urinary retention.
BLADDER DISORDERS 387
2. Hyperreflexia: This occurs when the bladder
loses the cerebrocortical inhibition that normally
exists to prevent bladder contractions. The bladder
usually does not contract unless it is full and when it
is socially acceptable to urinate. Hyperreflexia is
manifested by urinary frequency, urgency, and urge
incontinence. Unwanted detrusor contractions in the
absence of an identifiable neurological disorder are
termed detrusor instability and may be seen with
urinary tract infections and bladder outlet obstruc-
tion.
3. Hypocontractility: Loss of detrusor contracti-
lity can be due to a loss of innervation or a primary
muscular disorder (rare). In sensory loss, the brain
does not recognize that the bladder is full, so the
detrusor reflex cannot activate and the bladder does
not contract. In motor denervation, the efferent
message to the endorgan is diminished or lost.
Hypocontractility in its most severe form results in
detrusor areflexia. Patients with hypocontractility
may feel that their bladder does not empty com-
pletely or may experience urinary hesitancy.
4. Poor compliance: The bladder loses its com-
pliance (its capacity to store increasing volumes at
low pressure) when the bladder wall loses its elastic
properties. This can occur as a result of neurological
injury, typically occurring after many years of
‘‘decentralization’’ (loss of central nervous system
regulation as opposed to peripheral denervation) or
after prolonged periods of recurring inflammation or
infection that result in bladder wall fibrosis. Poor
detrusor compliance is deleterious to renal function,
as the high pressures within the bladder obstruct
urine flow from the kidneys or cause vesicoureteral
reflux. Renal insufficiency can result from prolonged
periods of low compliance. Symptomatically, the
patient may have urinary urgency, frequency, and
urge or total incontinence.
5. Sphincteric dysfunction: Sphincteric dysfunc-
tion can occur at either the internal bladder neck
sphincter or the external sphincter. In certain
neurological diseases, sphincters can become dyssy-
nergic (i.e., contracting at the same time the bladder
contracts), resulting in bladder outlet obstruction.
This commonly occurs in multiple sclerosis and
spinal cord lesions above the level of the conus.
The patient may report hesitancy, interrupted urinary
stream, or incomplete bladder emptying. Internal
sphincteric denervation occurs with lesions at
T10–T12, with a resultant open bladder neck.
External sphincter denervation occurs with lesions
of the conus or lesions of the pudendal nerve. There

Feske, U., Frank, E., Mallinger, A. G., et al. (2000). Anxiety as a
correlate of response to the acute treatment of bipolar I
disorder. Am. J. Psychiatry 157, 956–962.
Ghaemi, S. N., Sachs, G. S., Chiou, A. M., et al. (1999). Is bipolar
disorder still underdiagnosed? Are antidepressants overutilized?
J. Affect. Disord. 52, 135–144.
Jamison, K. R. (1995). An Unquiet Mind. Vintage Books, New York.
Leibenluft, E., and Suppes, T. (1999). Treating bipolar illness:
Focus on treatment algorithms and management of the sleep
wake cycle. Am. J. Psychiatry 156, 1976–1979.
Malkoff-Schwartz, S., Frank, E., Anderson, B., et al. (1998).
Stressful life events and social rhythm disruption in the onset of
manic and depressive bipolar episodes: A preliminary investiga-
tion. Arch. Gen. Psychiatry 55, 702–707.
Sachs, G. S., Printz, D. J., Kahn, D. A., et al. (2000). The expert
consensus guideline series: Medication treatment of bipolar
disorder [Special report]. Postgrad. Med., 1–104.
Sonne, S. C., and Brady, K. T. (1999). Substance abuse and bipolar
comorbidity. Psychiatry Clin. North Am. 22, 609–627.
Bladder Control
see Micturation
Bladder Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
LOWER urinary tract dysfunction is very common in
neurological disease and can manifest as urinary
frequency, urgency, incontinence (stress, urge, over-
flow, and total), hesitancy initiating urination,
nocturia, incomplete bladder emptying, and urinary
retention. Urodynamic testing, a procedure combin-
ing cystometry, fluoroscopy, and urethral sphincter
electromyography, can reveal various bladder dis-
orders that may or may not correspond with the
patient’s symptomatology. For a given individual
with a particular neuropathic process, any combina-
tion of the following urodynamic findings can occur:
1. Decreased sensation: With neurological dis-
eases of the peripheral nerves or spinal cord, there
can be a resultant loss of sensation from the bladder.
As a result, there is inadequate afferent input to the
supraspinal centers regulating bladder function to
initiate a strong detrusor contraction. The patient
may not be aware of the sensory loss, and there may
be a gradual increase in post-void residual volumes
until the patient reaches urinary retention.
BLADDER DISORDERS 387
2. Hyperreflexia: This occurs when the bladder
loses the cerebrocortical inhibition that normally
exists to prevent bladder contractions. The bladder
usually does not contract unless it is full and when it
is socially acceptable to urinate. Hyperreflexia is
manifested by urinary frequency, urgency, and urge
incontinence. Unwanted detrusor contractions in the
absence of an identifiable neurological disorder are
termed detrusor instability and may be seen with
urinary tract infections and bladder outlet obstruc-
tion.
3. Hypocontractility: Loss of detrusor contracti-
lity can be due to a loss of innervation or a primary
muscular disorder (rare). In sensory loss, the brain
does not recognize that the bladder is full, so the
detrusor reflex cannot activate and the bladder does
not contract. In motor denervation, the efferent
message to the endorgan is diminished or lost.
Hypocontractility in its most severe form results in
detrusor areflexia. Patients with hypocontractility
may feel that their bladder does not empty com-
pletely or may experience urinary hesitancy.
4. Poor compliance: The bladder loses its com-
pliance (its capacity to store increasing volumes at
low pressure) when the bladder wall loses its elastic
properties. This can occur as a result of neurological
injury, typically occurring after many years of
‘‘decentralization’’ (loss of central nervous system
regulation as opposed to peripheral denervation) or
after prolonged periods of recurring inflammation or
infection that result in bladder wall fibrosis. Poor
detrusor compliance is deleterious to renal function,
as the high pressures within the bladder obstruct
urine flow from the kidneys or cause vesicoureteral
reflux. Renal insufficiency can result from prolonged
periods of low compliance. Symptomatically, the
patient may have urinary urgency, frequency, and
urge or total incontinence.
5. Sphincteric dysfunction: Sphincteric dysfunc-
tion can occur at either the internal bladder neck
sphincter or the external sphincter. In certain
neurological diseases, sphincters can become dyssy-
nergic (i.e., contracting at the same time the bladder
contracts), resulting in bladder outlet obstruction.
This commonly occurs in multiple sclerosis and
spinal cord lesions above the level of the conus.
The patient may report hesitancy, interrupted urinary
stream, or incomplete bladder emptying. Internal
sphincteric denervation occurs with lesions at
T10–T12, with a resultant open bladder neck.
External sphincter denervation occurs with lesions
of the conus or lesions of the pudendal nerve. There
388 BLADDER DISORDERS
can also be intrinsic sphincteric dysfunction (ISD),
which is a result of previous injury (including obstetric
trauma) or operations in the area of the bladder neck
or external sphincter, which have resulted in scarring
and denervation of these structures. ISD invariably
will result in stress or total incontinence.
6. Outlet obstruction: Mechanical obstruction of
the bladder outlet and urethra, particularly in older
men as a result of prostatic hyperplasia, can
aggravate urinary symptoms in the face of neurolo-
gical disease. Often, urodynamic testing is necessary
to differentiate symptoms due to prostatic obstruc-
tion (which is easily treated) from symptoms due to
neurological bladder dysfunction. Symptoms of
obstruction include urinary hesitancy, slow urine
stream, and a sensation of incomplete bladder
emptying. Bladder outlet obstruction can occur in
women, but it is an uncommon cause of bladder
dysfunction.
BLADDER DYSFUNCTION IN
NEUROLOGICAL DISEASE
Neurological diseases can affect lower urinary
function in predictable patterns, depending on the
location of the neuropathology. Lesions above the
brainstem, where the pontine micturition center is
located, typically result in detrusor hyperreflexia,
and the sphincters are coordinated with voiding.
Patients with complete spinal cord injuries above the
level of the sacral cord have detrusor hyperreflexia,
detrusor hypocontractility, a variable degree of
sphincter dyssynergia, and loss of bladder sensation.
Pathology at the level of the sacral spinal cord and/or
peripheral nerves results in loss of bladder sensation,
with impaired motor function as well. Although
these patterns are typical for the diseases mentioned
later, each patient should be considered individually
because there may be multiple concurrent factors
causing bladder dysfunction. Vaginal parity and
hormonal changes with menopause may exacerbate
bladder dysfunction in women with neurological
disease.
Diseases of the Brain
Infarction of the frontal cortex or its pathways
subserving control of the urinary bladder results in
detrusor hyperreflexia. Patients complain of fre-
quency, nocturia, urgency, and urge incontinence.
The sphincters are coordinated with the contrac-
tions, so it is uncommon to find urinary retention
unless there is a concurrent peripheral bladder deficit
or obstructing prostate. Bladder dysfunction can also
be seen in patients with brain tumors in the super-
omedial portion of the frontal lobe, although
disorders of micturition are rarely initial symptoms
of brain tumors. The incidence of bladder dysfunc-
tion in Parkinson’s disease is high, ranging from 25 to
85%. The resultant bladder symptoms are the same
as in cerebrovascular disease. Some may not be able
to empty their bladders completely due to the
anticholinergic activity of anti-parkinsonian medica-
tions. The precise frequency of urinary bladder
dysfunction in dementia patients is unknown. Ur-
inary incontinence is typically a late manifestation of
the disease and may be the result of the patient’s
inability to acknowledge the need for social con-
tinence. Medications, patient immobility, and in-
attentiveness to bladder management by caretakers
may exacerbate bladder dysfunction.
Diseases of the Spinal Cord
In the initial spinal shock phase of injury, there is
urinary retention and detrusor areflexia. With
recovery of reflex function, one of several voiding
patterns may develop. Spinal cord injury (SCI) above
the level of the sacral cord typically results in
detrusor hyperreflexia, hypocontractility, and vari-
able levels of internal and external sphincter dyssy-
nergia. These persons have symptoms of frequency
and urgency (if bladder sensation is intact), incon-
tinence (stress, urge, and total), interrupted stream,
and incomplete bladder emptying. The severity of the
injury and the degree of urinary tract dysfunction are
interrelated, but the correlation between neurologi-
cal findings on physical examination and urodynamic
testing in SCI patients is not exact. A complete spinal
injury at a particular neurological level is based on
sensory and motor findings and does not necessarily
translate into a complete autonomic lesion at that
level. The same consideration can be made for
incomplete lesions. In addition, multiple injuries
may exist at different levels, even though the
sensorimotor findings on physical exam reflect a
single level of injury. Thus, management of the
urinary tract must be based on urodynamic principles
and findings.
Patients with SCI are at risk for developing a
poorly compliant bladder, with high detrusor
pressures. Elevated detrusor pressures may lead to
upper urinary tract deterioration, particularly if the
pressure at which the bladder is emptied or when
bladder leakage occurs (‘‘leak point pressure’’) is
440 cm H2O.

Autonomic dysreflexia is a symptom complex
resulting from noxious stimuli below the level of
the spinal injury. A common source of the stimuli
arises from the bladder (e.g., urinary retention,
traumatic catheter insertion, cystometry, or an
obstructed catheter). The basic mechanism is a
diffuse activation of viscero- or somatosympathetic
reflexes triggered by the stimuli, without the usual
supraspinal modulation of the sympathetic response.
The patient may experience an acute, rapid increase
in blood pressure, headache, sweating above the level
of the spinal injury, piloerection, nausea, anxiety, and
visual disturbance. The hypertension may become so
severe as to result in intracranial or subarachnoid
hemorrhage or cardiac arrhythmias. The first line of
management involves removal of the offensive
stimulus, which includes placement or changing of
a bladder catheter or aborting a cystometrogram.
Pharmacological prophylaxis against autonomic
dysreflexia can be administered prior to a noxious
procedure, such as a cystometrogram or cystoscopy.
Medications include nitroglycerine paste, oral alpha-
adrenergic blocking drugs, and sublingual nifedipine.
Myelodysplasia is primarily a pediatric problem,
but most of the affected children are now reaching
adulthood. Adult myelodysplastic patients typically
have an areflexic bladder with an open bladder neck,
which results in incontinence, urinary retention, or
both. External sphincter dyssynergia can also be a
problem. Many of these persons will have had
operations on their urinary tracts as children or
young adults.
Diseases of the Brain and Spinal Cord
The most common disease in this category is multiple
sclerosis (MS). Because demyelination can occur
anywhere in the central nervous system, no single
pattern of bladder dysfunction can be found in MS
patients. Detrusor hyperreflexia, detrusor hypocon-
tractility or areflexia, detrusor sphincter dyssynergia,
poor bladder sensation, and poorly compliant
bladders are found in MS. MS patients complain of
frequency, urgency, urge incontinence, interrupted
stream, hesitancy, nocturia, and incomplete bladder
emptying. These symptoms can sometimes be the
initial manifestation of the disease.
Diseases of Conus, Cauda Equina, and
Peripheral Nerves
These are diseases that result in a ‘‘lower motor
neuron’’-type bladder, one that has impaired sensa-
tion and flaccid motor function. Examples of the
BLEPHAROSPASM 389
diseases are autonomic neuropathy, traumatic injury,
lumbar spinal stenosis, sacral agenesis, myelodyspla-
sia, herpes zoster, cauda equina tumors, spinal
arachnoiditis, and Guillain–Barré disease. The blad-
der is typically areflexic (causing urinary retention),
and the internal sphincter is closed. The external
sphincter can be denervated in this type of injury and
does not provide much in the way of outlet
resistance. Symptomatically, this manifests as stress
incontinence (leakage of urine with increases in intra-
abdominal pressure), overflow incontinence, incom-
plete bladder emptying, and poor bladder sensation.
—Claire C. Yang
See also–Maple Syrup Urine Disease;
Micturation; Sphincter Disturbances
Further Reading
Andrew, J., and Nathan, P. W. (1964). Lesions of the anterior
frontal lobes and disturbances of micturition and defecation.
Brain 87, 233–265.
Haldeman, S., Glick, M., Bhatia, N. N., et al. (1982). Colono-
metry, cystometry and evoked potentials in multiple sclerosis.
Arch. Neurol. 39, 698–701.
Krane, R. J., and Siroky, M. B. (Eds.) (1991). Clinical Neuro-
Urology, 2nd ed. Little, Brown, Philadelphia.
McGuire, E. J., Woodside, J. R., Borden, T. A., et al. (1981).
Prognostic value of urodynamic testing in myelodysplastic
patients. J. Urol. 126, 205–209.
Wein, A. J. (1998). Pathophysiology and categorization of voiding
dysfunction. Campbell’s Urology, 7th ed., pp. 917–926.
Saunders, Philadelphia.
Wein, A. J., and Rovner, E. S. (1999). Adult voiding dysfunction
secondary to neurologic disease or injury. AUA Update Ser. 18,
42–47.
Blepharospasm
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BLEPHAROSPASM comprises a spectrum of disorders
that share involuntary eyelid closure as their com-
mon presenting sign. Blepharospasm can be very
disabling since patients are functionally blind during
eyelid closure and may be so impaired that they
cannot engage in activities that involve reading,
walking, driving a motor vehicle, or concentrating
visually in other ways. The advent of effective
treatments for eyelid spasm has caused renewed
interest in these disorders. The two most common
types of blepharospasm are ‘‘essential’’ blepharos-
pasm, which is a localized form of facial dystonia,

Autonomic dysreflexia is a symptom complex
resulting from noxious stimuli below the level of
the spinal injury. A common source of the stimuli
arises from the bladder (e.g., urinary retention,
traumatic catheter insertion, cystometry, or an
obstructed catheter). The basic mechanism is a
diffuse activation of viscero- or somatosympathetic
reflexes triggered by the stimuli, without the usual
supraspinal modulation of the sympathetic response.
The patient may experience an acute, rapid increase
in blood pressure, headache, sweating above the level
of the spinal injury, piloerection, nausea, anxiety, and
visual disturbance. The hypertension may become so
severe as to result in intracranial or subarachnoid
hemorrhage or cardiac arrhythmias. The first line of
management involves removal of the offensive
stimulus, which includes placement or changing of
a bladder catheter or aborting a cystometrogram.
Pharmacological prophylaxis against autonomic
dysreflexia can be administered prior to a noxious
procedure, such as a cystometrogram or cystoscopy.
Medications include nitroglycerine paste, oral alpha-
adrenergic blocking drugs, and sublingual nifedipine.
Myelodysplasia is primarily a pediatric problem,
but most of the affected children are now reaching
adulthood. Adult myelodysplastic patients typically
have an areflexic bladder with an open bladder neck,
which results in incontinence, urinary retention, or
both. External sphincter dyssynergia can also be a
problem. Many of these persons will have had
operations on their urinary tracts as children or
young adults.
Diseases of the Brain and Spinal Cord
The most common disease in this category is multiple
sclerosis (MS). Because demyelination can occur
anywhere in the central nervous system, no single
pattern of bladder dysfunction can be found in MS
patients. Detrusor hyperreflexia, detrusor hypocon-
tractility or areflexia, detrusor sphincter dyssynergia,
poor bladder sensation, and poorly compliant
bladders are found in MS. MS patients complain of
frequency, urgency, urge incontinence, interrupted
stream, hesitancy, nocturia, and incomplete bladder
emptying. These symptoms can sometimes be the
initial manifestation of the disease.
Diseases of Conus, Cauda Equina, and
Peripheral Nerves
These are diseases that result in a ‘‘lower motor
neuron’’-type bladder, one that has impaired sensa-
tion and flaccid motor function. Examples of the
BLEPHAROSPASM 389
diseases are autonomic neuropathy, traumatic injury,
lumbar spinal stenosis, sacral agenesis, myelodyspla-
sia, herpes zoster, cauda equina tumors, spinal
arachnoiditis, and Guillain–Barré disease. The blad-
der is typically areflexic (causing urinary retention),
and the internal sphincter is closed. The external
sphincter can be denervated in this type of injury and
does not provide much in the way of outlet
resistance. Symptomatically, this manifests as stress
incontinence (leakage of urine with increases in intra-
abdominal pressure), overflow incontinence, incom-
plete bladder emptying, and poor bladder sensation.
—Claire C. Yang
See also–Maple Syrup Urine Disease;
Micturation; Sphincter Disturbances
Further Reading
Andrew, J., and Nathan, P. W. (1964). Lesions of the anterior
frontal lobes and disturbances of micturition and defecation.
Brain 87, 233–265.
Haldeman, S., Glick, M., Bhatia, N. N., et al. (1982). Colono-
metry, cystometry and evoked potentials in multiple sclerosis.
Arch. Neurol. 39, 698–701.
Krane, R. J., and Siroky, M. B. (Eds.) (1991). Clinical Neuro-
Urology, 2nd ed. Little, Brown, Philadelphia.
McGuire, E. J., Woodside, J. R., Borden, T. A., et al. (1981).
Prognostic value of urodynamic testing in myelodysplastic
patients. J. Urol. 126, 205–209.
Wein, A. J. (1998). Pathophysiology and categorization of voiding
dysfunction. Campbell’s Urology, 7th ed., pp. 917–926.
Saunders, Philadelphia.
Wein, A. J., and Rovner, E. S. (1999). Adult voiding dysfunction
secondary to neurologic disease or injury. AUA Update Ser. 18,
42–47.
Blepharospasm
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BLEPHAROSPASM comprises a spectrum of disorders
that share involuntary eyelid closure as their com-
mon presenting sign. Blepharospasm can be very
disabling since patients are functionally blind during
eyelid closure and may be so impaired that they
cannot engage in activities that involve reading,
walking, driving a motor vehicle, or concentrating
visually in other ways. The advent of effective
treatments for eyelid spasm has caused renewed
interest in these disorders. The two most common
types of blepharospasm are ‘‘essential’’ blepharos-
pasm, which is a localized form of facial dystonia,
390 BLEPHAROSPASM
and hemifacial spasm, which is usually caused by
compression of the facial nerve. Both kinds of
blepharospasm can be symptomatically treated with
repeated injections of botulinum toxin. Essential
blepharospasm can be treated more permanently
with surgical removal or denervation of part of the
orbicularis oculi muscle. Hemifacial spasm can be
treated neurosurgically by displacement of the vessels
compressing the facial nerve. Oral medications may
be helpful in reducing symptoms of both disorders.
Blepharospasm arises from abnormalities in path-
ways responsible for the normal blinking response.
Blinking is initiated as a reflex in response to bright
light or corneal irritation. There are several areas of
cerebral cortex that project to the nucleus of the
facial nerve, including the facial portion of the motor
strip and the prefrontal cortex. Blinking may
particularly involve a pathway from the rostral
cingulate cortex to the dorsal and intermediate
portions of the facial nucleus. The cingulate cortex
receives input from the occipital lobe and the
amygdala. The dorsal and intermediate portions of
the facial nerve nucleus send axons to the orbicularis
oculi muscle to close the eyelids. Eyelid closure
occurs sequentially and recruits muscle fibers, start-
ing with the small fibers near the eyelid margins and
moving centrifugally to larger fibers that overlie the
rims of the orbital bones that surround the eye. The
muscle fibers of the pretarsal region are composed of
small, fast-contracting fibers, whereas the orbital
region is composed of larger, more slowly contract-
ing muscle fibers. The trigeminal nerve senses eye
irritation and triggers reflex blinking by signaling the
facial nucleus. The frequency and amplitude of
blinking are a learned behavior with adaptive
mechanisms that respond to changes in the stimulus
and the response. An effective blink requires that
eyelid opening (by the levator palpebrae) is recipro-
cally inhibited.
Essential blepharospasm describes the localized
form of the blepharospasm, oromandibular dystonia
spectrum (Meige’s or Brueghel’s syndrome). The
estimated prevalence of the disorder is 1 per 25,000
people in the United States. Many patients are
misdiagnosed as having excessive blinking due to
dry eyes. Moreover, many patients do not exhibit
blepharospasm in the physician’s office and may
present with confusing symptoms such as intermit-
tent blindness. The diagnosis is often postponed until
the eyelid spasms become more continuous, the
eyebrows become furrowed and depressed, and other
facial muscles are involved. Oromandibular dystonia
may include spasms of the jaw and lower facial
muscles as well as the eyelids. Spasm of the vocal
cords impairs phonation; spasms of the muscles of
mastication cause trouble with opening the mouth,
chewing, and swallowing; and spasms of the cervical
muscles cause neck rotation (torticollis), flexion
(anterocollis), extension (retrocollis), or head tilt
(laterocollis). In contrast to hemifacial spasm,
blepharospasm is absent during sleep.
The etiology of essential blepharospasm is not well
defined. Most cases are sporadic, but up to 10% may
be familial, implying a genetic predisposition. There
are two major lines of anatomical investigation
concerning the pathophysiology of essential blephar-
ospasm; one concentrates on the basal ganglia and
the other on brainstem reflex structures. Basal
ganglia abnormalities have been suspected because
of the similarity of blepharospasm to other dystonias
and to parkinsonian disorders. Extrapyramidal
movement disorders are often associated with blink
reflex abnormalities. The neurotransmitter dopamine
is important in several areas of the brain that are
involved in the control of blinking, including the
substantia nigra and the ventral tegmentum of the
midbrain. Eyelid spasms are a prominent feature of
tardive dyskinesia usually caused by dopamine-
blocking neuroleptic drugs. Positron emission topo-
graphy scans showing abnormalities in the basal
ganglia have been reported in essential blepharos-
pasm, and in rare patients with putaminal hemor-
rhage who have developed blepharospasm. There
may also be hyperactivation of the cortical and
subcortical motor circuits that also involve the area
prostriata, the central medial thalamus, and the
cerebellum.
Brainstem mechanisms have also been invoked to
explain blepharospasm, including supranuclear dis-
inhibition of the blink reflex and upregulation of the
blink reflex following facial palsy. Evidence for a
brainstem origin has come from electrophysiological
studies. Evidence of abnormal inhibition of the
levator palpebrae may be associated with eyelid
opening apraxia, in which the eyelids are involunta-
rily closed and the orbicularis oculi muscles are not
in spasm.
The course of essential blepharospasm is variable.
It affects women approximately three times more
frequently than men and usually begins in the fifth or
sixth decade of life. It generally progresses over 2 or
3 years and then stabilizes. Both eyes are almost
always equally involved. Patients may experience dry
eye symptoms and often prefer sunglasses, even

indoors. Spasm may be reduced by singing, hum-
ming, talking, or tapping on the side of the face.
Patients with blepharospasm sometimes develop
structural abnormalities of their eyelids that can
add to the spasm and limit the usefulness of therapy.
The diagnostic workup is generally limited. Mag-
netic resonance imaging or computed tomography of
the brain are usually not required. Differential
diagnosis includes reflex blepharospasm, which can
occur with voluntary eyelid closure or when the
patient involuntarily closes the eyes as the examiner
attempts to open them. Reflex blepharospasm occurs
most commonly on the nonparalyzed side in patients
who have had strokes in the temporoparietal lobe of
the nondominant hemisphere of the brain. In blephar-
oclonus, bursts of orbicularis oculi and levator
palpebrae superioris activity alternate involuntarily
raising and lowering the eyelid. The examination in a
blepharospasm patient is dedicated toward identify-
ing ocular movement abnormalities associated with
neurological disease and excluding ophthalmological
disorders that may give rise to physical irritation or
photophobia. An important aspect of the examina-
tion is the identification of apraxia of eyelid opening,
in which a patient cannot open the eyes for several
seconds in the absence of obvious spasm. This
phenomenon is often brought out by asking the
patient to close his or her eyes tightly and then
suddenly open them. Flaccid eyelid closure can be
accompanied by a raised forehead and eyebrows.
Apraxia of eyelid opening explains most cases in
which botulinum toxin fails to improve blepharos-
pasm significantly. In essential blepharospasm, elec-
tromyography demonstrates that repetitive and tonic
bursts of spasm generally last from 0.1 to 4.0 sec. The
examination may also reveal eyelid or eyebrow ptosis,
excess fold of upper lid skin (dermatochalasis), and
lateral canthal tendon disinsertion. These problems
often require oculoplastic surgery.
Treatment of most blepharospasm is directed at
the muscles that surround the eyelid and other local
structures. Oral medications may be useful, although
usually only in a supplementary role. The most
commonly used drugs are clonazepam, trihexyphe-
nidyl, baclofen, and gabapentin.
Hemifacial spasm causes involuntary unilateral
contraction of the muscles supplied by the facial
nerve. The condition is rarely bilateral or familial.
Prevalence is 15 per 100,000 women in the United
States. It is half as prevalent in men. The condition
may affect all branches of the facial nerve. It
generally begins around the eye and spreads to the
BLEPHAROSPASM 391
lower face. Voluntary or emotional activity of the
facial muscles is often followed by sustained con-
traction, which is a characteristic feature. Most cases
of hemifacial spasm are caused by compression at the
root exit zone of the facial nerve fibers at the inferior
lateral aspect of the pons. Compression usually
comes from one or more small arteries that normally
supply the brainstem or cerebellum. Compressive
damage may demyelinate facial nerve fibers, causing
both mild facial weakness and cross-talk (ephaptic)
transmission between facial nerve fibers supplying
specific muscles.
Hemifacial spasm usually begins in the fourth
decade or later. Symptoms develop over months or
years and usually reach a plateau after a few years. In
rare patients, hemifacial spasm is caused by tumors
or multiple sclerosis. Imaging studies are performed
in any patient in whom the diagnosis is in doubt—for
example, when there are other cranial never findings,
such as auditory or facial sensory loss.
Spasms around the eye may significantly interfere
with vision. Spasm and weakness elsewhere in the
face may be disfiguring and embarrassing. Hemi-
facial spasm localized to the eyelids is most amenable
to botulinum toxin therapy. The definitive treatment
of hemifacial spasm is usually with neurosurgical,
microvascular decompression of the facial nerve. The
procedure is approximately 90% effective in redu-
cing spasm, with permanent complications including
ipsilateral hearing loss (4%), increased facial nerve
weakness (2%), and stroke (1%). Recurrence of
hemifacial spasm may occur months or years after
surgery in up to 10% of patients. Medical treatment
includes oral medications, particularly anticonvul-
sants, which are especially useful for spasm of the
lower facial muscles, in which botulinum toxin
injections may cause unwanted weakness.
Local treatments for patients with blepharospasm
or hemifacial spasm include botulinum toxin injec-
tions and orbicularis myectomy combined with other
local oculoplastic surgical procedures. Most patients
with these disorders can achieve effective ameliora-
tion using these treatments alone or in combination.
Botulinum toxin is injected into various regions
of the orbicularis oculi and symptomatic relief is
typically obtained for 3 months or more. Botulinum
toxins bind irreversibly with presynaptic nerve ter-
minals and enter them by endocytosis. There, the
endocytic vesicles break the light chain away from
the heavy chain of the toxin. The light chains are
zinc-dependent endopeptidases that cleave intracel-
lular docking proteins, enabling the release of the
392 BOGAERT, LUDO VAN

neurotransmitter acetylcholine, SNAP25, VAMP, and Hallett, M. (1999). One man’s poison—Clinical applications of
Syntaxin. Deficiency of any of these molecules as a botulinum toxin. N. Engl. J. Med. 341, 118–120. [Editorial].
Scott, A. B. (1980). Botulinum toxin injection into extraocular
result of botulinum toxin causes temporary paralysis. muscles as an alternative to strabismus surgery. Ophthalmology
The nerve fiber retracts, but delayed axonal sprout- 87, 1044–1049.
ing reinnervates the neuromuscular junction. Wirtschafter, J. D., and McLoon, L. K. (1998). Long-term efficacy
Botulinum toxin serotypes A and B are available in of local doxorubicin chemomyectomy in blepherospasm and
the United States. Other serotypes have not been hemifacial spasm patients. Ophthalmology 195, 342–346.
found to be as effective in research trials. Botulinum
toxin B may be of use in patients who have developed
resistance to botulinum toxin A. For essential
blepharospasm, the drug is injected into the orbicu-
laris oculi, frontalis, corrugator supercilli, and
nasalis muscles. For orofacial dystonias, additional
Bloch-Sclzberger Syndrome
muscles injected include the masseter, temporalis, see Incontinentia Pigmenti
pterygoids, and submentalis. Botulinum toxin may
be injected into almost any affected facial muscles in
hemifacial spasm. In Meige’s syndrome, the muscles
of the vocal cords and neck may also be injected. The
side effects of ocular injections are local and include
bruising, eyelid ptosis, and double vision. Dry eye
Bogaert, Ludo van
Encyclopedia of the Neurological Sciences
symptoms may result from impaired blinking. These Copyright 2003, Elsevier Science (USA). All rights reserved.

are all transient. When larger doses of botulinum

toxin A are used in areas beyond the eyes, patients
may complain of dry mouth, trouble swallowing,
and flu-like symptoms. Drug resistance is dosage
related, and it is rare in patients injected only around
the eyes since doses are small, in proportion to the
muscles themselves.
Eyelid or eyebrow ptosis, dermatochalasis, and
lateral canthal tendon disinsertion occurring in eyelid
spasm patients can be treated surgically. Spasm may
be treated with partial removal of the orbicularis
oculi muscle (myectomy). It is usually combined with
other oculoplastic surgery. Many patients who have
had orbicularis myectomy may benefit from supple-
mental botulinum toxin injections. Some patients LUDO VAN BOGAERT (1897–1989), one of the great
return for lower lid myectomy at a later date. modern neurologists noted particularly for his
Liposome-encapsulated doxorubicin (Doxil) chemo- contributions to pediatric neurology, was born in
myectomy is being investigated as a permanent, Antwerp, Belgium. His father was a physician who
nonsurgical alternative. Treatment with nonlipo- had a profound influence on his career. Van Bogaert
some-encapsulated doxorubicin was found to be modeled his doctor–patient relationship and medical
effective but caused disfiguring scaring that pre- philosophy after those of his father. He fled occupied
vented its widespread adoption. Belgium following high school and began his first 2
—Jonathan D. Wirtschafter years of medical training at the University of Utrecht.
World War I further interrupted his studies when he
See also–Dystonia; Eyelids; Hemifacial Spasm; enlisted in the Belgian army as a volunteer. Van
Reflexes, Spinal Cord and Blink Bogaert was discharged in 1918 after suffering a
fractured spine and spinal concussion. He returned to
Further Reading
his medical studies at the Free University of Brussels
Anderson, R. L., Patel, B. C., Holds, J. B., et al. (1998).
and obtained his degree in 1922.
Blepharospasm, past, present, and future. Ophthal. Plast. Following graduation, he had the good fortune of
Reconstr. Surg. 14, 305–317. training in neurology in Paris with Pierre Marie. While
392 BOGAERT, LUDO VAN

neurotransmitter acetylcholine, SNAP25, VAMP, and Hallett, M. (1999). One man’s poison—Clinical applications of
Syntaxin. Deficiency of any of these molecules as a botulinum toxin. N. Engl. J. Med. 341, 118–120. [Editorial].
Scott, A. B. (1980). Botulinum toxin injection into extraocular
result of botulinum toxin causes temporary paralysis. muscles as an alternative to strabismus surgery. Ophthalmology
The nerve fiber retracts, but delayed axonal sprout- 87, 1044–1049.
ing reinnervates the neuromuscular junction. Wirtschafter, J. D., and McLoon, L. K. (1998). Long-term efficacy
Botulinum toxin serotypes A and B are available in of local doxorubicin chemomyectomy in blepherospasm and
the United States. Other serotypes have not been hemifacial spasm patients. Ophthalmology 195, 342–346.
found to be as effective in research trials. Botulinum
toxin B may be of use in patients who have developed
resistance to botulinum toxin A. For essential
blepharospasm, the drug is injected into the orbicu-
laris oculi, frontalis, corrugator supercilli, and
nasalis muscles. For orofacial dystonias, additional
Bloch-Sclzberger Syndrome
muscles injected include the masseter, temporalis, see Incontinentia Pigmenti
pterygoids, and submentalis. Botulinum toxin may
be injected into almost any affected facial muscles in
hemifacial spasm. In Meige’s syndrome, the muscles
of the vocal cords and neck may also be injected. The
side effects of ocular injections are local and include
bruising, eyelid ptosis, and double vision. Dry eye
Bogaert, Ludo van
Encyclopedia of the Neurological Sciences
symptoms may result from impaired blinking. These Copyright 2003, Elsevier Science (USA). All rights reserved.

are all transient. When larger doses of botulinum

toxin A are used in areas beyond the eyes, patients
may complain of dry mouth, trouble swallowing,
and flu-like symptoms. Drug resistance is dosage
related, and it is rare in patients injected only around
the eyes since doses are small, in proportion to the
muscles themselves.
Eyelid or eyebrow ptosis, dermatochalasis, and
lateral canthal tendon disinsertion occurring in eyelid
spasm patients can be treated surgically. Spasm may
be treated with partial removal of the orbicularis
oculi muscle (myectomy). It is usually combined with
other oculoplastic surgery. Many patients who have
had orbicularis myectomy may benefit from supple-
mental botulinum toxin injections. Some patients LUDO VAN BOGAERT (1897–1989), one of the great
return for lower lid myectomy at a later date. modern neurologists noted particularly for his
Liposome-encapsulated doxorubicin (Doxil) chemo- contributions to pediatric neurology, was born in
myectomy is being investigated as a permanent, Antwerp, Belgium. His father was a physician who
nonsurgical alternative. Treatment with nonlipo- had a profound influence on his career. Van Bogaert
some-encapsulated doxorubicin was found to be modeled his doctor–patient relationship and medical
effective but caused disfiguring scaring that pre- philosophy after those of his father. He fled occupied
vented its widespread adoption. Belgium following high school and began his first 2
—Jonathan D. Wirtschafter years of medical training at the University of Utrecht.
World War I further interrupted his studies when he
See also–Dystonia; Eyelids; Hemifacial Spasm; enlisted in the Belgian army as a volunteer. Van
Reflexes, Spinal Cord and Blink Bogaert was discharged in 1918 after suffering a
fractured spine and spinal concussion. He returned to
Further Reading
his medical studies at the Free University of Brussels
Anderson, R. L., Patel, B. C., Holds, J. B., et al. (1998).
and obtained his degree in 1922.
Blepharospasm, past, present, and future. Ophthal. Plast. Following graduation, he had the good fortune of
Reconstr. Surg. 14, 305–317. training in neurology in Paris with Pierre Marie. While

in Paris, he worked in the laboratory of Ivan Bertrand,
his first mentor in neuropathology. His work in Paris
also led to interactions with Constatin von Economo,
with whom he developed a strong friendship and
collegial relationship. Near the end of van Bogaert’s
career, this relationship would lead to his coauthorship
of a biography on the life of Economo. In the forward
to that book, van Bogaert speaks about the formative
time period of his neurology training in Paris:
[I] happened to be working under Pierre Marie in the Salpêtrière
just at the time when the great epidemic of encephalitis
lethargica was nearing the end of its second phase. This disease
absolutely preoccupied Marie and his school; indeed the great
man had himself written some observations that have remained
classics to this day on cases with symptoms of a rather peculiar
kind. It was in Marie’s service that Tretiakoff developed his
thesis emphasizing for the first time the significance of lesions in
the locus niger both in Parkinson’s disease and in the
Parkinsonian form of encephalitis. Feeling curious about the
arguments raging around the Bordeaux School’s claim to
priority, [I] determined to find out the truth for [my]self. By
good fortune [I] was able to meet Economo and Cruchet, both
of whom gave [me] access to their documents and preparations.
With Economo there grew up a lasting and supremely satisfying
friendship, not to mention scientific exchanges extending into
the field of cerebral architectonics and further still into
encephalitis lethargica as well as other encephalitides current
at that time.
Following this early neurology training in Paris,
van Bogaert returned to Antwerp in 1923 as an
assistant in medicine at St. Elizabeth Hospital. He
was then appointed staff physician at the Stuivenberg
Hospital, where he started a small pathological
laboratory. In 1925, he successfully defended his
doctoral thesis on amyotrophic lateral sclerosis. This
was a particularly productive time period for van
Bogaert, with 17 articles authored in 1924 and 30
the following year. This output occurred despite the
fact that he had to devote time to the preparation for
his thesis defense. During his time at Stuivenberg
Hospital, his expertise in child neurology was
recognized and he was frequently sought as a
consultant on difficult cases.
He continued to serve at Stuivenberg Hospital
until 1933, when the Institute of Bunge was
established under his directorship. This privately
funded institute was financed by businessman Ed-
ward Bunge and devoted to the development of
medical and surgical research. Hans Scherer was
recruited to the neuropathology laboratory and
Joseph Rademecker served as first clinical assistant.
In 1936, the first volume of reprints authored by
members of the institute was issued, attesting to the
wealth of knowledge generated by the group.
BOGAERT, LUDO VAN 393
Unfortunately, World War II temporarily reduced
this output, but at the end of the war the institute
added laboratories of electroencephalography, elec-
tromyography, biochemistry, and histochemistry.
Van Bogaert’s productivity accelerated at the same
time. Neurologists and neuropathologists from
around the world came to the institute for advanced
training.
Van Bogaert was instrumental in organizing a
number of scientific meetings. The most influential of
these was the gathering of more than 3000 partici-
pants in Brussels; from this meeting came the
formation of the World Federation of Neurology.
Van Bogaert was appropriately elected the first
president of the newly reorganized group and
traveled widely in that capacity. He also helped to
create multiple research groups, including a pediatric
neurology group. By 1957, he had garnered interna-
tional recognition and numerous awards. Elections
to more than 50 scientific societies and medical
academies were to follow.
He was said to be an excellent clinician who
treated each patient with compassion and a reassur-
ing manner. He learned his meticulous clinical skills
from the great French neurologists with whom he
trained and his equally meticulous pathological skills
from the school of the great German neuropatholo-
gists, as taught to him by Bertrand. Although
interested in all aspects of neurology, he is especially
remembered for his work in encephalitis, metabolic
disorders, degenerative diseases, inborn errors of
metabolism, and extrapyramidal disease. Diseases to
which he made seminal contributions include sub-
acute sclerosing encephalitis, cerebrotendinous
xanthomatosis, and familial spongy degeneration of
the brain. He often collaborated with neurochemists
in trying to understand disorders, and he realized the
limitations of strict morphological examination.
Van Bogaert fought against nationalistic bound-
aries in medicine and repeatedly tried to foster more
international scientific interchange between neurolo-
gists, neuropathologists, and neurochemists. He saw
the need for subspecialization in medicine and
neurology but decried the lack of interaction that
might ensue if the different subspecialists failed to
meet regularly. He died in 1989 at the end of a very
productive career.
—Bette Kleinschmidt-DeMasters
See also–Marie, Pierre (see Index entry
Biography for complete list of biographical
entries)
394 BORDERLINE PERSONALITY DISORDER
Further Reading
Aird, R. B. (1994). Foundations of Modern Neurology. A Century
of Progress. Raven Press, New York.
Phillipart, M. (1990). Ludo van Bogaert. In Founders of Child
Neurology (S. Ashwal, Ed.), pp. 854–861. Norman, San
Francisco.
Van Bogaert, L. V., and Thèodoridès, J. (1979). Constatin von
Economo: The Man and the Scientist. Verlag Der Österrei-
chischen Akademie Der Wissenschaften, Wien.
Borderline Personality
Disorder
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BORDERLINE PERSONALITY DISORDER (BPD) is one of
the cluster B personality disorders and has received
special emphasis and study in the psychiatric
research and clinical literature. It is a severe, chronic,
disabling condition characterized by pervasive diffi-
culties in interpersonal relationships, instability of
mood states, and impulsive aggressive behaviors. Of
those with BDP, 69–75% have self-destructive
behaviors, including self-mutilation, suicide at-
tempts, and abuse of alcohol and drugs. Completed
suicide rate estimates range between 3 and 9%.
People with BDP make extensive use of mental heath
services and account for 20% of psychiatric hospi-
talizations.
PSYCHOPATHOLOGY
There are three main domains of symptomatology in
BPD: affect dysregulation, impulsive aggression, and
identity disturbance. The affective domain comprises
emotional experiences such as intense bouts of anger
lasting hours, rapid fluctuations of mood states, and
episodes of profound dysphoria and anguish that are
at times relieved by attempts at self-injury.
Impulsive aggressive behaviors are impulsive acts
of aggression directed toward the self or others that
account for a substantial portion of the morbidity
and mortality associated with BPD. These acts
include self-injurious behavior (e.g., cutting), domes-
tic violence, assault, destruction of property, and
suicide. Forms of impulsive aggression directed at
self, such as repetitive skin cutting or burning, have
been demonstrated in up to 80% of BPD subjects.
Identity disturbance symptoms may include an
unstable sense of self, chronic feelings of emptiness,
and changing views of career, friendships, and values.
Individuals with BPD are prone to cognitive distor-
tions and experience a variety of dissociative
symptoms, including depersonalization, derealiza-
tion, and, during times of stress, vulnerability to
transient psychotic experiences.
The cluster of BDP symptoms results in inordinate
dysfunction in interpersonal relationships. Indivi-
duals with BPD have stormy connections with
people, are sensitive to criticism and rejection, are
easily disappointed, and frequently exert frantic
efforts to avoid being left or abandoned.
BPD is defined on Axis II in the Diagnostic and
Statistical Manual of Mental Disorders, fourth
edition (DSM-IV), as ‘‘a pervasive pattern of
instability of interpersonal relationships, self-image
and affects and marked impulsivity beginning by
early adulthood and present in a variety of contexts.’’
Five of the following nine criteria are necessary to
make the diagnosis:
1. Frantic efforts to avoid abandonment
2. Unstable and intense interpersonal relationships
3. Identity disturbance
4. Potentially self-damaging impulsivity
5. Recurrent suicidal or parasuicidal behavior
6. Affective instability
7. Chronic feelings of emptiness
8. Problems with anger
9. Dissociative symptoms or transient stress-re-
lated paranoid ideation
PREVALENCE
BPD affects 2% of the general population, and young
women are at greatest risk for the disorder. Addi-
tionally, 11% of psychiatric patients and 19% of
psychiatric outpatients carry the diagnosis of BPD.
There is speculation that females with BDP present to
mental health systems, whereas males with BDP are
more commonly located within the forensic system
and, consequently, have poor access to treatment.
COURSE
Key features of a personality disorder are its
pervasiveness across several areas of functioning,
stability over time, and relatively early onset in
development. This applies to BPD, which tends to
present in early adulthood and remain stable over
time. The extreme behaviors of suicidality and
394 BORDERLINE PERSONALITY DISORDER
Further Reading
Aird, R. B. (1994). Foundations of Modern Neurology. A Century
of Progress. Raven Press, New York.
Phillipart, M. (1990). Ludo van Bogaert. In Founders of Child
Neurology (S. Ashwal, Ed.), pp. 854–861. Norman, San
Francisco.
Van Bogaert, L. V., and Thèodoridès, J. (1979). Constatin von
Economo: The Man and the Scientist. Verlag Der Österrei-
chischen Akademie Der Wissenschaften, Wien.
Borderline Personality
Disorder
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BORDERLINE PERSONALITY DISORDER (BPD) is one of
the cluster B personality disorders and has received
special emphasis and study in the psychiatric
research and clinical literature. It is a severe, chronic,
disabling condition characterized by pervasive diffi-
culties in interpersonal relationships, instability of
mood states, and impulsive aggressive behaviors. Of
those with BDP, 69–75% have self-destructive
behaviors, including self-mutilation, suicide at-
tempts, and abuse of alcohol and drugs. Completed
suicide rate estimates range between 3 and 9%.
People with BDP make extensive use of mental heath
services and account for 20% of psychiatric hospi-
talizations.
PSYCHOPATHOLOGY
There are three main domains of symptomatology in
BPD: affect dysregulation, impulsive aggression, and
identity disturbance. The affective domain comprises
emotional experiences such as intense bouts of anger
lasting hours, rapid fluctuations of mood states, and
episodes of profound dysphoria and anguish that are
at times relieved by attempts at self-injury.
Impulsive aggressive behaviors are impulsive acts
of aggression directed toward the self or others that
account for a substantial portion of the morbidity
and mortality associated with BPD. These acts
include self-injurious behavior (e.g., cutting), domes-
tic violence, assault, destruction of property, and
suicide. Forms of impulsive aggression directed at
self, such as repetitive skin cutting or burning, have
been demonstrated in up to 80% of BPD subjects.
Identity disturbance symptoms may include an
unstable sense of self, chronic feelings of emptiness,
and changing views of career, friendships, and values.
Individuals with BPD are prone to cognitive distor-
tions and experience a variety of dissociative
symptoms, including depersonalization, derealiza-
tion, and, during times of stress, vulnerability to
transient psychotic experiences.
The cluster of BDP symptoms results in inordinate
dysfunction in interpersonal relationships. Indivi-
duals with BPD have stormy connections with
people, are sensitive to criticism and rejection, are
easily disappointed, and frequently exert frantic
efforts to avoid being left or abandoned.
BPD is defined on Axis II in the Diagnostic and
Statistical Manual of Mental Disorders, fourth
edition (DSM-IV), as ‘‘a pervasive pattern of
instability of interpersonal relationships, self-image
and affects and marked impulsivity beginning by
early adulthood and present in a variety of contexts.’’
Five of the following nine criteria are necessary to
make the diagnosis:
1. Frantic efforts to avoid abandonment
2. Unstable and intense interpersonal relationships
3. Identity disturbance
4. Potentially self-damaging impulsivity
5. Recurrent suicidal or parasuicidal behavior
6. Affective instability
7. Chronic feelings of emptiness
8. Problems with anger
9. Dissociative symptoms or transient stress-re-
lated paranoid ideation
PREVALENCE
BPD affects 2% of the general population, and young
women are at greatest risk for the disorder. Addi-
tionally, 11% of psychiatric patients and 19% of
psychiatric outpatients carry the diagnosis of BPD.
There is speculation that females with BDP present to
mental health systems, whereas males with BDP are
more commonly located within the forensic system
and, consequently, have poor access to treatment.
COURSE
Key features of a personality disorder are its
pervasiveness across several areas of functioning,
stability over time, and relatively early onset in
development. This applies to BPD, which tends to
present in early adulthood and remain stable over
time. The extreme behaviors of suicidality and

impulsivity, however, may diminish with increasing
age and treatment.
ETIOLOGICAL THEORIES OF BPD
For the past 50 years, there has been ongoing
controversy concerning the etiology of BPD. Origi-
nating with Stern, a psychoanalyst who described a
population of individuals on the ‘‘border’’ between
neurosis and psychosis, numerous attempts have been
made to reclassify BPD as a schizophrenia spec-
trum disorder, affective illness spectrum disorder,
impulse spectrum disorder, and, recently, a trauma
spectrum disorder. Each spectrum disorder hypothesis
has focused on a particular symptom dimension and
has failed to describe the entirety of BPD (Table 1).
ROLE OF CHILDHOOD TRAUMA
The most recent debate concerns the relationship of
childhood traumatic experience, most notably child-
hood sexual abuse (CSA), and the development of
BPD. Several studies of clinical populations of BPD
note extremely high abuse rates (490%). Herman
and van der Kolk interpreted these findings to
suggest that BPD is a ‘‘complex’’ form of post-
traumatic stress disorder (PTSD). They posit that
chronic childhood neglect and abuse, particularly
childhood sexual abuse, contribute to the develop-
ment of insecure attachments to caregivers that lead
to problems in self-regulation of emotions, feelings,
and impulses. Furthermore, BPD, and the prototypic
trauma-related disorder, PTSD, show significant
phenomenological overlap, including emotional la-
Table 1 BORDERLINE PERSONALITY DISORDER CHARACTERISTICS ASSOCIATED WITH SPECTRUM DISORDER THEORIES OF
BORDERLINE PERSONALITY DISORDERa
Borderline personality disorder criterion Schizophrenia
Avoid abandonment
Unstable relationships
Identity disturbance
Impulsivity
Parasuicidal/suicidal acts
Affective instability
Chronic emptiness X (negative symptoms)
Anger
Dissociation/paranoid ideation
a
From the DSM-IV (American Psychiatric Association, 1999).
BORDERLINE PERSONALITY DISORDER 395
bility, anger dyscontrol, suicidal thinking, and
dissociative processes. These ideas suggest that BPD
may be viewed as a trauma spectrum disorder,
requiring a significant traumatic event or series of
events in childhood and problematic repercussions in
coping and adaptation.
Individuals with BPD have significantly greater
rates of CSA compared to non-BPD patients, with
estimates ranging from 40 to 70% for BPD. Para-
meters of abuse, including penetration, multiple
perpetrators, sibling and nonrelative perpetrators,
duration of abuse, and overall physical abuse rate,
further discriminate BPD from non-BPD groups.
Despite an increased frequency of childhood
traumatic experiences in BPD, these events are not
unique to BPD and not all individuals with BPD have
been traumatized as children. Moreover, childhood
abuse has many potential outcomes in adulthood,
and it remains unclear how and why a particular
pathway, such as depression, substance abuse, PTSD,
or personality dysfunction, becomes expressed.
Current thinking has challenged the oversimplified
formulation that BPD is a trauma spectrum disorder
and has developed the premise that in certain
individuals, trauma interacts with temperament and
biological vulnerabilities to produce personality
dysfunction.
BIOLOGICAL UNDERPINNINGS
During the past 15 years, research on BPD psycho-
pathology has moved from a phenomenological to a
biological perspective secondary to advances in
psychopharmacology, neuroimaging, and genetics.
Spectrum disorder
Affective disorder Impulse disorder Trauma/PTSD
X X Possibly
Possibly
Possibly X
X X
X Possibly
X X X
X X
396 BORDERLINE PERSONALITY DISORDER
The major biological theory of BPD implicates the
neurotransmitter serotonin (5-HT), which is involved
in appetite, impulse control, sleep, sexual drive, and
mood regulation. Individuals with BPD have been
shown to have diminished brain serotonin levels.
Biological data from individuals carrying a diagnosis
of BPD suggest decreased levels of serotonin meta-
bolites in the cerebrospinal fluid, altered postsynaptic
serotonin receptor levels, and abnormally diminished
responses to serotonin-stimulating agents. Moreover,
gene studies examining genes that determine activity
of the serotonergic system—receptors, synthetic
enzymes, and uptake sites—have been performed
and associated with behavioral traits of BPD.
Differences in allelic variation of the enzyme
tryptophan hydroxlyase, the rate-limiting step in
the synthesis of serotonin and 5-HT 1-B receptor,
which may influence the amount of presynaptic
release of serotonin, have been associated with
impulsive aggression in BPD. Variations in the genes
of the serotonin system likely have small to modest
effects but contribute to the reduced responsiveness
of the serotonin system.
With the use of neuroimaging paradigms includ-
ing positron emission tomography scanning, reduced
ventral prefrontal cortex activity in BPD has
been reported. The prefrontal cortex is heavily
innervated by the serotonin system. After adminis-
tration of an agent that stimulates the brain’s
serotonergic system, BPD patients showed less
robust activity in the orbital frontal and cingulate
cortex compared to control subjects. Orbital frontal
cortex is a region that modulates aggression, and
lesions to this area have been associated with
profound personality changes, aggression, and an-
ger. The cingulate cortex is part of the limbic system
that evaluates incoming emotional stimuli in the
service of preparing for action. Thus, the orbital
frontal and cingulate serve as a brake for more
primitive parts of the brain that generate aggression.
The reduced serotonergic brain activity and respon-
sivity translate into less inhibition of aggressive
urges and more overt aggressive behavior seen
clinically in BPD as displays of anger, assaults, self-
mutilation, and suicide attempts.
The affective instability of BPD is believed to
be in part due to greater baseline limbic irritability.
Administration of procaine, which stimulates para-
limbic structures such as the amygdala and cingu-
late cortex, causes irritability and mood shifts in
subjects with BPD compared to control subjects.
Also, electroencephalogram studies in BPD suggest
greater baseline limbic responsivity. Together, these
studies suggest that paralimbic structures may
play a critical role in the affective processing and
emotional liability of BPD, although more direct
tests of activation of these regions are needed.
TREATMENT
Psychological
There is a long tradition of treating BPD with
psychodynamic psychotherapy, with significant con-
tributions from psychoanalysts such as Kernberg.
Other modalities include supportive psychotherapy,
group psychotherapy, and behavioral treatments.
The only empirically tested approach is a cognitively
behavioral therapy developed by Linehan called
dialectical behavioral therapy (DBT). DBT was
designed for severe self-mutilating and suicidal
patients with BPD and focuses on changing belief
systems and teaching more adaptive coping techni-
ques.
Patients with BPD are difficult to treat because
their difficulties with interpersonal relationships
extend to the clinicians who are attempting to
offer help. The self-destructive behaviors, anger,
mood instability, and pervasive fear of abandon-
ment all interfere with a clinician’s ability to
establish a therapeutic alliance and sustain a
successful treatment.
Pharmacotherapy
Given the heterogeneity of the disorder and that the
diagnosis requires any five of nine criteria, pharma-
cological treatment has evolved to treat particular
dimensions of the BPD rather than the disorder in its
entirety. The affective instability of BPD has been
targeted with agents including antidepressant medi-
cation, especially those that target the serotonin
system [i.e., selective serotonin reuptake inhibitors
(SSRIs)], and mood stabilizers such as lithium and
valproic acid. Impulsive aggression has been targeted
with SSRIs, atypical neuroleptics such as risperidone,
and opiod antagonists including naltrexone. Only
fluoxetine, a SSRI, has been studied in a placebo-
controlled, double-blind fashion with positive re-
sults. For the identity disturbance symptomatology
of BPD, both naltrexone and atypical antipsychotics
have been used, but low-dose atypical antipsychotics
are the agents of choice.
Caution should be used in the use of benzodiaze-
pines in this population. In addition to their

addiction potential, these medications are cross-
tolerant with alcohol and can cause behavioral
disinhibition.
CONCLUSION
This Axis II personality disorder, characterized by
affective instability, impulsive aggression, and iden-
tity disturbance, is chronic, severe, and potentially
lethal. Progress in elucidating the underlying biolo-
gical underpinnings in the serotonin system and
altered limbic responsivity for BPD offers promise
for the development of more effective treatment
strategies. Work integrating how environmental
stress such as childhood trauma interacts with
temperament and biological vulnerabilities to pro-
duce BPD dysfunction is needed.
—Marianne Goodman and Daniel S. Weiss
See also–Behavior, Neuropathology of; Bipolar
Disorder; Mood Disorders, Biology; Personality
Types and Disorders; Post-Traumatic Stress
Disorder (PTSD)
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed. American Psychiatric
Association, Washington, DC.
Coccarro, E., and Kavoussi, R. (1997). Fluoxetine and impulsive
aggressive behavior in personality-disordered subjects. Arch.
Gen. Psychiatry 54, 1081–1088.
Coccaro, E., Siever, L., Klar, M., et al. (1989). Serotonergic studies
in patients with affective and personality disorders. Arch. Gen.
Psychiatry 44, 573–588.
Herman, J. L., and van der Kolk, B. A. (1987). Traumatic
antecedents of borderline personality disorder. In Psychological
Trauma (B. A. van der Kolk, Ed.). American Psychiatric Press,
Washington, DC.
Kellner, C. H., Post, R. M., Putnam, F., et al. (1987).
Intravenous procaine as a probe of limbic system activity in
psychiatric patients and normal controls. Biol. Psychiatry 22,
1107–1126.
Linehan, M. M., and Koerner, K. (1993). A behavioral theory of
borderline personality disorder. In Borderline Personality
Disorder and Treatment (J. Paris, Ed.), pp. 103–121. American
Psychiatric Press, Washington, DC.
New, A., Goodman, M., Mitropoulou, V., et al. (2002). Genetic
polymorphisms and aggression. In Molecular Genetics and
Human Personality (J. Benjamin and R. Ebstein, Eds.),
pp. 231–244. American Psychiatric Press, Washington, DC.
Paris, J., and Zweig-Frank, H. (1992). A critical review of the role
of childhood sexual abuse in the etiology of borderline
personality disorder. Can. J. Psychiatry 37, 125–128.
Siever, L. J., and Davis, K. (1991). A psychobiological perspective
on the personality disorders. Am. J. Psychiatry 148,
1647–1658.
BORNA DISEASE VIRUS 397
Siever, L. J., Buchsbaum, M., New, A., et al. (1999).
d,l-Fenfluramine response in impulsive personality disorder
assessed with 18F-deoxyglucose positron emission tomography.
Neuropsychopharmacology 20(5), 413–423.
Soloff, P., Meltzer, C., Greer, P., et al. (2000). A fenfluramine-
activated FDG-PET study of borderline personality disorder.
Biol. Psychiatry 47, 540–547.
Stern, A. (1938). Psychoanalytic investigation of and therapy
in the borderline group of neuroses. Psychoanalytic Q. 7,
467–489.
Zanarini, M. C. (2000). Childhood experiences associated with the
development of borderline personality disorder. Psychiatry
Clin. North Am. 23, 89–101.
Zanarini, M., and Frankenburg, F. (1997). Pathways to the
development of borderline personality disorder. J. Personal.
Disord. 11, 93–104.
Borna Disease Virus
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BORNA DISEASE VIRUS (BDV) is the prototype of the
family Bornaviridae, genus Bornavirus, within the
nonsegmented negative-strand RNA viruses (order
Mononegavirales). This neurotropic virus appears to
be distributed worldwide and has potential to infect
most warm-blooded hosts. BDV is similar in genomic
organization to other nonsegmented, negative-
stranded (NNS) RNA viruses. The name Borna refers
to the city of Borna, Germany, where an equine
epidemic during the late 1800s crippled the Prussian
cavalry.
The geographic distribution of BDV is unknown.
Natural infection has been reported in Europe,
North America, and parts of Asia (Japan, Israel,
and Iran). However, this restriction may reflect
failure of case ascertainment due to lack of sensitive
methods and reagents for diagnosis of infection or a
failure to consider the possibility of BDV infection.
Recent reports of asymptomatic naturally infected
animals in Germany and Japan suggest that the virus
may be more widespread than previously appre-
ciated.
Neither the reservoir nor the mode for transmis-
sion of natural infection are known. An olfactory
route for transmission has been proposed because
intranasal infection is efficient and the olfactory
bulbs of naturally infected horses show inflammation
and edema early in the course of disease. Reports of
BDV nucleic acid and proteins in peripheral blood
mononuclear cells also indicate the possibility of
hematogeneous transmission. Experimental infection

addiction potential, these medications are cross-
tolerant with alcohol and can cause behavioral
disinhibition.
CONCLUSION
This Axis II personality disorder, characterized by
affective instability, impulsive aggression, and iden-
tity disturbance, is chronic, severe, and potentially
lethal. Progress in elucidating the underlying biolo-
gical underpinnings in the serotonin system and
altered limbic responsivity for BPD offers promise
for the development of more effective treatment
strategies. Work integrating how environmental
stress such as childhood trauma interacts with
temperament and biological vulnerabilities to pro-
duce BPD dysfunction is needed.
—Marianne Goodman and Daniel S. Weiss
See also–Behavior, Neuropathology of; Bipolar
Disorder; Mood Disorders, Biology; Personality
Types and Disorders; Post-Traumatic Stress
Disorder (PTSD)
Further Reading
American Psychiatric Association (1994). Diagnostic and Statis-
tical Manual of Mental Disorders, 4th ed. American Psychiatric
Association, Washington, DC.
Coccarro, E., and Kavoussi, R. (1997). Fluoxetine and impulsive
aggressive behavior in personality-disordered subjects. Arch.
Gen. Psychiatry 54, 1081–1088.
Coccaro, E., Siever, L., Klar, M., et al. (1989). Serotonergic studies
in patients with affective and personality disorders. Arch. Gen.
Psychiatry 44, 573–588.
Herman, J. L., and van der Kolk, B. A. (1987). Traumatic
antecedents of borderline personality disorder. In Psychological
Trauma (B. A. van der Kolk, Ed.). American Psychiatric Press,
Washington, DC.
Kellner, C. H., Post, R. M., Putnam, F., et al. (1987).
Intravenous procaine as a probe of limbic system activity in
psychiatric patients and normal controls. Biol. Psychiatry 22,
1107–1126.
Linehan, M. M., and Koerner, K. (1993). A behavioral theory of
borderline personality disorder. In Borderline Personality
Disorder and Treatment (J. Paris, Ed.), pp. 103–121. American
Psychiatric Press, Washington, DC.
New, A., Goodman, M., Mitropoulou, V., et al. (2002). Genetic
polymorphisms and aggression. In Molecular Genetics and
Human Personality (J. Benjamin and R. Ebstein, Eds.),
pp. 231–244. American Psychiatric Press, Washington, DC.
Paris, J., and Zweig-Frank, H. (1992). A critical review of the role
of childhood sexual abuse in the etiology of borderline
personality disorder. Can. J. Psychiatry 37, 125–128.
Siever, L. J., and Davis, K. (1991). A psychobiological perspective
on the personality disorders. Am. J. Psychiatry 148,
1647–1658.
BORNA DISEASE VIRUS 397
Siever, L. J., Buchsbaum, M., New, A., et al. (1999).
d,l-Fenfluramine response in impulsive personality disorder
assessed with 18F-deoxyglucose positron emission tomography.
Neuropsychopharmacology 20(5), 413–423.
Soloff, P., Meltzer, C., Greer, P., et al. (2000). A fenfluramine-
activated FDG-PET study of borderline personality disorder.
Biol. Psychiatry 47, 540–547.
Stern, A. (1938). Psychoanalytic investigation of and therapy
in the borderline group of neuroses. Psychoanalytic Q. 7,
467–489.
Zanarini, M. C. (2000). Childhood experiences associated with the
development of borderline personality disorder. Psychiatry
Clin. North Am. 23, 89–101.
Zanarini, M., and Frankenburg, F. (1997). Pathways to the
development of borderline personality disorder. J. Personal.
Disord. 11, 93–104.
Borna Disease Virus
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BORNA DISEASE VIRUS (BDV) is the prototype of the
family Bornaviridae, genus Bornavirus, within the
nonsegmented negative-strand RNA viruses (order
Mononegavirales). This neurotropic virus appears to
be distributed worldwide and has potential to infect
most warm-blooded hosts. BDV is similar in genomic
organization to other nonsegmented, negative-
stranded (NNS) RNA viruses. The name Borna refers
to the city of Borna, Germany, where an equine
epidemic during the late 1800s crippled the Prussian
cavalry.
The geographic distribution of BDV is unknown.
Natural infection has been reported in Europe,
North America, and parts of Asia (Japan, Israel,
and Iran). However, this restriction may reflect
failure of case ascertainment due to lack of sensitive
methods and reagents for diagnosis of infection or a
failure to consider the possibility of BDV infection.
Recent reports of asymptomatic naturally infected
animals in Germany and Japan suggest that the virus
may be more widespread than previously appre-
ciated.
Neither the reservoir nor the mode for transmis-
sion of natural infection are known. An olfactory
route for transmission has been proposed because
intranasal infection is efficient and the olfactory
bulbs of naturally infected horses show inflammation
and edema early in the course of disease. Reports of
BDV nucleic acid and proteins in peripheral blood
mononuclear cells also indicate the possibility of
hematogeneous transmission. Experimental infection
398 BORNA DISEASE VIRUS
of neonatal rats results in virus persistence and is
associated with the presence of virus in saliva, urine,
and feces. These secreta/excreta are known to be
important in transmission of other pathogenic
viruses (e.g., lymphocytic choriomeningitis virus
and hantaviruses); whether rats or other rodents
are potential significant natural reservoirs or vectors
for BDV is unknown.
Humans are likely to be susceptible to BDV
infection; however, the epidemiology and clinical
consequences of human infection remain controver-
sial. Most reports implicating BDV and human
disease have focused on neuropsychiatric disorders,
including unipolar depression, bipolar disorder, or
schizophrenia; however, BDV has also been linked to
chronic fatigue syndrome, AIDS encephalopathy,
multiple sclerosis, motor neuron disease, and brain
tumors (glioblastoma multiforme). There are only
rare reports of infectious virus being isolated from
humans; diagnosis of infection has typically been
based on serology or polymerase chain reaction
amplification of BDV genetic sequences in blood
or tissues. Methods used most commonly for
serological diagnosis of infection include indirect
immunofluorescence with infected cells, Western
immunoblot, and enzyme-linked immunosorbent
assays with extracts of infected cells or recombinant
proteins. There are only two reports in which BDV
nucleic acids were found in human brain (hippo-
campal sclerosis and schizophrenia) by in situ
hybridization. However, most investigators whose
results indicate human infection of blood or brain
have used nested reverse transcription-polymerase
chain reaction (nRT-PCR), a method that is prone to
artifacts due to inadvertent introduction of template
from laboratory isolates or cross-contamination of
samples. Amplification products representing bona
fide isolates and those due to nRT-PCR amplification
of low-level contaminants cannot be readily distin-
guished by sequence analysis. To determine the
epidemiology of BDV and its role in human disease,
large multicenter studies have been initiated wherein
standardized methods will be employed for clinical
diagnosis and blinded laboratory assessment of
infection.
Cells of many different lineages and species can
be infected in vitro with BDV; however, virus
production is more efficient in neural than in
nonneural cells. BDV is also neurotropic in vivo,
with a particular predilection for neurons of the
limbic system. Cells initially targeted in natural
infection of horses and experimental infection of
rats include neurons of the hippocampus and
amygdala. The virus later spreads throughout the
central nervous system (CNS) to infect astrocytes,
Schwann cells, and ependymal cells. Viral transport
is presumably axonal and trans-synaptic. Follow-
ing intranasal infection, viral antigen is detected
sequentially in olfactory receptor cells, olfactory
nerve fibers, cells of the olfactory bulb, and
olfactory cortex. In hippocampus, viral antigen is
localized in axon terminals that form synaptic
contacts with CA1 pyramidal cell dendrites prior
to appearing in pyramidal cell bodies. Similar to
rabies virus, it is likely that the spread of BDV
infection within the CNS is mediated primarily by
ribonucleoprotein particles rather than enveloped
virions.
No specific vaccine or antiviral therapy are
established for BDV. Although one report found
BDV to be sensitive to amantadine in vitro and in
vivo, three other reports found no antiviral activity in
vitro or in vivo. The nucleoside analog ribavirin
inhibits viral replication in vitro. Whether it has an
impact on viral replication in vivo or on severity of
disease is unknown.
—W. Ian Lipkin, Mady Hornig, and Thomas Briese
See also–Viral Vaccines and Antiviral Therapy
Further Reading
Briese, T., Schneemann, A., Lewis, A. J., et al. (1994). Genomic
organization of Borna disease virus. Proc. Natl. Acad. Sci. USA
91, 4362–4366.
De La Torre, J. C., Gonzalez-Dunia, D., Cubitt, B., et al. (1996).
Detection of Borna disease virus antigen and RNA in human
autopsy brain samples from neuropsychiatric patients. Virology
223, 272–282.
Lipkin, W. I., Travis, G. H., Carbone, K. M., et al. (1990).
Isolation and characterization of Borna disease agent cDNA
clones. Proc. Natl. Acad. Sci. USA 87, 4184–4188.
Ludwig, H., Bode, L., and Gosztonyi, G. (1988). Borna disease: A
persistent disease of the central nervous system. Prog. Med.
Virol. 35, 107–151.
Narayan, O., Herzog, S., Frese, K., et al. (1983). Behavioral
disease in rats caused by immunopathological responses
to persistent Borna virus in the brain. Science 220,
1401–1403.
Solbrig, M. V., Koob, G., Fallon, J. H., et al. (1994). Tardive
dyskinetic syndrome in rats infected with Borna disease virus.
Neurobiol. Dis. 3, 111–119.
Staeheli, P., Sauder, C., Hausmann, J., et al. (2000). Epidemiology
of Borna disease virus. J. Gen. Virol. 81, 2123–2135.
Zimmerman, W., Breter, H., Rudolph, M., et al. (1994). Borna
disease virus: Immunoelectron microscopic characterization of
cell-free virus and further information about the genome.
J. Virol. 68, 6755–6758.

Botulism
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BOTULISM is a paralyzing disease caused by one
of the most potent toxins. The toxin is produced
by an anaerobic, spore-forming, gram-positive bac-
teria named Clostridium botulinum. The classic
(food-borne) form of botulism results from the
ingestion of toxin in food contaminated with toxin-
producing bacteria. Infant botulism is caused by
the ingestion of spores that then germinate and
produce toxin in the infant’s gastrointestinal tract.
Other less common forms include wound botulism,
the hidden form (adult form of infant botulism), and
inadvertent botulism (inadvertent muscle paralysis
after injection of botulinum toxin when used as a
treatment).
Clostridium botulinum is a sturdy pathogenic
bacterium found in soil. It proliferates under
anaerobic and alkaline conditions and produces a
powerful toxin. The bacteria generate spores that can
survive extreme weather and temperature conditions.
Unlike the toxin, which is heat labile, the spores are
relatively heat resistant. Temperatures of 1201C may
be required to kill the spores, whereas heating at
851C inactivates the toxin.
The toxin has been called the most poisonous
poison. It has been estimated that doses as small as
0.05–0.1 mg can cause death in humans. Genetically
distinct groups of organisms produce neurotoxins
with similar pharmacological activity. Eight immu-
nologically distinct toxins (A, B, C1, C2, and D–G)
of C. botulinum have been identified.
MECHANISM OF ACTION OF TOXIN
For many years, physicians understood that the
muscle paralysis was the result of a blockade to the
release of the transmitter acetylcholine at the
junction between nerves and muscles. Recent studies
have elucidated where and how the toxin acts at the
nerve terminals. The toxin binds to the presynaptic
terminal and enters the cell by endocytosis. The
disulfide bond linking the two botulinum toxin
chains is broken. The light chain is translocated out
of the endocytotic vesicle and into the cytoplasm.
Each type of botulinum toxin works by enzymatic
cleavage of proteins that are needed for the
exocytosis of acetylcholine. Toxins A, C, and E
cleave the protein SNAP-25; types B, D, F, and G
BOTULISM 399
cleave a synaptobrevin vesicle-associated membrane
protein; and type C cleaves syntaxin. As a result of
these chemical actions, acetylcholine cannot be
released and the muscle is paralyzed.
CLINICAL PRESENTATION
Cranial nerve palsies are followed by descending
weakness of the limbs and, in some cases, respiratory
paralysis. Early symptoms include blurred or double
vision, dizziness, trouble swallowing, and trouble
speaking. These symptoms can be followed by
weakness of the arms and then the legs. If symptoms
progress, patients should be hospitalized and ob-
served closely in critical care units. In severe cases,
patients develop breathing difficulties and may
require ventilatory assistance. There are five recog-
nized forms of botulism: classic, infant, wound,
hidden, and inadvertent.
Classic (Food-Borne)
The symptoms of food-borne botulism begin several
hours to days after the ingestion of contaminated
food. Home-canned food contaminated with toxin-
producing bacterial spores is often the source of the
toxin. When commercially canned food is contami-
nated, there is danger of a larger epidemic. There are
eight serotypes of botulinum toxin. Most human
cases are caused by types A, B, and E. Type E is most
often found in cases of contaminated fish and
seafood. Fatalities have been reported with all three
types. Although the clinical presentations of A, B,
and E can be similar, type A cases may be more
severe and longer lasting than type B cases. Other
toxin types have had less epidemiological impact.
The bacterial spores are resistant to heat and may
survive the home-canning process at temperatures
below 1201C. Boiling food prior to canning at high
elevations may not provide a high enough tempera-
ture to destroy the spores.
Environmental factors that favor spore germina-
tion and toxin production are low acidity (pH 45),
low oxygen, and high water content. Home-canned
foods containing fish, vegetables, and potatoes have
been implicated in outbreaks of botulism. Other
vehicles for food-borne botulism include olives,
garlic in oil, sautéed onions, and salsa. In contrast,
high acid content foods, such as vinegar and tomato,
are rarely associated with botulism. Since some new
varieties of tomatoes have a low acid content, lemon
juice should be added when canning tomatoes.
Boiling of food to ensure thorough heating of the
400 BOTULISM
interior should destroy the toxin. In contrast to the
heat-resistant properties of the spores, the exotoxin is
heat labile. Consumers should know that baked
potatoes wrapped in aluminum foil present a special
hazard. Baking may not kill C. botulinum spores
in a foil-wrapped potato because the temperature
at the surface of the potato may not exceed
1001C. Consequently, toxin formation can take
place when the foil-wrapped potato is left at room
temperature.
Although the number of restaurant-associated
outbreaks is small (2%), the number of cases of
botulism per epidemic is often much greater than the
number who become sick from contaminated home-
prepared food. Because there is a potential for many
patrons of a restaurant to be exposed to contami-
nated food, the Centers for Disease Control and
Prevention (CDC) and state health departments
should be notified immediately.
The clinical presentation of food-borne botulism is
stereotypical. Within 2–36 hr after ingestion of
contaminated food, most patients develop signs and
symptoms related to oculobulbar muscle weakness,
including blurring of vision, diplopia, ptosis,
ophthalmoplegia, dysarthria, and dysphagia. Tongue
weakness is often profound. These abnormalities of
cranial nerve muscles are followed by a descending
pattern of weakness affecting the upper limbs and
then lower limbs, and in some cases respiratory
muscle weakness occurs. Limb and ocular weakness
are usually bilateral but can be asymmetric. Dilata-
tion of the pupils is found in less than 50% of
patients.
Patients with the severe, paralyzing form usually
present earlier and progress more rapidly than
patients with only minimal weakness. Those with
mild symptoms are often diagnosed when they
accompany their more sick family members or
friends to the doctor’s office or emergency depart-
ment. Patients who show signs of progression must
be carefully monitored for respiratory difficulties.
With improvements in critical care management,
fatality rates have declined from 50% of documented
cases during much of the 20th century to 9% in
recent years. Nevertheless, when hospitalized pa-
tients die, death is likely from a complication of long-
term ventilatory care.
The sensory system and mentation are spared,
although there have been reports of sensory abnorm-
alities. The few patients who have sensory abnorm-
alities may or may not have an additional unrelated
malady.
Botulinum toxin inhibition of acetylcholine release
affects the parasympathetic and sympathetic systems
as well as the neuromuscular junction. Autonomic
signs and symptoms include constipation, dry mouth,
postural hypotension, urinary retention, and pupil-
lary abnormalities. The autonomic dysfunction of
botulism patients is suggested by heart rate R-R
interval variation, the absence of sympathetic skin
response, and a low level of plasma norepinephrine.
Although constipation is the most frequent gastro-
intestinal problem, nausea, vomiting, and diarrhea
may also occur early in the illness.
Recovery from botulism is prolonged and usually
complete. Symptoms of general fatigue and dry mouth
can persist after normal muscle strength is regained.
The long recuperation (weeks or months) probably
results from nerve terminal sprouting at motor end
plates. Recovery of autonomic function may take
longer than that of neuromuscular transmission.
The differential diagnosis of botulism encompasses
other neuromuscular disorders, including myasthenia
gravis (MG), Lambert–Eaton myasthenic syndrome
(LEMS), Guillain–Barré syndrome (GBS), tick pa-
ralysis, Miller–Fisher syndrome (MFS), and
diphtheritic neuropathy. The pattern of descending
weakness is a clinical hallmark of botulism and
distinguishes it from the classic form of GBS, which
usually presents with ascending weakness. The
Miller–Fisher variant of GBS, with ocular and bulbar
abnormalities, may present a more difficult diagnos-
tic challenge. The preservation of deep tendon
reflexes would be more in keeping with botulism
than MFS. It has been estimated that 90% of MFS
patients with ophthalmoplegia have autoantibodies
to GQ1b in acute phase sera.
Electrophysiological studies can be done at the
bedside and are often valuable in locating the site of
the lesion at either the neuromuscular junction,
consistent with botulism, or at the level of the
peripheral nerve, consistent with GBS. Diphtheritic
neuropathy with bulbofacial weakness is character-
ized by sore throat, tonsillar exudate, and, weeks
later, a demyelinating neuropathy. Electrodiagnostic
studies should help identify the patient with LEMS,
in which postactivation facilitation is more pro-
nounced than in botulism.
Some patients with botulism show a beneficial
response to anticholinesterase drugs. Patients with
mild botulism may mimic MG with signs of clinical
pathological fatigue and dramatic response to short-
acting intravenous anticholinesterase agents, such as
edrophonium chloride.

Infant botulism
Infant botulism was first described in 1976. Since
1990, the number of cases of infant botulism
reported to the CDC has exceeded those of food-
borne botulism by approximately two to one, even
though food-borne cases often occur in epidemics of
multiple cases. Epidemics are not characteristic of
infant botulism.
In the classic adult form, preformed toxin is
ingested with contaminated food. In infant botulism,
spores of C. botulinum are ingested and germinate in
the intestinal tract. The infant intestinal tract often
lacks both the protective bacterial flora and the
clostridium-inhibiting bile acids found in normal
adult intestinal tract. Consequently, the infant
intestinal tract is more susceptible to colonization
by toxin producing C. botulinum. When the diag-
nosis is suspected, fecal samples should be examined
for toxin and cultured for C. botulinum. If an infant
were to ingest preformed toxin, he or she would most
likely be poisoned by the toxin rather than have the
usual infant form.
Most cases occur before the age of 6 months.
Constipation may be the first sign of trouble. Perhaps
the decreased intestinal mobility allows ingested
spores to germinate and produce toxin. Other
common early signs are weak cry, difficulty feeding,
and weakness of bulbar and limb muscles. Addi-
tional manifestations of muscle weakness usually
progress over 1–3 days and include poor sucking
ability, loss of head control, hypotonia, and a
decrease in spontaneous movements. Findings con-
sistent with blockade of the parasympathetic nervous
system include constipation, tachycardia, hypoten-
sion, neurogenic bladder, and dry mouth. With
adequate supportive care, most infants recover in
weeks or months without sequelae. However, mor-
tality rates have been reported to be as high as 5%.
The differential diagnosis of infant botulism
comprises several other neuromuscular disorders
associated with hypotonia, including myopathies,
GBS, familial infantile MG, spinal muscular atrophy,
and poliomyelitis.
Breast-feeding as a risk factor has been controver-
sial. It has been suggested that breast-feeding
increases the risk and, paradoxically, that it offers
protection. In fact, infant botulism occurs in both
bottle-fed and breast-fed infants.
Epidemiological studies have implicated honey
consumption as a significant risk factor for infant
botulism. Honey is more likely to harbor type B
BOTULISM 401
organisms than type A bacteria. Microbiological
surveys of honey products have reported the presence
of clostridial spores in up to 25% of products. For
these reasons, honey should not be fed to children
during the first year of life. The C. botulinum
organism is ubiquitous and may be found in dirt,
possibly on fruit and vegetables, and on infant toys
that have not been washed.
Wound Botulism
Until recently, wound botulism was considered to be
a rare form of botulism. It occurred almost exclu-
sively in patients with traumatic and surgical
wounds. Since the bacteria are ubiquitous and found
in soil samples, it is surprising that cases of wound
botulism in trauma situations are so uncommon. Its
rarity has been attributed to the failure of the
clostridial spores to germinate readily in tissues.
Since 1991, the numbers of cases of wound
botulism have increased dramatically. Nearly all of
these new cases have occurred in injecting drug users.
Small abscesses at injection sites in a drug abuser
may harbor C. botulinum bacteria. Sinusitis second-
ary to cocaine abuse can also be the source of C.
botulinum. The organism has been cultured from the
abscesses of intravenous heroin users and from sinus
aspirate of a patient who developed botulism
following intranasal cocaine abuse. The toxin can
be absorbed from all mucous membranes, broken
skin, as well as wounds.
The neurological features of wound botulism are
similar to those of food-borne botulism. The
diagnosis should be considered in any wound case
when the patient develops bulbar signs and increas-
ing weakness. In one-third to one-half of wound
botulism cases, toxin is not detected in serum and C.
botulinum is not isolated from the wound. In such
cases, electrodiagnostic studies can be very helpful in
establishing the correct diagnosis.
The treatment of wound botulism is largely the
same as that of classic botulism, with the addition of
surgical treatment of the wound. The surgeon should
debride the wound and remove devascularized tissue
that might facilitate anaerobic conditions. Antibio-
tics should be considered in some instances.
Hidden Botulism
Hidden botulism is diagnosed in adult botulism
patients in whom the source of the toxin has been
hidden from clinicians because there is no known
contaminated food, no wound, and no history of
drug abuse. Most of these cases are adult variations
402 BOTULISM
of infant botulism (i.e., these patients accommodate
toxin-producing clostridial bacteria in their intestinal
tract). A diagnostic clue is some abnormality of the
gastrointestinal tract, such as prior surgery, achlor-
hydria, Crohn’s disease, or recent antibiotic treat-
ment. The finding of C. botulinum in feces of adult
patients is almost always associated with clinical
botulism. The organism ‘‘hides’’ in the adult gastro-
intestinal tract, germinates, and produces toxin,
leading to botulism. Since most adult cases are
acquired from eating preformed toxin or from
contaminated wounds, this rare ‘‘infant form’’ has
been called the hidden form.
Inadvertent Botulism
This is the most recent form of botulism to be
recognized. In one of the stranger ironies of medicine
and science, the toxin that is responsible for botulism
is now being used to treat dystonic and other
movement disorders. In an extraordinary double
twist, botulism has been reported in a few patients
treated with intramuscular injections of botulinum
toxin. These patients demonstrated moderate to
marked clinical weakness. In addition, some of these
patients exhibited electrophysiological abnormalities
consistent with botulism. They had been treated with
doses considered therapeutic or below the maximum
recommended dose. Some patients develop auto-
nomic nervous system effects following injections of
toxin. Patients without clinical weakness have been
found to have prolonged jitter values and increased
blocking on single-fiber electromyography (EMG)
recorded from muscles distant from the injection.
The toxin probably circulates in the blood to
produce blockade of transmitter release both at
distant neuromuscular junctions and in the auto-
nomic nervous system.
Patients with cervical dystonia treated with botu-
linum toxin often experience dysphagia after sterno-
cleidomastoid injections are attributed to the spread
of toxin to neighboring muscles. Inadvertent general-
ized weakness and autonomic nervous system symp-
toms are likely consequences of toxin circulating in
the blood. Inadvertent focal weakness probably
occurs following the spread of toxin from an injected
muscle to adjacent noninjected muscles.
DIAGNOSTIC METHODS
Laboratory proof of botulism is established with the
detection of toxin in the patient’s serum, stool, or
wound. Detection of C. botulinum in the stool
should also be considered evidence of clinical
botulism. Rarely, however, C. botulinum has been
isolated from the stool of normal control infants.
Clostridium botulinum is found in the stool of 60%
of patients with botulism and almost never in the
stool of healthy adults. The suspected food, if still
available, should also be tested. The CDC and many
state health facilities can be useful in collecting and
testing specimens. The toxin type can be identified
using mouse bioassay studies with antitoxin neutra-
lization. In many patients, laboratory tests are not
confirmatory, especially when collection of the
specimens has been deferred for days after the onset
of symptoms. If the serum samples are secured more
than 2 days after ingestion of the toxin, the chance of
obtaining a positive test is less than 30%. Only 36%
of stool cultures are positive after 3 days.
ELECTRODIAGNOSTIC FINDINGS
Electrophysiological testing can provide presumptive
evidence of botulism in patients with the clinical
picture of botulism and in whom bioassay studies for
botulinum toxin are negative and stool cultures are
negative. The most consistent electrophysiological
abnormality is a small evoked muscle action poten-
tial (MAP) in response to a single supramaximal
nerve stimulus in a clinically affected muscle.
The following are the expected electrical findings
in botulism:
1. Sensory nerve amplitudes, velocities, and la-
tencies are normal.
2. Motor conduction velocities are normal. The
amplitude of the MAP after a single nerve
stimulus is reduced in many affected muscles.
This abnormality is found in 85% of patients
with botulism.
3. A decremental response of the MAP to slow
rates of nerve stimulation (2–3 Hz) is seen
infrequently.
4. Post-tetanic facilitation (PTF) similar to but less
conspicuous than that seen in LEMS can be
found in some affected muscles. PTF is mea-
sured after rapid rates (50 Hz) of supramaximal
nerve stimulation or after 10 sec of isometric
exercise, which is less painful. The degree of
PTF in botulism is usually between 30 and
100%, whereas in LEMS potentiation is often
twofold or more and lasts for only 30–60 sec. In
some, but not all, cases of botulism, PTF of

40% or more can persist for several minutes.
PTF may be absent in severely affected muscles.
5. Needle EMG studies reveal an increased num-
ber of brief polyphasic motor unit action
potentials and spontaneous denervation poten-
tials.
6. Single-fiber EMG studies typically, but not
consistently, reveal increased jitter and blocking
that become less marked following activation.
Jitter is due to a variable delay at the synapse
and is a measure of the safety factor of
neuromuscular transmission.
TREATMENT
The main treatment for severe botulism is advanced
medical and nursing supportive care with special
attention to respiratory status. Physicians should
carefully observe patients for progression of limb and
respiratory muscle weakness. Elective intubation
should be considered for those at risk for respiratory
failure. Patients who suffer a respiratory arrest
before intubation are more likely to die than those
intubated electively. Critical care teams should be
especially vigilant in their management because
recovery from botulism is not only possible but also
common. Convalescence in severe cases may take
weeks or months.
Other forms of therapy can be categorized as
adjunctive and/or experimental. They are not a
substitute for medical management in an intensive
care unit.
Antitoxin administration is controversial because
of lack of efficacy in many cases and the danger of
allergic reactions. Beneficial effects are more likely
with type E botulism than with types A or B. To be of
benefit, antitoxin must be given early while the toxin
is still in the blood and before it is internalized and
bound at the nerve terminal. Serious side effects
occur in as many as 20% of patients. Most
commercially available botulinum antitoxins are of
equine origin and allergic responses are attributed to
antibody products of nonhuman origin.
Guanidine and 4-aminopyridine (4-AP) have
been reported to improve ocular muscle and limb
muscle strength in some patients. Unfortunately, they
have little or no effect in reversing respiratory
paralysis. Both drugs enhance the release of acet-
ylcholine from nerve terminals. The serious side
effects of guanidine, bone marrow suppression and
nephritis, are dose and time related. 4-AP therapy
can be complicated by the development of seizures.
BOTULISM 403
The experience with both drugs is limited and results
are variable.
Steroids, plasmapheresis, and intravenous immune
globulin have been given to a small number of
patients with ambiguous or dubious benefits. These
therapeutic approaches must be considered either
adjunctive or experimental.
BOTULINUM TOXIN AS TREATMENT
In the past 20 years, we have witnessed the strangest
of all ironies in the history of medicine. The very
lethal botulinum toxin is now being used as a
treatment for a variety of ophthalmic and neurolo-
gical disorders, including those of ocular motility,
movement disorders such as spasticity, and migraine
headache. There is a growing list of other specialists,
including plastic surgeons, gastroenterologists, and
colon and rectal surgeons, who use botulinum toxin
injections to treat conditions in their fields. Plastic
surgeons use botulinum toxin A for cosmetic
purposes. It has been used as a nonsurgical treatment
of glabellar frown lines and hypertrophic platysma
muscle bands of the ‘‘aging neck.’’ Gastroenterolo-
gists have injected the toxin into the lower esopha-
geal sphincter to treat achalasia. Colon and rectal
surgeons have successfully treated chronic anal
fissure with botulinum toxin injections.
With these new treatments have come new
problems. Inadvertent weakness of both generalized
and local distribution has been seen following the
therapeutic injection of botulinum toxin. This weak-
ness, distant to the muscle being treated, is unwanted
and inadvertent. Patients who develop generalized
weakness have an inadvertent form of botulism
because it was not the intention to cause generalized
weakness or local weakness in sites distant from the
injection. This is not an overdose effect. The
generalized weakness occurred even though recom-
mended doses were given. Other patients have
developed autonomic nervous system effects (inad-
vertent and unwanted) following recommended
doses. Antibodies are very rarely found in survivors
of botulism, but antibodies to toxin A do develop in
some patients who have been injected repeatedly for
movement disorders. With the development of
antibodies, these patients cannot be further treated
with injections of toxin A. Other toxin serotypes
(especially B and F) are being evaluated and may
soon be available to treat patients who are resistant
to type A toxin.
—Michael Cherington
404 BOVINE SPONGIFORM ENCEPHALOPATHY
See also–Basal Ganglia, Diseases of; Guillain-
Barré Syndrome, Clinical Aspects; Migraine
Treatment; Neurotoxicology, Overview
Further Reading
Angulo, F. J., Getz, J., Taylor, J. P., et al. (1998). A large outbreak
of botulism: The hazardous baked potato. J. Infect. Dis. 178,
172–177.
Arnon, S. S. (1986). Infant botulism: Anticipating the second
decade. J. Infect. Dis. 154, 201–205.
Bahkeit, A. M. O., Ward, C. D., and Mclellan, D. L. (1997).
Generalized botulism-like syndrome after intramuscular injec-
tions of botulinum toxin type A: A report of two cases. J.
Neurol. Neurosurg. Psychiatry 62, 198.
Chen, J. T., Chen, C. C., Lin, K. P., et al. (1999). Botulism: Heart
rate variation, sympathetic skin responses and plasma norepi-
nephrine. Can. J. Neurol. Sci. 26, 123–126.
Cherington, M. (1982). Electrophysiologic methods as an aid in
diagnosis of botulism. Muscle Nerve 5, S28–S29.
Cherington, M. (1998). Clinical spectrum of botulism. Muscle
Nerve 21, 701–710.
Girlanda, P., Vita, G., Nicolosi, C., et al. (1992). Botulinum toxin
therapy: Distant effects on neuromuscular transmission and
autonomic nervous system. J. Neurol. Neurosurg. Psychiatry
55, 844–845.
Hayes, M. T., Soto, O., and Ruoff, K. L. (1997). Case records of
the Massachusetts General Hospital: Case 22-1997. N. Engl. J.
Med. 337, 184–190.
Lamana, C. (1959). The most poisonous poison. Science 130,
763–772.
Maselli, R. A. (1998). Pathogenesis of human botulism. Ann. N. Y.
Acad. Sci. 841, 122–139.
Munchau, A., and Bhatia, K. P. (2000). Uses of botulinum toxin
injection in medicine today. Br. Med. J. 320, 161–165.
Padua, L., Aprile, I., Monaco, M. L., et al. (1999). Neurophysio-
logical assessment in the diagnosis of botulism: Usefulness of
single-fiber EMG. Muscle Nerve 22, 1388–1392.
Pickett, J. B., Berg, B., Chaplin, E., et al. (1976). Syndrome of
botulism in infancy: Clinical and electrophysiologic study. N.
Engl. J. Med. 295, 770–772.
Shapiro, B. E., Soto, O., Shafqat, S., et al. (1997). Adult botulism.
Muscle Nerve 20, 100–102.
Shapiro, R. L., Hatheway, C., and Swerdlow, D. L. (1998).
Botulism in the United States: A clinical and epidemiologic
review. Ann. Int. Med. 129, 221–228.
Townes, J. M., Cieslak, P. R., Hatheway, C. L., et al. (1996). An
outbreak of type a botulism associated with a commercial
cheese sauce. Ann. Int. Med. 125, 558–563.
Bovine Spongiform
Encephalopathy (BSE)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) is
popularly known as mad cow disease. It is a new
disease of domestic cattle (hence bovine), especially
adult dairy cows, and is currently confined to
Europe. Confirmation of the disease can only be
made after death. One way to do this is by
microscopic examination of the brain, which reveals
microscopic holes in nerve cells and in nearby gray
matter such that the appearance is like a section
through a sponge (hence spongiform). Most com-
monly known infectious diseases of the brain caused
by bacteria or viruses, such as cerebral listeriosis,
rabies, and louping ill, result in inflammation of the
brain or encephalitis. BSE, however, is caused by an
unconventional agent called variously a prion
(hence prion disease), a virino (prion protein
concealing an unidentified agent genome), or an
undefined virus that does not produce inflammation.
These agents cause degeneration of the brain without
inflammation (hence encephalopathy rather than
encephalitis).
BSE belongs to the group of diseases previously
known as the subacute, transmissible, spongiform
encephalopathies (TSEs) and now often referred to as
prion diseases. The latter name is given because the
agent that is responsible may be a prion, which is a
proteinaceous infectious particle composed, perhaps
entirely, of a modified form of host protein called
prion protein or PrP. The PrP gene (Fig. 1) codes for
this protein.
The PrP present in normal nervous and some other
tissues is called PrP cellular (PrPC). PrPC is entirely
denatured (degraded) when treated with proteinac-
eous enzymes called proteases. In disease, the normal
host protein is converted to PrP scrapie (PrPSc),
which is partially protease resistant. This is an
important feature that has led to the development
of many additional tests for prion diseases that are
based on their ability to detect PrPSc and distinguish
Figure 1
Relationship between the PrP gene and prion protein in health and
disease (Crown copyright).
404 BOVINE SPONGIFORM ENCEPHALOPATHY
See also–Basal Ganglia, Diseases of; Guillain-
Barré Syndrome, Clinical Aspects; Migraine
Treatment; Neurotoxicology, Overview
Further Reading
Angulo, F. J., Getz, J., Taylor, J. P., et al. (1998). A large outbreak
of botulism: The hazardous baked potato. J. Infect. Dis. 178,
172–177.
Arnon, S. S. (1986). Infant botulism: Anticipating the second
decade. J. Infect. Dis. 154, 201–205.
Bahkeit, A. M. O., Ward, C. D., and Mclellan, D. L. (1997).
Generalized botulism-like syndrome after intramuscular injec-
tions of botulinum toxin type A: A report of two cases. J.
Neurol. Neurosurg. Psychiatry 62, 198.
Chen, J. T., Chen, C. C., Lin, K. P., et al. (1999). Botulism: Heart
rate variation, sympathetic skin responses and plasma norepi-
nephrine. Can. J. Neurol. Sci. 26, 123–126.
Cherington, M. (1982). Electrophysiologic methods as an aid in
diagnosis of botulism. Muscle Nerve 5, S28–S29.
Cherington, M. (1998). Clinical spectrum of botulism. Muscle
Nerve 21, 701–710.
Girlanda, P., Vita, G., Nicolosi, C., et al. (1992). Botulinum toxin
therapy: Distant effects on neuromuscular transmission and
autonomic nervous system. J. Neurol. Neurosurg. Psychiatry
55, 844–845.
Hayes, M. T., Soto, O., and Ruoff, K. L. (1997). Case records of
the Massachusetts General Hospital: Case 22-1997. N. Engl. J.
Med. 337, 184–190.
Lamana, C. (1959). The most poisonous poison. Science 130,
763–772.
Maselli, R. A. (1998). Pathogenesis of human botulism. Ann. N. Y.
Acad. Sci. 841, 122–139.
Munchau, A., and Bhatia, K. P. (2000). Uses of botulinum toxin
injection in medicine today. Br. Med. J. 320, 161–165.
Padua, L., Aprile, I., Monaco, M. L., et al. (1999). Neurophysio-
logical assessment in the diagnosis of botulism: Usefulness of
single-fiber EMG. Muscle Nerve 22, 1388–1392.
Pickett, J. B., Berg, B., Chaplin, E., et al. (1976). Syndrome of
botulism in infancy: Clinical and electrophysiologic study. N.
Engl. J. Med. 295, 770–772.
Shapiro, B. E., Soto, O., Shafqat, S., et al. (1997). Adult botulism.
Muscle Nerve 20, 100–102.
Shapiro, R. L., Hatheway, C., and Swerdlow, D. L. (1998).
Botulism in the United States: A clinical and epidemiologic
review. Ann. Int. Med. 129, 221–228.
Townes, J. M., Cieslak, P. R., Hatheway, C. L., et al. (1996). An
outbreak of type a botulism associated with a commercial
cheese sauce. Ann. Int. Med. 125, 558–563.
Bovine Spongiform
Encephalopathy (BSE)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) is
popularly known as mad cow disease. It is a new
disease of domestic cattle (hence bovine), especially
adult dairy cows, and is currently confined to
Europe. Confirmation of the disease can only be
made after death. One way to do this is by
microscopic examination of the brain, which reveals
microscopic holes in nerve cells and in nearby gray
matter such that the appearance is like a section
through a sponge (hence spongiform). Most com-
monly known infectious diseases of the brain caused
by bacteria or viruses, such as cerebral listeriosis,
rabies, and louping ill, result in inflammation of the
brain or encephalitis. BSE, however, is caused by an
unconventional agent called variously a prion
(hence prion disease), a virino (prion protein
concealing an unidentified agent genome), or an
undefined virus that does not produce inflammation.
These agents cause degeneration of the brain without
inflammation (hence encephalopathy rather than
encephalitis).
BSE belongs to the group of diseases previously
known as the subacute, transmissible, spongiform
encephalopathies (TSEs) and now often referred to as
prion diseases. The latter name is given because the
agent that is responsible may be a prion, which is a
proteinaceous infectious particle composed, perhaps
entirely, of a modified form of host protein called
prion protein or PrP. The PrP gene (Fig. 1) codes for
this protein.
The PrP present in normal nervous and some other
tissues is called PrP cellular (PrPC). PrPC is entirely
denatured (degraded) when treated with proteinac-
eous enzymes called proteases. In disease, the normal
host protein is converted to PrP scrapie (PrPSc),
which is partially protease resistant. This is an
important feature that has led to the development
of many additional tests for prion diseases that are
based on their ability to detect PrPSc and distinguish
Figure 1
Relationship between the PrP gene and prion protein in health and
disease (Crown copyright).

it from PrPC. In the diseased state PrPSc is usually
abundant in the brain.
Other members of the prion disease group include
scrapie of sheep and goats, known since at least the
18th century, and Creutzfeldt–Jakob disease (CJD) in
humans, which was first reported in the early 1920s.
With the exception of scrapie, and recently BSE, all
the diseases are rare. Some, such as BSE and another
rare TSE of humans, kuru, are geographically
confined. On the other hand, CJD and, to a lesser
extent, scrapie have a much wider geographical
distribution. However, there was no evidence that the
human diseases transmitted naturally to animals or
vice versa until BSE in cattle was confirmed in Great
Britain by brain examination in November 1986.
CLINICAL SIGNS
The clinical signs are principally neurological,
progressive, and insidious in onset. They are more
readily detected in the early stages by those familiar
with the individual cow’s habits, such as herdsmen,
who might detect subtle changes in behavior.
Subsequently, the signs may be obvious to all,
although the term ‘‘mad’’ is not a sound description
of all cases. The principal signs are changes in mental
status exhibited as apprehension, frenzy, and ner-
vousness of doorways; changes in sensation, notably
hyperesthesia to sound and touch; abnormalities of
posture and movement, particularly low head car-
riage, hindlimb ataxia, tremors, and falling; and
nonspecific signs, including loss of bodily condition
and milk yield, reduction in cud chewing, and
slowing of heart rate. The duration of signs is 7
days to more than 1 year but commonly 1 or 2
months. The occurrence and severity of signs may be
influenced by removal of environmental stresses.
Latent signs may become clinically evident, for
example, by the increased stress of transport.
PATHOLOGY
There are no gross lesions attributable to BSE.
Microscopic examination of the fixed brain reveals
the classic tetrad of lesions: spongiform change in the
gray matter neuropil, neuronal vacuolation, neuronal
loss, and astrocytosis. PrPSc is also detectable by
immunohistochemistry, immunoblotting, and a vari-
ety of other related methods. Following detergent
extraction of unfixed gray matter, protein-
ase K treatment, negative staining, and examination
in the electron microscope, it is possible to detect
BOVINE SPONGIFORM ENCEPHALOPATHY 405
brain-specific fibrils called scrapie-associated fibrils
(SAFs). These are regarded as pathological aggre-
gates of prion protein.
The hindbrain shows the most severe lesions and
the medulla oblongata at the obex is the preferred
site for examination. Unlike in scrapie, the lesion
profile in BSE is consistent among cases and over
time, thus supporting the view that a single agent
strain is responsible.
DIAGNOSIS
The clinical signs of BSE are distinctive but there are
differential diagnoses to consider, including cerebral
listeriosis, polioencephalomalacia (a disease condi-
tion in cattle characterized by necrosis of the
cerebrocortical region of the brain), tumors, and
other degenerative conditions and abscesses. How-
ever, the accuracy of clinical diagnosis is high
(approximately 85%), although it declines as the
disease approaches elimination.
Confirmation of disease is classically by micro-
scopic examination of the brain, with or without
supporting evidence from the various tests for PrPSc
or the detection of SAFs.
There is currently no available validated test to
detect BSE in a live animal or in a dead one predating
the onset of clinical signs by more than approxi-
mately 3 months.
EPIDEMIOLOGY
BSE is a disease transmitted in the feed, specifically
concentrate feed (feed other than forage, hay, or
silage). The vehicle in this feed is meat and bonemeal
(MBM) containing ruminant protein derived from
animals infected with the BSE agent.
MBM is one of the major products of the
rendering industry, which collects and cooks (ren-
ders) unwanted animal materials from abattoirs and
butchers’ shops. The first objective is to remove
water and thus concentrate the bulk, and then the fat
(tallow fraction) is separated from the proteinaceous
fraction called greaves. Greaves is ground to produce
MBM.
The fat content of greaves varies from approxi-
mately 1 to 15% depending on the method of
extraction of the tallow. In the past, if this was done
by creaming off, pressing, or centrifugation, then the
fat content was at the high end of the range. If, in
addition, hydrocarbon solvents were used to increase
the tallow yield, then the fat content of the MBM
406 BOVINE SPONGIFORM ENCEPHALOPATHY
was very low. Because the solvents were expensive,
toxic, and required for reuse, a second heat process
using steam was used to separate them from the
greaves. Market forces (tallow prices), safety, and
other concerns resulted in the elimination of the
solvent extraction method at approximately the time
at which the first exposures of UK cattle to BSE via
feed occurred (1981–1982). Thus, the timing of the
changes in the UK rendering industry was closely
associated with the first exposures of cattle to
infected feed.
The incubation period of BSE is 60 months on
average, although it ranges from 20 months to
possibly the full life span of a cow. Because most
affected cattle are infected as calves, most cattle with
BSE are approximately 4–6 years old. Some adult
exposures also occur that probably account for
occasional cases as old as 18 years.
Dairy cows are much more commonly affected
than beef cattle due to the different systems of
rearing. In general, beef calves are suckled and do not
receive concentrate rations often. If they do, they do
so at an older age. Dairy calves, on the other hand,
are removed from the dam shortly after birth and are
fed artificial milk that is not derived from a single
cow source. This is supplemented from approxi-
mately 3 weeks of age with solid concentrate feed
that frequently contained MBM. This clearly demon-
strates why adult dairy cows are at greater risk of
developing disease than are pedigree breeding beef
cattle. Some beef suckler cows do get BSE; they are
usually crossbred cattle originating in the dairy herd
and therefore have the same risk of exposure as dairy
calves.
Prime beef cattle reared for meat are killed at
approximately 212 to 3 years of age on average, well
below the age at which clinical BSE usually develops.
Nevertheless, some of these animals, if they have
been exposed to infection in feed, incubate the
disease at the time of slaughter. This is one of the
problems of BSE, as such animals are clinically silent
and even postmortem tests may not reveal their true
state.
Whether or not BSE originated from sheep with
scrapie (a known reservoir of TSE infection in the
United Kingdom and several other European coun-
tries) or from clinically silent or undetected cattle
infected with a cattle-adapted scrapie-like agent is
not known. A recently expressed view by the BSE
Inquiry in the United Kingdom is that a single cow
developed a PrP gene mutation that spontaneously
caused the cow to develop a fatal infection that was
then recycled through MBM in the manner de-
scribed. There is no evidence to support this
hypothesis, but if it is true it is possible for cattle in
any country to develop BSE in the same manner, as a
rare event.
GEOGRAPHICAL DISTRIBUTION OF BSE
A small number of cases of BSE have been found
outside Europe, including Canada, the Falkland
Islands, and the Sultanate of Oman. These were
cattle exported from the United Kingdom in the
incubation period of the disease. If detected, slaugh-
tered, and destroyed, the hazard is removed and
there is no risk.
BSE has been detected in native-born cattle in
several European countries (including imported
cases) as of January 2001 as follows: Belgium, 21
cases; Denmark, 1 þ 1 imported; France, 175 þ 1;
Germany, 18 þ 5; Ireland, 567 þ 12; Italy, 2 þ 2;
Liechtenstein, 2; Luxembourg, 1; The Netherlands,
6; Portugal, 489 þ 7; Spain, 2; Switzerland, 364;
United Kingdom (including islands), 180,706.
France, Switzerland, and UK data include some
cases identified in recent years by active surveillance
systems (data source: OIE, Paris, January 2001).
CONTROL OF BSE
The main agencies concerned with the protection of
public and animal health from BSE are the World
Health Organization (WHO; public health), the
Office International des Epizooties (OIE; animal
health), the European Commission for the European
Union (EU) member states (both), and national
governments, usually via departments of agriculture,
health, and food standards/safety agencies (both).
Current measures to protect public health include
the compulsory notification, slaughter, and total
destruction of suspect clinical cases and compulsory
removal and destruction of specified risk materials
(SRMs) from slaughtered, killed, or dead animals of
a specified age. These materials include tissues of
cattle that do or may carry infectivity during the
incubation period or clinical phase of disease. Some
materials from sheep and goats are also removed in
order to reduce any risk of a possible future
occurrence of BSE in these species.
Since 1996 in the United Kingdom, cattle more
than 30 months old are not permitted in the human
food chain or animal feed chain. Instead, they are
incinerated or rendered and then incinerated. This
 BOVINE SPONGIFORM ENCEPHALOPATHY 407

scheme is called the over 30 months scheme. This is

now becoming the standard in parts of the EU and is
mandatory if compulsory PrP testing of cattle older
than 30 months of age reveals an infected animal.
The main animal health protection measure is a
ban on the use of ruminant protein in feed for cattle
(in the United Kingdom since 1988) or mammalian
MBM in feed for all food animal species (in the
United Kingdom since 1996 and in the EU since
January 2001). This has been introduced temporarily
in the EU because it has been found that cross-
contamination of ruminant diets with feed intended
for pigs and poultry, which could legally contain
mammalian MBM, is a very important part of the
infection chain. This most likely occurs in feed mills
or in transport (Fig. 2).
Milk derived from healthy cows has a negligible
risk in regard to BSE. The WHO, OIE, and all major
agencies concerned with food safety support this
view. Beef also presents a negligible risk because
there is no detectable infectivity present in either the
clinical phase or the incubation period. However,
there are ways in which beef can become cross-
contaminated during or after slaughter. Strict hygiene
rules reduce this risk to negligible proportions if they
are completely and consistently enforced.
Mechanically recovered meat (MRM) from bone
residues that could contain residual nervous tissues,
such as the vertebral column, could present a risk
Figure 2
How infected transport or mill equipment can accidentally infect
feed for cattle. One gram of infected cow brain can contain more
than one oral infectious dose for a calf (Crown copyright).
and are now prohibited for this purpose in the EU.
There are also controls on rendering procedures
(stemming from research results), disposal of waste,
gelatin manufacture, veterinary and human medi-
cines, and biologicals and a range of other commod-
ities. These controls are uniform in the EU. Figure 3
summarizes the measures in the U.K. to protect the
food and feed chains.
The OIE performs an important role by being a
central reporting point for cases of BSE. Further-
more, via its International Animal Health Code
(2000) and its Manual of Standards for Diagnostic
Tests and Vaccines (2000), the OIE contributes

Figure 3
Simple model of BSE in cattle. Fallen stock, animals found dead; OTMS, over 30 months scheme; SRM, specified risk materials (Crown
copyright).
408 BOVINE SPONGIFORM ENCEPHALOPATHY

Table 1 BSE AGENT: NATURAL* AND EXPERIMENTAL** HOST RANGEa

Primates Ruminantia Felidae Mustelidae Rodentia Other artiodactyla

Man* Cattle* Domestic cat* Mink** Mice** Pigs**(parenteral routes only)

Lemur?* Nyala* Puma*
Rhesus monkey?* Gemsbok* Cheetah*
Monkeys** Greater kudu* Ocelot*
Marmoset** Arabian oryx* Tiger*
Macaque** Eland* Lion*
Squirrelb** Scimitar-horned oryx*
Capuchinb** Horned oryx*
Lemurs?** Ankole*
Bison bison*
Sheep**
Cattle**
Goats**
a
Hamsters and chickens challenged by parenteral routes did not succumb. Chickens and pigs challenged by the oral route did not succumb.
Monkeys have not been experiementally challenged by the oral route (Crown copyright).
b
Unpublished information courtesy of the late C. J. Gibbs, Jr.

significantly to the harmonization of test procedures INFECTIVITY OF CATTLE TISSUES

for BSE and the safe trading of cattle and cattle
products. Both the OIE and the WHO strongly
support surveillance for TSE in all animal species,
including BSE of cattle and all forms of CJD in man.
HOST RANGE
The natural and experimental host range for BSE is
shown in Table 1. In regard to the natural host range,
two main families (Bovidae and Felidae) are at risk
from BSE-related TSE, as shown by their temporal
(1986–2000) and geographical (mainly the United
Kingdom) occurrence. No food animals other than
cattle have been affected, and of all domesticated
animals affected, the only one besides cattle is the
domestic cat. Curiously, one case each of feline TSE
has occurred in Norway and Liechtenstein, without
obvious connection to the United Kingdom. The
number of these cases is small. Captive bovidae were
almost certainly infected via MBM, just like cattle
and possibly domestic cats. The MBM feed ban now
protects these species. In regard to the captive wild
Felidae, the infection route was most likely from
consumption of uncooked cattle heads and vertebral
columns that contained infected central nervous
tissue. The 1989 SRM ban was extended in 1990
in the United Kingdom and has since protected the
large cats from exposure via this route. A network
for the exposure of animals via feed is shown in
Fig. 4.
In naturally affected cattle, of approximately 50
tissues tested, only brain, spinal cord, and retina
tissue have revealed infectivity. In experimentally
infected cattle, infection has also been detected up to
3 months before clinical onset in cranial and spinal
ganglia. Furthermore, the distal ileum (the terminal
part of the small intestine) shows infectivity 6
months after dosing and for the majority of the
incubation period.
STRAIN TYPING OF THE BSE AND
RELATED AGENTS
Biological strain typing is the only reliable way of
clearly and unequivocally distinguishing the BSE
agent from other agents. This involves inoculating a
series of inbred mice strains with infected brain
material, measuring the incubation period, and
defining the pattern of lesion in the brain. In this
way, the BSE agent was clearly distinguished from
the several strains of scrapie agents and strains
causing sporadic CJD (the most common form).
However, the BSE strain type has been isolated from
three cats with feline TSE; a greater kudu and a nyala
with TSE; a pig, sheep, and goats with experimental
BSE (Fig. 5); and, importantly, three human patients
with a newly reported form of CJD called variant
CJD (vCJD) (Fig. 6). This has clearly assisted in
defining a presumed pathway for the origin of vCJD
probably from the consumption of infected bovine

Figure 4
The exposure chain (Crown copyright).
meat products before any offal’s ban was instituted
in 1989.
CONCLUSION
The United Kingdom has had by far the most cases
of confirmed BSE. However, as a result of the
occurrence of vCJD first reported as 10 cases in 1996
in the United Kingdom, the measures in place at that
time have been extended and vigorously enforced.
The declining epidemic of BSE in the United King-
dom at that time has continued and the cattle disease
seems to be heading for elimination. In contrast, the
Figure 5
Strain typing of animal isolates (Crown copyright).
BOVINE SPONGIFORM ENCEPHALOPATHY 409
incidence of BSE is increasing in most other
European countries (except Switzerland), which
have reported cases in native-born cattle. Some
other European countries are reporting their first
cases. The European Commission has applied tough
new measures to control and eliminate the epidemic
in these countries. Among these is the need to test
brains of cattle older than 30 months of age for
BSE and to permit only those that pass the test
into the food or feed chain. The United Kingdom
has banned the consumption of any part of cattle
older than 30 months of age since 1996. If all the
lessons that the United Kingdom has learned and
that give confidence that its epidemic is almost
eliminated are adopted elsewhere and policed with
equal vigor, the EU should be able to eliminate the
Figure 6
Strain typing of human isolates (Crown copyright).
410 BOXING, NEUROLOGY OF
disease within 10 years. The epidemic of vCJD is
small (o90 cases in the United Kingdom, 1 in
Ireland, and 2 or 3 in France) but future numbers are
more difficult to forecast due to uncertainties of the
length of the incubation period and other key
parameters.
—Ray Bradley
See also–Creutzfeldt-Jakob Disease (CJD)
Further Reading
Bradley, R. (1997). Animal prion diseases. In Prion Diseases (J.
Collinge and M. S. Palmer, Eds.), pp. 89–129. Oxford Univ.
Press, Oxford.
Bradley, R. (1999). BSE transmission studies with particular
reference to blood. Dev. Biol. Stand. 99, 35–40.
Bruce, M., Chree, A., McConnell, I., et al. (1994). Transmission of
bovine spongiform encephalopathy and scrapie to mice: Strain
variation and the species barrier. Philos. Trans. R. Soc. London
B 343, 405–411.
Kimberlin, R. H. (1992). Bovine spongiform encephalopathy. Rev.
Sci. Tech. Off. Int. Epiz. 11, 347–390.
MAFF (2000). Bovine Spongiform Encephalopathy: A Progress
Report. MAFF, London.
Phillips, Lord of Worth Matravers., Bridgeman, J., and Ferguson-
Smith, M. (2000). Report, Evidence and Supporting Papers of
the Inquiry into the Emergence and Identification of Bovine
Spongiform Encephalopathy (BSE) and Variant Creutzfeldt–
Jakob Disease (vCJD) and the Action Taken in Response to It
up to March 1996. Stationery Office, Norwich, UK.
Schreuder, B. E. C. (1994). BSE agent hypotheses. Livest. Prod. Sci.
38, 23–33.
Taylor, D. M., Woodgate, S. L., and Atkinson, M. J. (1995).
Inactivation of the bovine spongiform encephalopathy agent by
rendering procedures. Vet. Rec. 137, 605–610.
Wells, G. A. H., Scott, A. C., Johnson, C. T., et al. (1987). A novel
progressive spongiform encephalopathy in cattle. Vet. Rec. 121,
419–420.
Wilesmith, J. W. (1998). Manual on Bovine Spongiform Encepha-
lopathy, Food and Agriculture Organization Animal Health
Manual No. 2. Food and Agriculture Organization of the
United Nations, Rome.
Boxing, Neurology of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
TRAUMATIC BRAIN INJURY (TBI) is an inevitable
consequence of boxing. The acute and chronic
neurological sequela of TBI secondary to boxing
have been well recognized in the clinical literature.
This entry highlights the neurological consequences
associated with boxing.
ACUTE TRAUMATIC BRAIN INJURY
Acute traumatic brain injury (ATBI) can be defined
as the immediate neurological outcome secondary to
trauma-mediated mechanical forces to the brain. The
severity of ATBI can range from mild to severe. Mild
traumatic brain injury (MTBI) is the most frequently
occurring ATBI and is often synonymous with the
term cerebral concussion. MTBI or cerebral concus-
sion tends to be a relatively short-lived, self-limited
transient neurological impairment secondary to brain
trauma. Symptoms include headache, disorientation,
confusion, concentration difficulties, memory im-
pairment, motor incoordination, and/or loss of
consciousness. It is important to acknowledge that
MTBI can occur in the absence of loss of conscious-
ness. Although moderate or severe forms of ATBI are
rarely encountered in boxing, these are associated
with significantly more morbidity and mortality. Any
boxer suspected of experiencing an ATBI should
undergo a detailed neurological examination that
usually should include neuroimaging. Certain struc-
tural lesions (such as epidural or subdural hemor-
rhage or cerebellar hematoma) may necessitate
neurosurgical intervention, whereas other lesions
(such as subarachnoid or minor intracerebral bleed-
ing) typically require observation and supportive
care. Occasionally, a boxer may experience pro-
longed neurological symptoms after an MTBI or
concussion. This condition is often referred to as
postconcussion syndrome. Any boxer who exhibits
postconcussion syndrome should also undergo a
detailed neurological evaluation that will often
require neuroimaging to rule out a more severe
injury.
A boxer who experiences postconcussion syn-
drome or remains symptomatic from a cerebral
concussion and sustains an additional head trauma
may develop second-impact syndrome. The second-
impact syndrome is a condition in which an athlete
sustains a second TBI, while symptomatic from an
initial TBI, and displays an exaggerated neurological
response to the second impact. This exaggerated
neurological response can result in the rapid devel-
opment of coma, brain failure, respiratory distress,
and death. This condition has been described in
tackle football, ice hockey, and boxing.
CHRONIC TRAUMATIC BRAIN INJURY
Chronic traumatic brain injury (CTBI) typically
occurs in the professional boxer who has experienced
410 BOXING, NEUROLOGY OF
disease within 10 years. The epidemic of vCJD is
small (o90 cases in the United Kingdom, 1 in
Ireland, and 2 or 3 in France) but future numbers are
more difficult to forecast due to uncertainties of the
length of the incubation period and other key
parameters.
—Ray Bradley
See also–Creutzfeldt-Jakob Disease (CJD)
Further Reading
Bradley, R. (1997). Animal prion diseases. In Prion Diseases (J.
Collinge and M. S. Palmer, Eds.), pp. 89–129. Oxford Univ.
Press, Oxford.
Bradley, R. (1999). BSE transmission studies with particular
reference to blood. Dev. Biol. Stand. 99, 35–40.
Bruce, M., Chree, A., McConnell, I., et al. (1994). Transmission of
bovine spongiform encephalopathy and scrapie to mice: Strain
variation and the species barrier. Philos. Trans. R. Soc. London
B 343, 405–411.
Kimberlin, R. H. (1992). Bovine spongiform encephalopathy. Rev.
Sci. Tech. Off. Int. Epiz. 11, 347–390.
MAFF (2000). Bovine Spongiform Encephalopathy: A Progress
Report. MAFF, London.
Phillips, Lord of Worth Matravers., Bridgeman, J., and Ferguson-
Smith, M. (2000). Report, Evidence and Supporting Papers of
the Inquiry into the Emergence and Identification of Bovine
Spongiform Encephalopathy (BSE) and Variant Creutzfeldt–
Jakob Disease (vCJD) and the Action Taken in Response to It
up to March 1996. Stationery Office, Norwich, UK.
Schreuder, B. E. C. (1994). BSE agent hypotheses. Livest. Prod. Sci.
38, 23–33.
Taylor, D. M., Woodgate, S. L., and Atkinson, M. J. (1995).
Inactivation of the bovine spongiform encephalopathy agent by
rendering procedures. Vet. Rec. 137, 605–610.
Wells, G. A. H., Scott, A. C., Johnson, C. T., et al. (1987). A novel
progressive spongiform encephalopathy in cattle. Vet. Rec. 121,
419–420.
Wilesmith, J. W. (1998). Manual on Bovine Spongiform Encepha-
lopathy, Food and Agriculture Organization Animal Health
Manual No. 2. Food and Agriculture Organization of the
United Nations, Rome.
Boxing, Neurology of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
TRAUMATIC BRAIN INJURY (TBI) is an inevitable
consequence of boxing. The acute and chronic
neurological sequela of TBI secondary to boxing
have been well recognized in the clinical literature.
This entry highlights the neurological consequences
associated with boxing.
ACUTE TRAUMATIC BRAIN INJURY
Acute traumatic brain injury (ATBI) can be defined
as the immediate neurological outcome secondary to
trauma-mediated mechanical forces to the brain. The
severity of ATBI can range from mild to severe. Mild
traumatic brain injury (MTBI) is the most frequently
occurring ATBI and is often synonymous with the
term cerebral concussion. MTBI or cerebral concus-
sion tends to be a relatively short-lived, self-limited
transient neurological impairment secondary to brain
trauma. Symptoms include headache, disorientation,
confusion, concentration difficulties, memory im-
pairment, motor incoordination, and/or loss of
consciousness. It is important to acknowledge that
MTBI can occur in the absence of loss of conscious-
ness. Although moderate or severe forms of ATBI are
rarely encountered in boxing, these are associated
with significantly more morbidity and mortality. Any
boxer suspected of experiencing an ATBI should
undergo a detailed neurological examination that
usually should include neuroimaging. Certain struc-
tural lesions (such as epidural or subdural hemor-
rhage or cerebellar hematoma) may necessitate
neurosurgical intervention, whereas other lesions
(such as subarachnoid or minor intracerebral bleed-
ing) typically require observation and supportive
care. Occasionally, a boxer may experience pro-
longed neurological symptoms after an MTBI or
concussion. This condition is often referred to as
postconcussion syndrome. Any boxer who exhibits
postconcussion syndrome should also undergo a
detailed neurological evaluation that will often
require neuroimaging to rule out a more severe
injury.
A boxer who experiences postconcussion syn-
drome or remains symptomatic from a cerebral
concussion and sustains an additional head trauma
may develop second-impact syndrome. The second-
impact syndrome is a condition in which an athlete
sustains a second TBI, while symptomatic from an
initial TBI, and displays an exaggerated neurological
response to the second impact. This exaggerated
neurological response can result in the rapid devel-
opment of coma, brain failure, respiratory distress,
and death. This condition has been described in
tackle football, ice hockey, and boxing.
CHRONIC TRAUMATIC BRAIN INJURY
Chronic traumatic brain injury (CTBI) typically
occurs in the professional boxer who has experienced

a long-term exposure to the sport of boxing. It has
been estimated that 17% of retired boxers will
exhibit the syndrome. Established factors include late
age of retirement, an excessive numbers of bouts, and
a longer career duration. Boxers more likely to
experience neurological impairment are those who
display poor defensive skills, are notorious for taking
a punch, are considered sluggers, and/or are difficult
to knock out.
Clinically, the boxer who develops CTBI may
exhibit a variety of motor, cognitive, and behavioral
dysfunction. The motor abnormalities may resemble
parkinsonism, with tremor, rigidity, slowed move-
ments, facial fixity, and a stooped posture. In other
instances, unsteadiness and incoordination are more
conspicuous. In both instances, slurring of speech is
common. Cognitively, boxers may initially present
with difficulty in complex attention, which pro-
gresses to full-blown dementia characterized by
memory impairment and problems with executive
cognitive functions, such as planning, reasoning,
judgment, set shifting, multitasking organization,
and sequency. Behaviorally, the boxer may display
personality changes that can include impulsivity,
agitation, irritability, and disinhibition. Personality
changes may be difficult to discern unless the boxer is
well-known to the examiner, trainer, family mem-
bers, or friends.
Any boxer suspected of developing or experiencing
CTBI should undergo a complete neurological
examination that includes imaging of the brain along
with appropriate laboratory tests, if deemed neces-
sary. Imaging of the brain can be performed by using
computerized tomography or magnetic resonance
imaging (MRI) scans. The MRI scan is the preferable
test between the two. It may show cortical atrophy,
hydrocephalus, or both. It occasionally shows a
lesion that requires surgical treatment, such as a
chronic subdural hematoma or a communicating
hydrocephalus. Occasionally, more sophisticated
imaging, such as single photon emission computed
tomography and positron emission tomography, is
helpful.
Pathologically, the brain of a boxer who exhibits
end stage CTBI or the condition that follows,
referred to as dementia pugilistica, will resemble
that of a patient with Alzheimer’s disease. Neuro-
pathological findings seen in CTBI and Alzheimer’s
disease include neurofibrillary tangles and amyloid
plaques. A gene well described as increasing an
individual’s risk of Alzheimer’s disease may also
increase a boxer’s risk of developing CTBI.
BRACHIAL PLEXOPATHIES 411
Treatment of CTBI is limited. Medications that are
of benefit for cognitive impairment in Alzheimer’s
disease may be administered to a boxer with CTBI.
However, the efficacy of such treatment has not been
fully established. Antidepressants, antipsychotics, and
antianxiety medications may be utilized to treat any
specified behavioral or psychiatric symptoms. Since
CTBI often presents long after a boxer has retired
from the sport and treatment options are relatively
limited, prevention is of paramount importance. The
mainstay of preventive measures of CTBI is to limit a
boxer’s adverse exposure to the sport. Boxers who are
extremely poor performers should be medically
suspended from the sport and undergo more detailed
neurological testing. If these boxers exhibit clinical
signs of CTBI, their privilege to continue boxing
should be revoked. Serial examinations sensitive to
subtle changes in neurological function should also be
implemented. In addition, the putative genetic risk of
CTBI needs to be further explored.
CONCLUSION
ATBI and CTBI associated with boxing are two
distinct clinical conditions with different pathophy-
siological mechanisms. Severe ATBI is infrequently
encountered in boxing, and the most challenging
public health concern is CTBI. Further medical
research is needed to maximize safety in boxing.
—Barry D. Jordan
See also–Brain Injury, Traumatic:
Epidemiological Issues; Brain Trauma, Overview;
Cognitive Impairment; Concussion; Dementia
Further Reading
Jordan, B. D. (1993). Medical Aspects of Boxing. CRC Press, Boca
Raton, FL.
Jordan, B. D. (2000). Chronic traumatic brain injury associated
with boxing. Semin. Neurol. 20, 179–185.
Jordan, B. D., Tsairis, P., and Warren, R. F. (1998). Sports
Neurology. Lippincott-Williams, Philadelphia.
Brachial Plexopathies
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRACHIAL PLEXUS is one of the largest structures
in the peripheral nervous system (PNS). It is also one
of its most vulnerable for the following reasons: (i) It

a long-term exposure to the sport of boxing. It has
been estimated that 17% of retired boxers will
exhibit the syndrome. Established factors include late
age of retirement, an excessive numbers of bouts, and
a longer career duration. Boxers more likely to
experience neurological impairment are those who
display poor defensive skills, are notorious for taking
a punch, are considered sluggers, and/or are difficult
to knock out.
Clinically, the boxer who develops CTBI may
exhibit a variety of motor, cognitive, and behavioral
dysfunction. The motor abnormalities may resemble
parkinsonism, with tremor, rigidity, slowed move-
ments, facial fixity, and a stooped posture. In other
instances, unsteadiness and incoordination are more
conspicuous. In both instances, slurring of speech is
common. Cognitively, boxers may initially present
with difficulty in complex attention, which pro-
gresses to full-blown dementia characterized by
memory impairment and problems with executive
cognitive functions, such as planning, reasoning,
judgment, set shifting, multitasking organization,
and sequency. Behaviorally, the boxer may display
personality changes that can include impulsivity,
agitation, irritability, and disinhibition. Personality
changes may be difficult to discern unless the boxer is
well-known to the examiner, trainer, family mem-
bers, or friends.
Any boxer suspected of developing or experiencing
CTBI should undergo a complete neurological
examination that includes imaging of the brain along
with appropriate laboratory tests, if deemed neces-
sary. Imaging of the brain can be performed by using
computerized tomography or magnetic resonance
imaging (MRI) scans. The MRI scan is the preferable
test between the two. It may show cortical atrophy,
hydrocephalus, or both. It occasionally shows a
lesion that requires surgical treatment, such as a
chronic subdural hematoma or a communicating
hydrocephalus. Occasionally, more sophisticated
imaging, such as single photon emission computed
tomography and positron emission tomography, is
helpful.
Pathologically, the brain of a boxer who exhibits
end stage CTBI or the condition that follows,
referred to as dementia pugilistica, will resemble
that of a patient with Alzheimer’s disease. Neuro-
pathological findings seen in CTBI and Alzheimer’s
disease include neurofibrillary tangles and amyloid
plaques. A gene well described as increasing an
individual’s risk of Alzheimer’s disease may also
increase a boxer’s risk of developing CTBI.
BRACHIAL PLEXOPATHIES 411
Treatment of CTBI is limited. Medications that are
of benefit for cognitive impairment in Alzheimer’s
disease may be administered to a boxer with CTBI.
However, the efficacy of such treatment has not been
fully established. Antidepressants, antipsychotics, and
antianxiety medications may be utilized to treat any
specified behavioral or psychiatric symptoms. Since
CTBI often presents long after a boxer has retired
from the sport and treatment options are relatively
limited, prevention is of paramount importance. The
mainstay of preventive measures of CTBI is to limit a
boxer’s adverse exposure to the sport. Boxers who are
extremely poor performers should be medically
suspended from the sport and undergo more detailed
neurological testing. If these boxers exhibit clinical
signs of CTBI, their privilege to continue boxing
should be revoked. Serial examinations sensitive to
subtle changes in neurological function should also be
implemented. In addition, the putative genetic risk of
CTBI needs to be further explored.
CONCLUSION
ATBI and CTBI associated with boxing are two
distinct clinical conditions with different pathophy-
siological mechanisms. Severe ATBI is infrequently
encountered in boxing, and the most challenging
public health concern is CTBI. Further medical
research is needed to maximize safety in boxing.
—Barry D. Jordan
See also–Brain Injury, Traumatic:
Epidemiological Issues; Brain Trauma, Overview;
Cognitive Impairment; Concussion; Dementia
Further Reading
Jordan, B. D. (1993). Medical Aspects of Boxing. CRC Press, Boca
Raton, FL.
Jordan, B. D. (2000). Chronic traumatic brain injury associated
with boxing. Semin. Neurol. 20, 179–185.
Jordan, B. D., Tsairis, P., and Warren, R. F. (1998). Sports
Neurology. Lippincott-Williams, Philadelphia.
Brachial Plexopathies
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRACHIAL PLEXUS is one of the largest structures
in the peripheral nervous system (PNS). It is also one
of its most vulnerable for the following reasons: (i) It
412 BRACHIAL PLEXOPATHIES
is situated near the highly mobile neck and shoulder,
and thus it is very susceptible to traction (stretch)
injures, and (ii) various portions of it are at risk of
injury secondarily because of primary involvement of
nearby structures (e.g., metastases from lung cancer,
radiation directed toward the axillary lymph nodes,
hematomas resulting from damage to the subclavian
and axillary blood vessels, and fractures and
dislocations of the humeral head).
ANATOMY
The brachial plexus consists of five components
(from proximal to distal): (i) five ‘‘roots’’: the C5–T1
anterior and posterior primary roots and mixed
spinal nerves, as well as the anterior primary rami
that are situated deep in the neck between the
scalenus anticus and medius muscles; (ii) three trunks
(upper, middle, and lower) located superior to the
mid- and medial portions of the clavicle in the
anteroinferior portion of the posterior triangle of the
neck; (iii) six divisions (three anterior and three
posterior) situated behind the clavicle and in front of
the first thoracic rib; (iv) three cords (lateral, poster-
ior, and medial) positioned in the more proximal
axilla—the cords receive their names from their
relationships to the second segment of the axillary
artery, which they envelop; and (v) five terminal
nerves (axillary, musculocutaneous, radial, median,
and ulnar) that arise from the cords—these are
located in the axilla and are continuous with the five
major peripheral nerves of the upper limb, which
have the same names.
Clinically, the brachial plexus is divided into two
portions, supraclavicular and infraclavicular, based
on the fact that the clavicle, when the upper limb is
adducted, overlies the divisions (Fig. 1). (The divi-
sions are designated the ‘‘retro’’ or ‘‘subclavicular’’
plexus.) Consequently, the supraclavicular plexus
encompasses the roots and trunks, whereas the
infraclavicular plexus consists of the cords and
terminal nerves. This clinical segmentation is quite
useful in part because these two portions of the
brachial plexus tend to be injured by different
mechanisms. Thus, closed traction injuries character-
istically affect the supraclavicular elements, whereas
gunshot wounds and humeral head fractures and
dislocations typically involve infraclavicular ele-
ments. In many instances, initially it is difficult to
distinguish lesions of the trunks from those involving
the roots from which they derive. For this reason,
supraclavicular plexopathies are subdivided into
Figure 1
The brachial plexus viewed from the front. Note that the clavicle
overlies the divisions, allowing the plexus to be divided into
supraclavicular and infraclavicular (and also subclavicular)
portions.
those that involve the upper plexus (i.e., C5–C6
roots or upper trunk), the middle plexus (i.e., the C7
root or the middle trunk), and the lower plexus (i.e.,
the C8–T1 roots or lower trunk). In addition to
dividing and subdividing the brachial plexus verti-
cally, clinicians also divide it longitudinally based on
whether it has been injured proximal to, at, or distal
to, the dorsal root ganglia. These structures, which
contain the cell bodies of sensory axons that pass
both peripherally and centrally into the spinal cord,
are situated on the distal aspect of the primary
(dorsal) sensory roots, within or near the very
proximal portion of the intervertebral foramina.
Most brachial plexopathies involve the plexus axons
distal to the dorsal root ganglia (e.g., they injure the
trunks, cords, or terminal nerves). These are called
extraforaminal or postganglionic lesions. In contrast,
occasionally the primary roots are severely damaged;
most often they are torn from the spinal cord by
severe closed traction. These are referred to as
preganglionic injuries. Although the terms pregan-
glionic and postganglionic technically apply only to
the sensory roots, by convention they are used to
describe lesions affecting motor as well as sensory
nerve fibers.
PATHOLOGY AND PATHOPHYSIOLOGY
Similar to all other disorders of the PNS, lesions that
involve brachial plexus axons produce one of two

types of pathology (axon loss or focal demyelination)
or both, and at least three types of pathophysiology
(conduction failure, conduction block due to either
axon discontinuity or focal demyelination, and
conduction slowing). The majority of brachial
plexopathies are the result of axon loss, which for
a few days after onset presents as axon discontinuity
conduction block but thereafter as conduction fail-
ure. In contrast, only a minority are due to focal
demyelination causing conduction block. The latter
process most often results from acute, relatively
mild trauma and is short-lived (typically 3–6
weeks’ duration); clinically, a demyelinating conduc-
tion block lesion resulting from mild traction or
compression is referred to as neurapraxia. A very
different type of demyelinating conduction block is
characteristic of two brachial plexopathies: those
produced by radiation and those produced by multi-
focal motor neuropathy. With these disorders, the
demyelinating conduction blocks persist for several
years and then gradually convert to axon loss. They
never resolve spontaneously, as do those resulting
from trauma.
DIAGNOSIS
Typically, the diagnosis of a brachial plexopathy
rests on the history and the clinical neurological
assessment, usually supplemented by two laboratory
diagnostic procedures: the electrodiagnostic (EDX)
examination and a variety of neuroimaging studies.
These differ considerably in their usefulness, de-
pending on the specific brachial plexus lesion
present. Nonetheless, in most instances both are
indicated.
With the EDX examination, excluding those
sensory fibers arising from the C5 root, virtually
every element of the brachial plexus can be assessed
for axon loss with nerve conduction studies, whereas
nearly every muscle innervated via the brachial
plexus can be sampled on needle electrode examina-
tion. Also, using percutaneous stimulation, focal
abnormalities producing conduction block can be
demonstrated as far proximal as the upper-mid-
portion of the trunks. Utilizing the EDX examina-
tion, the underlying pathology of the brachial
plexopathy (axon loss vs demyelination) can be
determined. Moreover, usually the location, severity,
and full extent of the lesion can be established.
The neuroimaging studies used in brachial plexus
assessment include plain neck x-rays, cervical myelo-
grams, computed tomography, magnetic resonance
BRACHIAL PLEXOPATHIES 413
imaging studies, arterograms, and, occasionally,
venograms. In general, neuroimaging studies are
most useful in assessing patients with very proximal
lesions (i.e., those within the cervical intraspinal
canal), disorders in which bony abnormalities coexist
(e.g., humeral head fractures and dislocations), those
caused by radiation and certain neoplasms, and those
associated with vascular damage.
SPECIFIC BRACHIAL PLEXUS DISORDERS
Closed Traction Injuries
Overall, these are by far the most common cause of
brachial plexopathies. Typically, they affect the
supraclavicular plexus, especially the upper plexus
fibers. Often, they are due to high-velocity trauma,
such as occurs during vehicular accidents (especially
motorcycle accidents), falls from heights, certain
industrial injuries, and a few sports (e.g., skiing).
However, they can also be due to milder degrees of
injury (e.g., the birth process and trauma to the
shoulder sustained during contact sporting events).
Consequently, the underlying pathology ranges from
demyelinating conduction block to severe axon loss;
therefore, the prognosis is extremely variable. Avul-
sion injuries, in which the primary roots are torn
from the spinal cord, are the most severe type of
traction damage the brachial plexus can sustain.
They do not recover spontaneously, and there is no
effective surgical remedy for the motor and sensory
deficits. Whenever multiple root avulsions occur,
patients are essentially rendered functionally one-
armed. Moreover, especially when all or nearly all of
the five roots have been avulsed, a particularly
distressing type of pain called avulsion pain often
appears. It is resistant to almost all treatment
except destruction of the dorsal root entry zones
(DREZs) on the spinal cord, from which the primary
sensory roots were torn. This operation is called a
DREZ procedure or Nashold procedure (after the
neurosurgeon who devised it). Both the EDX
examination and neuroimaging studies are helpful
in assessing closed traction lesions; neuroimaging
studies are of more benefit, however, in identifying
root avulsions.
Classical Postoperative Paralysis
This supraclavicular brachial plexopathy results
from patients being malpositioned on the operating
table while undergoing an operation under general
anesthesia so that the distal upper trunk fibers are
414 BRACHIAL PLEXOPATHIES
compressed or stretched. Often, the surgery is
performed at some distance from the brachial plexus
(e.g., a cholecystectomy or a hysterectomy), so there
is no possibility of the plexus being injured by direct
instrumentation. This disorder characteristically
manifests in the immediate postoperative period as
profound, painless weakness of the shoulder and
upper arm muscles, sometimes accompanied by
paresthesias along the lateral forearm and extending
into the thumb. Fortunately, the underlying patho-
physiology is predominantly, if not solely, demyeli-
nating conduction block, so recovery typically occurs
within a few weeks. The EDX examination is very
helpful in localizing and determining the pathophy-
siology of these lesions. However, few patients
undergo such assessments because their symptoms
resolve promptly. Unfortunately, this is the only type
of postoperative brachial plexopathy that consis-
tently has an excellent prognosis. Nonetheless, many
surgeons mistakenly assume that all brachial plexo-
pathies that present after surgery are equally benign
in character and, without justification, reassure
patients that their early disabling postoperative
symptoms will rapidly resolve. Medicolegal action
is frequently initiated when the symptoms, especially
pain and weakness, persist.
Postmedian Sternotomy
Brachial Plexopathy
This supraclavicular disorder results from cardiac
surgery in which access to the heart is gained by
longitudinal splitting of the sternum. Characteristi-
cally, the damage is confined to the C8 anterior
primary ramus before it fuses with the T1 anterior
primary ramus to form the lower trunk. Since the
bulk of the ulnar nerve derives from the C8 root,
these lesions are frequently mistaken for postopera-
tive ulnar neuropathies. The clinical presentations
can be quite similar: weakness of ulnar intrinsic hand
muscles as well as sensory loss, paresthesias, and
sometimes pain in the medial hand and medial two
fingers. However, the extensor forearm muscles
innervated by the C8 root, via the radial nerve, are
also affected with this brachial plexopathy. The
underlying pathology varies between axon loss and
demyelination causing conduction block, or combi-
nations of both, so the prognosis is variable. None-
theless, in most instances, it is good. The EDX
examination can be very helpful in identifying this
disorder and demonstrating the relative amounts of
conduction failure and conduction block present. It
can also prevent needless surgical procedures being
performed (e.g., ulnar nerve transportation) to treat
misdiagnosed postoperative ulnar neuropathy at the
elbow.
True Neurogenic Thoracic Outlet Syndrome
Most patients with this congenital supraclavicular
disorder are women. They present with unilateral
hand weakness accompanied by wasting that always
is more severe at, or limited to, the lateral thenar
(i.e., median nerve-innervated) hand muscles. On
direct questioning, many patients report having
experienced intermittent aching along the medial
forearm and hand (i.e., in a C8–T1 distribution) for
many years. Plain neck x-rays reveal an ipsilateral
rudimentary cervical rib (often an even larger
cervical rib is present on the contralateral, asympto-
matic side). The EDX examination discloses an
almost pathognomonic combination of abnormal-
ities, indicative of a lesion involving principally the
T1 anterior primary ramus or predominantly the T1
component of the proximal lower trunk. These
plexus elements at surgery, which should be per-
formed promptly after diagnosis, are shown to be
angulated around a taut congenital band extending
from the tip of the cervical rib to the first thoracic
rib. After this band is sectioned, they assume a more
normal position. As with all very chronic axon loss
disorders that involve the lower trunk (or medial
cord), no substantial postoperative improvement
occurs in the intrinsic hand muscle weakness and
wasting. Nonetheless, the motor deterioration stops,
and the sensory symptoms usually resolve.
Brachial Plexopathy after Surgery for
Disputed Thoracic Outlet Syndrome
Among the five distinct disorders labeled thoracic
outlet syndrome (TOS), one is diagnosed quite
frequently and often treated with surgery, consisting
of either transaxillary first rib resection or anterior
and middle scalenectomies. Unfortunately, patients
sometimes awaken from these operations with lower
trunk brachial plexopathies manifested as hand
weakness, soon followed by wasting along with
sensory disturbances involving the medial forearm
and hand. Severe, persistent pain is frequently
present as well. The EDX examination establishes
the pathology, extent, and severity of these lesions.
The prognosis with these iatrogenic lesions is often
poor. Surgery performed on the damaged plexus
element(s) may alleviate some of the pain, but
intrinsic hand function may be permanently im-
paired.

Obstetrical Paralysis
During delivery, infants may sustain a supraclavicu-
lar brachial plexopathy. Predisposing factors include
large babies, unusual presentations, and difficult
deliveries. Characteristically, the upper plexus or
upper and middle plexus are involved, resulting in
weakness and wasting about the shoulder girdle,
arm, and sometimes portions of the forearm.
Depending on the severity of the lesion, the
pathology is axon loss alone or a combination of
axon loss and demyelination causing conduction
block. The axon loss, in turn, can be due to ruptures
or severe lesions in continuity of the trunks or even
avulsion injuries of the roots. The EDX examination
is of less benefit with these brachial plexopathies
than with almost any other due to a combination of
the infants’ small size and their inability to cooperate
with the testing. Neuroimaging studies are most
helpful when lesions are located within the cervical
intraspinal canal. The appropriate treatment of
obstetrical paralysis is debated. Conservative therapy
is most often employed even though many patients,
as adults, are functionally one-armed and would
probably have benefited from operative repair of the
injured plexus elements.
Neoplastic Brachial Plexopathies
Primary neoplasms of the brachial plexus are
relatively rare. Far more often, neoplastic involve-
ment results from extension or metastases from
malignancies involving nearby structures, particu-
larly the breast and lung. These typically present with
pain, sensory loss, and weakness; initially most often
in a lower trunk distribution. However, many of
these patients, for uncertain reasons, are not ade-
quately assessed until their lesions are far more
extensive—sometimes pan-plexus in appearance. The
underlying pathology is always axon loss. Both the
EDX examination and neuroimaging studies are
helpful in assessing these patients. As expected, their
prognosis is dismal.
Radiation-Induced Brachial Plexopathies
Patients who received radiation treatments to the
neck or shoulder region may develop, often many
years later, a progressive brachial plexopathy, usually
infraclavicular in location. Often, this occurs in
women who had radiation directed to their axillary
lymph nodes during treatment for ipsilateral breast
carcinoma. Typically, the first symptom is the
appearance of persistent numbness in one of the
BRACHIAL PLEXOPATHIES 415
median nerve-innervated fingers due to lateral cord
involvement. As time passes, the paresthesias spread
throughout the hand and upper limb. At some point,
weakness also appears, most often beginning in the
biceps, brachialis, or pronator teres and then
involving progressively more limb muscles. Some
patients also experience severe pain, but the number
that do so is debated. Often, slow progression
occurs, leading ultimately to a useless arm due to a
combination of marked sensory ataxia and substan-
tial muscle denervation. The underlying pathology,
initially and for many years thereafter, is demyelina-
tion causing conduction block. However, as the years
pass, progressively more axon loss supervenes. Both
the EDX examination and neuroimaging studies are
helpful in documenting these lesions. Unfortunately,
there is no effective treatment, so the prognosis is
very poor.
Burner Syndrome
Many high school and college students engaged in
contact sports, especially football and wrestling,
sustain what most authorities consider to be a special
type of upper trunk brachial plexopathy called
burners or stingers (because of its most prominent
symptom). These occur when the athlete receives a
forceful blow on the shoulder or head. The involved
limb suddenly becomes diffusely weak and dyses-
thetic (burning sensation). All symptoms are usually
very short-lived, resolving completely in 1 or 2 min.
However, occasionally some weakness, most often
subjective, persists in an upper plexus distribution.
The EDX examination reveals evidence of minimal
axon loss in the distribution of the C6 root or upper
trunk. The clinical diagnosis is usually the same: C6
compressive radiculopathy versus mild upper trunk
brachial plexopathy. Because the former is never
detected on neuroimaging studies, an upper trunk
lesion is the most likely etiology. The prognosis is
good, although most sports physicians insist that the
athlete avoid participation in contact sports until the
weakness resolves.
Gunshot Wounds and Stab Wounds
The majority of both gunshot wounds and stab
wounds damage the infraclavicular plexus (i.e., the
cords or terminal nerves). With most low-velocity
penetrating injuries (e.g., stab wounds), the neural
elements injured are cut and often transected. In
contrast, with gunshot wounds, the involved neural
elements are actually transected in o10% of cases.
Far more often, they sustain stretch–contusion
416 BRACHIAL PLEXOPATHIES
injuries due to high-velocity trauma but remain in
continuity. For both stab wounds and gunshot
wounds, secondary infraclavicular plexopathies re-
sulting from primary damage to the axillary blood
vessels with subsequent hematoma formation are
substantial threats. The pathology for stab wounds is
axon loss; in contrast, for gunshot wounds, it may be
axon loss alone or often a combination of axon loss
and demyelination causing conduction block. The
EDX examination helps determine the extent,
severity, and the underlying pathology of these
lesions. Neuroimaging studies are also very helpful,
particularly when blood vessel damage may coexist.
Often, these lesions require operative repair to both
nerve fibers and blood vessels. The prognosis is
variable, depending principally on the underlying
pathology, the particular plexus elements damaged,
and the completeness of the lesion.
Traumatic Shoulder Injuries Causing
Brachial Plexopathy
Injury to various bony structures near the shoulder,
particularly humeral head fractures and dislocations,
may damage elements of the infraclavicular brachial
plexus. With dislocations, the axillary terminal nerve
is at particular risk. The pathology is variable,
ranging from total axon loss to near total demyelina-
tion conduction block. Both the EDX examination
and neuroimaging studies are helpful in assessing
these lesions. The prognosis varies but often is good.
Orthopedic Procedures Causing
Brachial Plexopathy
Elements of the brachial plexus—most often the
cords or terminal nerves—can be injured during a
variety of orthopedic procedures, including shoulder
arthroscopy, shoulder arthroplasty, attempted reduc-
tion of shoulder dislocations, and operations per-
formed to treat recurrent shoulder dislocation. The
underlying pathology varies with the specific proce-
dure, but axon loss predominates. Usually, the
specific elements injured and the underlying pathol-
ogy can be established by the EDX examination.
Operative repair of the damaged neural elements is
frequently necessary. The prognosis varies by in-
dividual cases.
Invasive Diagnostic and Therapeutic
Procedures Causing Brachial Plexopathy
Elements of both the supraclavicular and infraclavi-
cular plexus can be injured during a variety of
diagnostic and therapeutic procedures performed on
the base of the neck, shoulder, and axilla. The
majority of these, however, involve the infraclavicu-
lar plexus and most are due to either transaxillary
percutaneous arteriography or transaxillary regional
anesthetic block. The brachial plexus elements are
usually not injured directly but, rather, by hematoma
or pseudoaneurysm formation that results from
initial axillary artery injury. Consequently, the
appearance of the first neurological symptoms—
typically pain followed by weakness in a median
terminal nerve distribution—can vary substantially,
from immediately following the procedure to up to 2
weeks afterwards. The extent of plexus element
damage also varies widely, from terminal median
nerve fibers alone to involvement of virtually all the
terminal nerves (median, ulnar, radial, axillary, and
musculocutaneous). Because the injurious mechan-
ism is a compartment syndrome (specifically, these
are referred to as medial brachial fascial compart-
ment syndromes), the underlying pathology soon
after clinical manifestations appear is axon loss.
Unless there is prompt surgical decompression,
permanent residuals (weakness, sensory loss, and
very often pain) are almost inevitable. Because of the
urgency of the situation, no laboratory studies are
indicated prior to operative treatment. Subsequent
EDX examination, performed weeks after onset of
symptoms, typically reveals total axon loss involving
the median nerve and often other major upper limb
peripheral nerves as well.
Neuralgic Amyotrophy
This disorder, of unknown cause but probably
immune mediated, consists of a precipitating event
(also known as a trigger) followed after a variable
latent period by forequarter pain and, subsequently,
weakness of various forequarter muscles. Although
almost invariably this disorder is discussed with
brachial plexopathies, in most instances the lesion
actually appears to involve one or more peripheral
nerves, with the majority derived from the upper or
upper and middle plexuses, rather than the brachial
plexus itself. Both familial and sporadic forms of
neuralgic amyotrophy are seen, although the latter is
far more common. It affects persons of either sex,
with a slight male predominance, and it tends to be
restricted to adolescents and adults.
This curious PNS disorder was first described in the
1940s by various British neurologists who had seen
many cases of it among military personnel in World
War II. The best article on the subject was authored
by Parsonage and Turner in 1948 and concerned

136 patients. These investigators suggested that this
entity should be called neuralgic amyotrophy (painful
wasting), although many others refer to it as the
Parsonage–Turner syndrome. It has acquired several
other names, including idiopathic brachial plexitis
and cryptogenic brachial neuropathy.
Most of the known triggering events are in the
medical realm. They consist of any type of infectious
disease (e.g., influenza), systemic disease (e.g., lupus),
operation (e.g., appendectomy), inoculation (e.g.,
tetanus), invasive diagnostic or therapeutic proce-
dure (e.g., arterogram), and dental procedure. Other
known triggers include child birth and vigorous use
of a limb. Typically, a latent period of several hours
to 3 or 4 weeks follows the triggering event, and then
forequarter pain abruptly occurs. This is usually
unilateral, often awakens the patient from sleep,
reaches maximal intensity quite rapidly, and is very
severe. Often, it is experienced along the lateral
deltoid muscle (in the sensory distribution of the
axillary nerve), but it may be situated interscapularly,
in the antecubital fossa, or along the lateral thorax,
depending on the particular peripheral nerve af-
fected. The pain generally spontaneously resolves
after 7–10 days, at which time weakness of one or
more muscle groups is noted. Because the nerve
damage is often severe, wasting frequently appears
soon thereafter. Neuralgic amyotrophy has a marked
tendency to involve solely or predominantly motor
nerves (e.g., long thoracic, suprascapular, axillary,
anterior interosseous, spinal accessory, and posterior
interosseous nerves). Sometimes, the affected nerves
are not derived from the brachial plexus (e.g., spinal
accessory, phrenic, and laryngeal nerves).
The underlying pathophysiology in most instances
is axon loss. The EDX examination is extremely
helpful in assessing patients with these lesions; often,
it can demonstrate involvement of muscles that were
thought to be unaffected on clinical examination.
The prognosis is variable, particularly when total
denervation is present in the distribution of one or
more peripheral nerves. There is no effective treat-
ment for neuralgic amyotrophy, although the pain
may respond to high doses of steroids. Proper
recognition of this disorder can prevent two un-
desired results: unnecessary surgical decompression
of the affected nerves, which are mistakenly thought
to be entrapped (this is particularly true for the
suprascapular and anterior interosseous nerves), and
erroneously considering the nerve lesions to be
iatrogenic in nature, resulting in legal action being
taken against various medical personnel.
BRACHYTHERAPY 417
CONCLUSION
The brachial plexus is a large PNS structure that is
highly susceptible to injury, due in large part to its
unprotected location. Most disorders that affect it
tend to damage its elements in a predictable fashion
and produce predictable pathology.
—Asa J. Wilbourn
See also–Lumbar Plexopathy; Nerve Roots;
Thoracic Nerve, Long
Further Reading
Birch, R., Bonney, G., and Wynn-Parry, C. B. (1998). Surgical
Disorders of the Peripheral Nerve. Churchill Livingstone,
London.
Clemente, C. D. (Ed.) (1985). Gray’s Anatomy, 30th ed. Williams
& Wilkins, Baltimore.
Kline, D. G., and Hudson, A. R. (1995). Nerve Injuries. Saunders,
Philadelphia.
Parsonage, M. U., and Turner, A. U. W. (1948). Neuralgic
amyotrophy: The shoulder girdle syndrome. Lancet 1, 973–978.
Wilbourn, A. J. (1993). Brachial plexus disorders. In Peripheral
Neuropathy (P. J. Dyck and P. K. Thomas, Eds.), 3rd ed., pp.
911–950. Saunders, Philadelphia.
Wilbourn, A. J., and Ferrante, M. A. (2001). Plexopathy. In
Neuromuscular Diseases: Expert Clinicians’ Views (R. Pour-
mand, Ed.), pp. 493–527. Butterworth-Heinemann, Boston.
Brachytherapy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TERM BRACHYTHERAPY derives from the Greek
brachio, meaning short, and denotes treatment using
a radioisotope over a short range. In contradistinc-
tion, teletherapy or external beam therapy refer to
radiation treatment at a distance and typically
involve a linear accelerator. Brachytherapy began
remarkably soon after the 1896 discovery of radio-
activity in Paris by Henri Becquerel and the extrac-
tion of radium from pitchblende by Marie and Pierre
Curie in 1898. For these landmark achievements,
Becquerel and the Curies were jointly awarded the
Nobel Prize in 1903, by which time brachytherapy
had been introduced as a modality to treat disease.
In the earliest instances, radium was simply placed
over lesions, such as tumors of the skin. In 1903,
brachytherapy was used successfully to treat basal
cell skin carcinoma. By 1905, radium had been used
by physicians in Paris, Munich, London, and New
York. Within the next few years, it was ingeniously

136 patients. These investigators suggested that this
entity should be called neuralgic amyotrophy (painful
wasting), although many others refer to it as the
Parsonage–Turner syndrome. It has acquired several
other names, including idiopathic brachial plexitis
and cryptogenic brachial neuropathy.
Most of the known triggering events are in the
medical realm. They consist of any type of infectious
disease (e.g., influenza), systemic disease (e.g., lupus),
operation (e.g., appendectomy), inoculation (e.g.,
tetanus), invasive diagnostic or therapeutic proce-
dure (e.g., arterogram), and dental procedure. Other
known triggers include child birth and vigorous use
of a limb. Typically, a latent period of several hours
to 3 or 4 weeks follows the triggering event, and then
forequarter pain abruptly occurs. This is usually
unilateral, often awakens the patient from sleep,
reaches maximal intensity quite rapidly, and is very
severe. Often, it is experienced along the lateral
deltoid muscle (in the sensory distribution of the
axillary nerve), but it may be situated interscapularly,
in the antecubital fossa, or along the lateral thorax,
depending on the particular peripheral nerve af-
fected. The pain generally spontaneously resolves
after 7–10 days, at which time weakness of one or
more muscle groups is noted. Because the nerve
damage is often severe, wasting frequently appears
soon thereafter. Neuralgic amyotrophy has a marked
tendency to involve solely or predominantly motor
nerves (e.g., long thoracic, suprascapular, axillary,
anterior interosseous, spinal accessory, and posterior
interosseous nerves). Sometimes, the affected nerves
are not derived from the brachial plexus (e.g., spinal
accessory, phrenic, and laryngeal nerves).
The underlying pathophysiology in most instances
is axon loss. The EDX examination is extremely
helpful in assessing patients with these lesions; often,
it can demonstrate involvement of muscles that were
thought to be unaffected on clinical examination.
The prognosis is variable, particularly when total
denervation is present in the distribution of one or
more peripheral nerves. There is no effective treat-
ment for neuralgic amyotrophy, although the pain
may respond to high doses of steroids. Proper
recognition of this disorder can prevent two un-
desired results: unnecessary surgical decompression
of the affected nerves, which are mistakenly thought
to be entrapped (this is particularly true for the
suprascapular and anterior interosseous nerves), and
erroneously considering the nerve lesions to be
iatrogenic in nature, resulting in legal action being
taken against various medical personnel.
BRACHYTHERAPY 417
CONCLUSION
The brachial plexus is a large PNS structure that is
highly susceptible to injury, due in large part to its
unprotected location. Most disorders that affect it
tend to damage its elements in a predictable fashion
and produce predictable pathology.
—Asa J. Wilbourn
See also–Lumbar Plexopathy; Nerve Roots;
Thoracic Nerve, Long
Further Reading
Birch, R., Bonney, G., and Wynn-Parry, C. B. (1998). Surgical
Disorders of the Peripheral Nerve. Churchill Livingstone,
London.
Clemente, C. D. (Ed.) (1985). Gray’s Anatomy, 30th ed. Williams
& Wilkins, Baltimore.
Kline, D. G., and Hudson, A. R. (1995). Nerve Injuries. Saunders,
Philadelphia.
Parsonage, M. U., and Turner, A. U. W. (1948). Neuralgic
amyotrophy: The shoulder girdle syndrome. Lancet 1, 973–978.
Wilbourn, A. J. (1993). Brachial plexus disorders. In Peripheral
Neuropathy (P. J. Dyck and P. K. Thomas, Eds.), 3rd ed., pp.
911–950. Saunders, Philadelphia.
Wilbourn, A. J., and Ferrante, M. A. (2001). Plexopathy. In
Neuromuscular Diseases: Expert Clinicians’ Views (R. Pour-
mand, Ed.), pp. 493–527. Butterworth-Heinemann, Boston.
Brachytherapy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TERM BRACHYTHERAPY derives from the Greek
brachio, meaning short, and denotes treatment using
a radioisotope over a short range. In contradistinc-
tion, teletherapy or external beam therapy refer to
radiation treatment at a distance and typically
involve a linear accelerator. Brachytherapy began
remarkably soon after the 1896 discovery of radio-
activity in Paris by Henri Becquerel and the extrac-
tion of radium from pitchblende by Marie and Pierre
Curie in 1898. For these landmark achievements,
Becquerel and the Curies were jointly awarded the
Nobel Prize in 1903, by which time brachytherapy
had been introduced as a modality to treat disease.
In the earliest instances, radium was simply placed
over lesions, such as tumors of the skin. In 1903,
brachytherapy was used successfully to treat basal
cell skin carcinoma. By 1905, radium had been used
by physicians in Paris, Munich, London, and New
York. Within the next few years, it was ingeniously
418 BRACHYTHERAPY
adapted for the treatment of not only superficial
lesions but also deeper tumors. The utility of
brachytherapy was readily manifest and expanded
to include many tumors.
Despite the initial success of brachytherapy, it fell
from favor for several reasons. Constructing radio-
active sources and calculating doses were difficult. A
limited number of training centers were expert in its
use. There were also legitimate concerns about the
effects of radiation on physicians and staff after
repeated exposure. The advent of the atomic era and
new radionuclides, the evolution of computers to
calculate dose distributions accurately and rapidly,
and extensive technological developments, including
remote afterloading of radioactive sources, have
largely addressed these issues.
Brachytherapy is now part of the standard
armamentarium for cervix and uterine carcinomas,
some head and neck cancers, thyroid cancer, prostate
cancer, and sarcomas. It is also frequently used in the
treatment of tumors of the lung, breast, esophagus,
gastrointestinal tract, and central nervous system
(CNS). Its discreet use for nonmalignant processes,
such as pterygia, keloids, and heterotopic ossifica-
tion, is now standard. Endovascular brachytherapy is
an auspicious recent development for the treatment
of benign lesions and has resulted in decreased rates
of restenosis after angioplasty for peripheral and
coronary artery disease.
The first recorded use of radium for an intracranial
tumor was for benign disease, a pituitary adenoma,
in 1912. By 1914, brachytherapy had been used to
treat parenchymal brain tumors. Despite these early
inroads, the broader application of brachytherapy to
CNS tumors awaited recent advances in treatment
planning and stereotaxis, which now provide a
strong rational foundation for brachytherapy. Radia-
tion, in the form of external beam therapy, has
documented efficacy for many CNS tumors. Despite
these benefits, the dominant failure patterns for
many CNS tumors continue to include local recur-
rences. Theoretically, higher radiation doses would
prevent recurrences, but this approach is precluded
by the limited tolerance of surrounding normal brain
and other tissues. Brachytherapy addresses this
limitation by deploying the radiation within the
tumor and takes advantage of the fact that the dose
of radiation decreases rapidly as distance from the
tumor increases. The result is higher doses of
radiation directly to the tumor and lower radiation
doses to smaller volumes of normal tissue. The most
thorough experience with brachytherapy is with
malignant gliomas, but it has also been used to treat
craniopharyngiomas, meningiomas, metastatic le-
sions, and paraspinal tumors.
Important clinical investigations have improved
the median length of survival and the quality of life
for patients with malignant gliomas. Nonetheless,
these tumors continue to frustrate clinicians and
scientists. Their local failure and high mortality rates
have confounded even aggressive combinations of
local and systemic therapies. In the initial manage-
ment of malignant gliomas, brachytherapy has had
modest success as an adjunct to surgery, external
beam irradiation, and chemotherapy and has demon-
strated some efficacy for the treatment for recurrent
disease.
As part of the planned initial approach to
patients with malignant glioma, the Brain Tumor
Cooperative Group evaluated brachytherapy in a
prospective randomized trial. Patients were ran-
domly assigned to one of two treatment groups:
standard external beam irradiation with carmustine
chemotherapy or the same treatment preceded by
brachytherapy. A formal, peer-reviewed report of
this study has not been issued, but a preliminary
review suggested that the addition of brachytherapy
to the treatment protocol extends survival. The
differences, however, failed to reach statistical
significance (p ¼ 0.08).
A detailed report from the University of California
at San Francisco indicated that survival may have
improved in 133 patients with recurrent malignant
gliomas who were treated with temporary radio-
iodide (125I) brachytherapy. For all 307 patients, the
median survival was 88 weeks for patients with a
glioblastoma and 142 weeks for those with an
anaplastic astrocytoma. For the 133 patients treated
for recurrence, the respective median survival from
the date of brachytherapy was 49 and 52 weeks. The
median survival from the date of brachytherapy was
49 weeks for patients with a glioblastoma and 52
weeks for those with an anaplastic astrocytoma. The
respective 3-year survival rates were 22 and 15%.
These results are notable and similar to the expected
rates of survival of most patients with a malignant
glioma from the time of their initial diagnosis. In
addition to a beneficial therapeutic effect, this finding
may reflect the selection bias of a patient cohort
chosen for brachytherapy with relatively small, focal
recurrences.
The mainstays of treatment for craniopharyngio-
mas are surgery and external beam irradiation.
Long-term survival rates typically exceed 75%. A

novel application of brachytherapy has been devel-
oped for patients with recurrent, predominantly
cystic craniopharyngiomas. Under stereotactic gui-
dance, the craniopharyngioma cyst is aspirated. A
radioactive isotope in a liquid suspension is injected
to deliver a high dose of radiation to the lining of the
cyst. This treatment has led to high rates of cyst
regression (88% in a recent series) and acceptable
longer term control rates (67% at 3 years in the
same report).
Surgery is the initial treatment for meningiomas
that can be resected. Convexity tumors can often
be gross-totally resected—an outcome more difficult
to achieve with basal meningiomas. Typically, radia-
tion therapy is reserved for patients with incomplete
resections; with aggressive histologies, such as
atypical, papillary, or malignant variants; or with
recurrent tumors. Depending on the clinical scenario,
radiation can be delivered as external beam, stereo-
tactic radiosurgery, or brachytherapy. 125I seeds
have been placed under either direct open visualiza-
tion or stereotactic guidance. A recent report
indicates that the implantation of 125I is safe and
effective, with a 69% complete response rate.
However, this study included only 13 patients and
the median follow-up was only 15 months. The
generalizability of this study and other brachyther-
apy series is limited by the small number of patients
and the lack of long-term data. This information is
particularly important for meningiomas, which can
have protracted natural histories. More extensive
and mature data document the efficacy of radiation
therapy in the forms of external irradiation or
stereotactic radiosurgery.
The optimal treatment for patients with brain
metastasis is the subject of considerable discussion
and study and undergoing continual refinements.
Currently, the standard for most metastatic tumors
includes whole brain external radiation therapy
combined with surgical resection or radiosurgery
in selected cases. Brachytherapy has been used
successfully in small series, but surgery and
radiosurgery have met with broader success and
acceptance.
For malignant tumors of the spine that compress
the spinal cord, brachytherapy has been used as an
adjunct to surgical resection, both as the primary
treatment and to treat recurrences after prior
systemic, radiation, or surgical therapy. Recently,
23 patients underwent intraoperative permanent 125I
brachytherapy along with surgical resection and
spinal cord decompression. Of the patients with a
BRACHYTHERAPY 419
local recurrence after undergoing prior external
beam irradiation, 69% attained durable local control
after brachytherapy.
The juxtaposition of intracranial and spinal
tumors to critical, radiation-sensitive normal struc-
tures makes it technically difficult and often infea-
sible to deliver adequate doses of radiation.
Recurrent, previously irradiated tumors further
accentuate these difficulties. Brachytherapy entails
meticulous placement of radioactive sources in or
immediately adjacent to the target tumor tissue and
exposes lesions to higher doses of radiation than
could be achieved by conventional external beam
irradiation. It is often technically demanding but can
reap rewards when used judiciously. The develop-
ment of more sophisticated methods of external
beam delivery, such as stereotactic radiosurgery and
intensity-modulated radiation therapy, poses new
challenges to brachytherapy. However, further tech-
nical developments, new isotopes, and radioconju-
gated immune and molecular therapies hold promise
and bode well for the continued role of brachyther-
apy in the treatment of many benign and malignant
ailments, including those of the CNS.
—C. Leland Rogers
See also–Brain Tumors, Clinical Manifestations
and Treatment; Childhood Brain Tumors; Glial
Tumors; Meningiomas; Neuroradiology,
Diagnostic; Spinal Cord Tumors, Treatment of
Further Reading
Frazier, C. H. (1920). The effects of radiation emanations upon
brain tumors. Surg. Gynecol. Obstet. 31, 237–239.
Kumar, P. P., Patil, A. A., Leibrock, L. G., et al. (1991).
Brachytherapy: A viable alternative in the management of basal
meningiomas. Neurosurgery 29, 676–680.
Pollock, B. E., Lunsford, L. D., Kondziolka, D., et al. (1995).
Phosphorus-32 intracavitary irradiation of cystic craniophar-
yngiomas: Current technique and long-term results. Int. J.
Radiat. Oncol. Biol. Phys. 33, 437–446.
Prados, M., Leibel, S., Barnett, C. M., et al. (1989). Interstitial
brachytherapy for metastatic brain tumors. Cancer 63,
657–660.
Rogers, L., Theodore, N., Sonntag, V., et al. (2002). Permanent
I-125 seed paraspinal brachytherapy for malignant tumors with
spinal cord compression. Radiother. Oncol., in press.
Scharfen, C. O., Sneed, P. K., Wara, W. M., et al. (1992). High
activity iodine-125 interstitial implant for gliomas. Int. J.
Radiat. Oncol. Biol. Phys. 24, 583–591.
Shapiro, W. R., Shapiro, J. R., and Walker, R. W. (2000). Central
nervous system. In Clinical Oncology (M. D. Abeloff, J. O.
Armitage, A. S. Lichter, and J. E. Neiderhuber, Eds.), 2nd ed.
Churchill Livingstone, New York.
420 BRAIN ANATOMY
Brain Abscess
see Abscess
Brain Anatomy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRAIN is a complex arrangement of nuclei and
neural pathways that provides humans the capacity
to process, modulate, and interpret sensory stimuli;
regulate the activity of visceral, endocrine, and
musculoskeletal functions; and perform higher men-
tal functions involving memory, imagination, and
creative thought. The weight of an average adult
human brain is approximately 1400 g, which is
approximately 2% of total body weight. The brain
and the spinal cord, which together constitute the
central nervous system, contain as many as 100
billion neurons.
The brain is commonly described as consisting of
the cerebrum, brainstem, and cerebellum. However,
the brain can be more precisely defined as the
composite of five major subdivisions derived from
neural vesicles formed in the embryonic stages of
development: myelencephalon, metencephalon, me-
sencephalon, diencephalon, and telencephalon. The
cerebrum comprises the cerebral hemispheres (tele-
ncephalon) and diencephalon, and the brainstem
consists of the midbrain (mesencephalon), pons
(metencephalon), and medulla oblongata (myelence-
phalon). The cerebellum, which is often considered
as a separate brain structure from the brainstem, is
also derived from the metencephalon (Fig. 1).
Figure 1
Midsagittal section of the brain.
The most caudal aspect of the brainstem, the
medulla oblongata, is commonly referred to simply
as the medulla. Consistent with its confluence with
the spinal cord, the medulla regulates primal body
functions. Several centers responsible for vital auto-
matic functions, such as digestion, breathing, and
heart rate control, are situated here.
Located rostral to the medulla are two anatomi-
cally distinct but functionally related structures
derived from the metencephalon. The first of these,
the cerebellum, develops from the dorsal aspect of
the metencephalon. Although constituting only 10%
of the total brain volume, the cerebellum contains
nearly 50% of the total number of neurons in the
central nervous system. This densely populated
structure is involved in processing unconscious
sensory information for body movements and
modulating the direction, amplitude, force, and
timing of movements. It has a major function in the
learning of motor tasks, and it plays an important
role in regulating equilibrium and muscle tone. The
second structure, the pons, arises from the ventral
portion of the metencephalon and serves largely as a
massive neural relay station between the cerebellum
and different regions of the brain. The dorsal portion
of the pons (pontine tegmentum) contains pairs of
cranial nerve nuclei, reticular nuclei, and ascending
and descending nerve tracts. The ventral aspect of the
pons (pons proper) consists of pontine nuclei and
longitudinal fiber bundles that allow neural connec-
tions between the cerebral hemispheres and the
cerebellum and between the cerebellum, brainstem,
and spinal cord. Together, the medulla and the pons
constitute the bulbar region of the brainstem.
The last component of the brainstem, the mid-
brain, is derived from the mesencephalon. This
region controls many sensory and motor functions,
including eye movement and the coordination of
visual and auditory reflexes. The dorsal region
(tectum) differentiates into the superior colliculus
and inferior colliculus. The superior colliculus (optic
tectum) is involved in the control of eye movements,
and the inferior colliculus serves as an important
relay for the processing of auditory information. The
ventral region of the midbrain (tegmentum) contains
both the substantia nigra and the red nucleus, which
are two cell groups involved in the subconscious
control of voluntary body movements.
Along the course of the brainstem are situated
cranial nerves III–XII (Fig. 2). The occulomotor (III)
and trochlear (IV) nerves emerge from the midbrain;
the trigeminal (V), abducens (VI), facial (VII), and

Figure 2
Ventral view of the brain showing cranial nerves.
vestibulocochlear (VIII) nerves emerge from the pons
and the junction between the pons and medulla; and
the glossopharyngeal (IX), vagus (X), accessory (XI),
and hypoglossal (XII) nerves emerge from the
medulla. Cranial nerves III, IV, VI, XI, and XII are
motor nerves that innervate muscles of the eye, neck,
or tongue. Cranial nerves V, VII, IX, and X are mixed
nerves that contain both a sensory and motor
distribution. They mediate cutaneous and proprio-
ceptive sensations from the face and mouth, and they
innervate the muscles of mastication, facial expres-
sion, the tongue, and autonomic visceral functions.
Cranial nerve VIII is exclusively a sensory nerve that
is associated with hearing, balance, postural reflexes,
and orientation of the head in space. The cranial
nerve nuclei are organized into columns within the
brainstem on the basis of their embryologic origins.
The diencephalon constitutes the central core of
the cerebrum. The name diencephalon means ‘‘be-
tween brain,’’ which refers to its location between the
brainstem and cerebral hemispheres. The largest
component of the diencephalon, the thalamus,
consists of several nuclei that serve as relay centers
to process information from the rest of the central
nervous system before it reaches the cerebral cortex.
The thalamus receives inputs from sensory pathways
(including vision and audition), cortical areas in-
volved in complex mental processes, neural circuits
related to emotions, and motor pathways of the
cerebellum and basal ganglia. A second major
structure of the diencephalon, the hypothalamus,
contains several nuclei and has a variety of important
functions. Through connections with the autonomic
BRAIN ANATOMY 421
nervous system, it is involved in the regulation of
body temperature and circulation. As part of the
endocrine system, the hypothalamus produces hor-
mones that regulate food and water intake, and as
part of the limbic system, the hypothalamus is
involved in aspects of emotional behavior. Also
found within the diencephalon is the subthalamus.
This area contains sensory tracts that project to the
thalamus, nerve fibers that originate in the cerebel-
lum, and the subthalamic nucleus, which is an
important component of the motor function of the
basal ganglia.
The cerebral hemispheres, derived from the telen-
cephalon, form by far the largest region of the brain.
They each surround a lateral ventricle, the largest of
a series of ventricles that contain cerebrospinal fluid
used to cushion and provide a chemical equilibrium
for the brain and spinal cord. The lateral ventricles
merge into the third ventricle, located in the
diencephalon, which then transitions through the
fourth ventricle of the pons and medulla to become
the central canal of the spinal cord. The cerebral
hemispheres are composed of a 1.5- to 5.0-mm-thick
cerebral cortex of cell bodies (gray matter) and an
extensive network of nerve fibers (white matter) that
project within and across the cerebral hemispheres as
well as to the thalamus, the brainstem, and the spinal
cord. Located deep within each of the cerebral
hemispheres are three distinct nuclei: the basal
ganglia, the hippocampal formation, and the amyg-
dala. The basal ganglia participate in regulating
motor performance, the hippocampus in aspects of
memory storage, and the amygdala in numerous
aspects of emotions, including autonomic and endo-
crine responses to emotional states.
The cerebral cortex is highly convoluted, which
serves to increase its total surface area. Prominent
ridges (gyri) and grooves (sulci) of the cortex are used
to delineate five major lobes for each cerebral
hemisphere: the frontal, parietal, temporal, and
occipital lobes on the lateral surface and the limbic
lobe on the medial surface (Fig. 3). Each lobe is
generally dedicated to a specific set of brain func-
tions, although a clear distinction in function is less
pronounced at the interface between adjacent lobes.
The frontal lobe is involved in attention, decision
making, motor planning, and the initiation of
voluntary movements. The primary motor area is
located in the precentral gyrus, which lies in the
posterior region of the frontal lobe. The anterior
aspect of the parietal lobe contains the primary
somatosensory area located in the postcentral gyrus.
422 BRAIN ANATOMY
Figure 3
Lateral view of the cerebral hemisphere and cerebellum.
The parietal lobe is associated with the processing of
somatosensory information, in aspects of spatial
orientation and perception, and with portions of the
temporal lobe in language comprehension. The
occipital lobe is dedicated to visual function. The
primary visual cortex is located here and the entire
lobe is involved in higher order processing of visual
information. The temporal lobe contains the primary
auditory cortex and is involved in complex aspects of
learning and memory. The temporal lobe also assists
the occipital lobe in higher order processing of visual
information. The limbic lobe is the only lobe described
on the medial surface of the cerebral hemisphere. It
shares medial components of the frontal, parietal, and
temporal lobes and is intimately connected to the
hippocampus. It is an important area for emotional
responses, drive-related behavior, and memory.
Discussing components of the brain as separate
entities is somewhat contrived because it is the
extensive and intimate connections between the
components of the brain that allow efficient control
of the human body to occur. A great deal of
convergence occurs between related brain structures,
and the divergence of neuronal projections provides
an efficient means of coordination and distributed
control for the central nervous system. Although it is
impossible to discuss all the major connections that
exist between components of the brain, a few are
described here to offer insight to the organization of
the brain.
Within each cerebral hemisphere, the white matter
contains bundles of association fibers that connect
and coordinate one cortical region with another
(Fig. 4). The most prominent of these are the superior
longitudinal (arcuate) fasciculus, the superior and
inferior occipitofrontal fasciculi, and the cingulum.
The major fiber bundle that connects one cerebral
hemisphere to another is the corpus callosum, a
broad band of commissural fibers that covers the
anterior, superior, and posterior surface of the lateral
ventricles. The corpus callosum is an important
avenue for the integration of information processed
in the two hemispheres. Other commissural fibers
run between the temporal lobes passing through the
anterior commissure. In the midbrain, the posterior
commissure provides an important component for
pupillary light reflexes.
An example of the connections that exist between
different subdivisions of the brain is characterized by
the internal capsule (Fig. 4). Almost all the neural
connections made with the cerebral cortex pass from
the thalamus to the cortex or from the cortex back to
the diencephalon and brainstem through the internal
capsule. This fiber bundle passes between the deep-
lying cell bodies of the basal ganglia as it courses to
and from the cerebral cortex. A wide divergence of
brainstem fibers occurs as they travel to the cerebral
cortex, and a massive convergence occurs as the
cortex projects to the brainstem. This arrangement
provides a mechanism for the dissemination of
information from the sensory pathways of the
brainstem to the cortex and for the organization of
motor output that is directed to the brainstem.
In addition to the local connections made between
adjacent regions of the brain, all of the regions of the
brain act in concert to support a number of
specialized pathways. For example, visual and audi-
tory pathways utilize cranial nerves in the region of
the pons and medulla, specific areas of the midbrain
and thalamus, and association fibers and specific
primary regions of the cerebral cortex to carry out
their functions. Similarly, the circuits involved in
postural control include cranial nerves, the cerebel-
lum, and related parts of the cerebrum. Thus,
Figure 4
Coronal section of the brain.

although separate anatomical components of the
brain can be identified, the control of many sensor-
imotor functions is distributed throughout the brain.
—S. C. Sharma and M. J. Majsak
See also–Art and the Brain; Brain Death; Brain
Development, Normal Postnatal; Brain
Evolution, Human; Brain Trauma, Overview;
Central Nervous System, Overview;
Physiological Brain Imaging; Skull; Spinal Cord
Anatomy; Vertebrate Nervous System,
Development of
Further Reading
Bear, M., Fusco, M., and Dewey, M. (2001). Neuroscience:
Exploring the Brain, 2nd ed. Lippincott Williams & Wilkins,
Philadelphia.
DeArmond, S., Conners, M., and Paradiso, M. (1989). Structure of
the Human Brain: A Photographic Atlas, 3rd ed. Oxford Univ.
Press, New York.
Gluhbegovic, N., and Williams, T. (1980). The Human Brain: A
Photographic Guide. Harper & Row, Hagerstown, MD.
Kandel, E., Schwartz, J., and Jessell, T. (2000). Principles of
Neural Science, 4th ed. Elsevier, New York.
Noback, C., Strominger, N., and Ruggiero, D. (1996). The Human
Nervous System: Structure and Function, 5th ed. Williams &
Wilkins, Philadelphia.
Nolte, J. (1999). The Human Brain: An Introduction to Its
Functional Anatomy, 4th ed. Mosby, New York.
Brain Death
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
DEATH is defined as the irreversible end of life. Unlike
the definitions of other medical disorders, death is
entrusted to the law rather than to medicine. In other
words, the law has the ultimate authority to declare a
person dead. Prior to the concept of brain death,
death was identified as irreversible cessation of
heartbeat and respirations. This definition still
applies, but since the advent of intensive care units
and ventilators, another form of death—death of the
brain—has been recognized as being equivalent to
death of the individual.
In 1959, the term coma depassé (the state beyond
coma) was coined by French neurologists to describe
the state of such individuals. This concept was
slow to be accepted in other countries until the
published conclusions of the 1968 study, ‘‘A Defini-
tion of Irreversible Coma: A Report of the Ad Hoc
BRAIN DEATH 423
Committee of the Harvard Medical School to
Examine the Definition of Brain Death.’’ Subse-
quently, there has been a general acceptance that
death of the brain is a necessary and sufficient
condition for death of the individual.
Declaring brain death allows for the transplanta-
tion of organs to a living recipient if permission is
granted. Because of the finality of the diagnosis of
brain death, strict criteria are needed.
CRITERIA FOR BRAIN DEATH
The 1968 report of the Harvard Committee is of
great historical importance because it gave official
recognition to brain death and it served as a model
for other efforts to develop criteria for determining
brain death in a reliable and timely manner.
Subsequent refinements of brain death criteria were
made in the United States and other countries.
Clinical guidelines can be validly applied only when
(i) there is an acute central nervous system cata-
strophe that is capable of causing brain death, (ii)
conditions that might prevent valid application of
clinical criteria (severe electrolyte, acid–base, or
endocrine disturbance or shock with systolic blood
pressure less than 90 mmHg) have been excluded,
(iii) drug intoxication and poisoning are absent, and
(iv) the core body temperature is at least 32.21C.
CLINICAL EVALUATION
Before considering brain death, the diagnosis should
be known and the condition should be one that is
capable of causing neuronal death, including trauma,
intracranial hemorrhage, or severe brain swelling.
Determination of irreversibility is dependent on the
cause, completeness of the dysfunction, the passage
of time, and confirmation by retesting. With anato-
mical disruption of the brainstem (e.g., by hemor-
rhage or trauma), the intervals between assessments
can be a few hours. With generalized anoxic–
ischemic encephalopathy from cardiac arrest or with
fat or air embolism, it may take longer (e.g., 24 hr) to
establish a prognosis.
Ancillary tests (e.g., those of cerebral perfusion)
can be used to make earlier diagnoses of brain death
or a more timely prognostic evaluation. They can
also be used in situations in which the clinical criteria
cannot be applied.
The presence of potentially reversible causes of
coma (especially sedatives or hypothermia), neuro-
muscular blocking agents, severe neuropathy, or

although separate anatomical components of the
brain can be identified, the control of many sensor-
imotor functions is distributed throughout the brain.
—S. C. Sharma and M. J. Majsak
See also–Art and the Brain; Brain Death; Brain
Development, Normal Postnatal; Brain
Evolution, Human; Brain Trauma, Overview;
Central Nervous System, Overview;
Physiological Brain Imaging; Skull; Spinal Cord
Anatomy; Vertebrate Nervous System,
Development of
Further Reading
Bear, M., Fusco, M., and Dewey, M. (2001). Neuroscience:
Exploring the Brain, 2nd ed. Lippincott Williams & Wilkins,
Philadelphia.
DeArmond, S., Conners, M., and Paradiso, M. (1989). Structure of
the Human Brain: A Photographic Atlas, 3rd ed. Oxford Univ.
Press, New York.
Gluhbegovic, N., and Williams, T. (1980). The Human Brain: A
Photographic Guide. Harper & Row, Hagerstown, MD.
Kandel, E., Schwartz, J., and Jessell, T. (2000). Principles of
Neural Science, 4th ed. Elsevier, New York.
Noback, C., Strominger, N., and Ruggiero, D. (1996). The Human
Nervous System: Structure and Function, 5th ed. Williams &
Wilkins, Philadelphia.
Nolte, J. (1999). The Human Brain: An Introduction to Its
Functional Anatomy, 4th ed. Mosby, New York.
Brain Death
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
DEATH is defined as the irreversible end of life. Unlike
the definitions of other medical disorders, death is
entrusted to the law rather than to medicine. In other
words, the law has the ultimate authority to declare a
person dead. Prior to the concept of brain death,
death was identified as irreversible cessation of
heartbeat and respirations. This definition still
applies, but since the advent of intensive care units
and ventilators, another form of death—death of the
brain—has been recognized as being equivalent to
death of the individual.
In 1959, the term coma depassé (the state beyond
coma) was coined by French neurologists to describe
the state of such individuals. This concept was
slow to be accepted in other countries until the
published conclusions of the 1968 study, ‘‘A Defini-
tion of Irreversible Coma: A Report of the Ad Hoc
BRAIN DEATH 423
Committee of the Harvard Medical School to
Examine the Definition of Brain Death.’’ Subse-
quently, there has been a general acceptance that
death of the brain is a necessary and sufficient
condition for death of the individual.
Declaring brain death allows for the transplanta-
tion of organs to a living recipient if permission is
granted. Because of the finality of the diagnosis of
brain death, strict criteria are needed.
CRITERIA FOR BRAIN DEATH
The 1968 report of the Harvard Committee is of
great historical importance because it gave official
recognition to brain death and it served as a model
for other efforts to develop criteria for determining
brain death in a reliable and timely manner.
Subsequent refinements of brain death criteria were
made in the United States and other countries.
Clinical guidelines can be validly applied only when
(i) there is an acute central nervous system cata-
strophe that is capable of causing brain death, (ii)
conditions that might prevent valid application of
clinical criteria (severe electrolyte, acid–base, or
endocrine disturbance or shock with systolic blood
pressure less than 90 mmHg) have been excluded,
(iii) drug intoxication and poisoning are absent, and
(iv) the core body temperature is at least 32.21C.
CLINICAL EVALUATION
Before considering brain death, the diagnosis should
be known and the condition should be one that is
capable of causing neuronal death, including trauma,
intracranial hemorrhage, or severe brain swelling.
Determination of irreversibility is dependent on the
cause, completeness of the dysfunction, the passage
of time, and confirmation by retesting. With anato-
mical disruption of the brainstem (e.g., by hemor-
rhage or trauma), the intervals between assessments
can be a few hours. With generalized anoxic–
ischemic encephalopathy from cardiac arrest or with
fat or air embolism, it may take longer (e.g., 24 hr) to
establish a prognosis.
Ancillary tests (e.g., those of cerebral perfusion)
can be used to make earlier diagnoses of brain death
or a more timely prognostic evaluation. They can
also be used in situations in which the clinical criteria
cannot be applied.
The presence of potentially reversible causes of
coma (especially sedatives or hypothermia), neuro-
muscular blocking agents, severe neuropathy, or
424 BRAIN DEATH
drugs with anticholinergic effects preclude applica-
tion of the clinical criteria alone. This applies
whether such factors are present in isolation or in
association with potentially lethal etiologies.
After it is established that the patient’s condition is
due to irreversible brain damage of known etiology,
three necessary clinical components of brain death
are unresponsiveness, the absence of brainstem
reflexes, and apnea.
Unresponsiveness
There should be no motor response of the limbs or
grimacing to nail bed and supraorbital pressure.
Because of the possibility of a neuropathy or spinal
cord lesion, applying a stimulus to a somatosensory
branch of a cranial nerve is essential. The supraorbi-
tal branch of the ophthalmic division of the cranial
nerve is the most practical one to test: One applies
pressure with a finger against the medial supraorbital
region. For peripheral stimulation, vigorous com-
pression of the patient’s nail bed by a pen is
adequate.
No spontaneous movements caused by the brain
(e.g., dystonic, decerebrate, or decorticate posturing
or seizures) should be present. Movements of spinal
cord origin may occur during hypoxia or hypoten-
sion (Lazarus’ sign). There may be neck and hip
flexion, arching of the back, or short excursion
breathing movements. Testing motor responsiveness
is not valid if there is neuromuscular paralysis from a
severe neuropathy or neuromuscular blockade. If
neuromuscular blocking agents have been adminis-
tered, it should be demonstrated that the block is no
longer operative by eliciting deep tendon reflexes or
by the use of a peripheral nerve stimulator.
The Absence of Brainstem Reflexes
Pupils: A bright light is shone in each pupil
independently, examining for direct and consensual
(opposite) pupillary constriction. The pupils could be
midposition or dilated but should not react to light.
Round, oval, or irregular-shaped pupils are all
compatible with brain death.
Atropine inadvertently dropped on the cornea,
overdoses of drugs with antimuscarinic blocking
properties, or traumatic mydriasis may cause pupil-
lary nonreactivity. In conventional doses, intrave-
nous atropine does not affect the pupillary response.
A report of fixed, dilated pupils after extremely high
doses of intravenous dopamine has not been con-
firmed. Fixed pupils in the context of both shock and
high doses of dopamine have been observed, how-
ever.
Ocular Movements: In brain death, ocular move-
ments are absent with the oculocephalic (head
turning) and oculovestibular maneuvers. Caloric
testing is a more potent stimulus; it should always
be used if the oculocephalic reflex is absent. A syringe
is used to inject 50 cc of ice water into the canal. In
the unconscious patient with an intact brainstem,
both eyes tonically deviate to the irrigated side. One
minute of observation should be allowed after each
injection, and 5 min should be allowed between
injections.
Closed head injury, facial trauma, lid edema, or
chemosis of the conjunctiva can preclude assessment
of eye movements. Basal skull fractures involving the
petrous bone (often with Battle’s sign or hemotypa-
num) may abolish the caloric response on the same
side. The canals should be cleared of clotted blood
and cerumen, and oculovestibular reflex testing
should be repeated after visual inspection reveals
the ear canals to be clear.
Facial Sensation and Movements: Corneal reflexes
are usually tested with a cotton swab. Facial move-
ments can be assessed by applying pressure to the
supraorbital ridge or over the condyles near the
temporomandibular joint. Severe facial trauma can
limit validity of the interpretation.
Pharyngeal and Tracheal Reflexes: The gag re-
sponse is tested by touching the posterior pharynx
with a tongue depressor. This is often difficult in the
orally intubated patient, in whom the cough reflex
can be demonstrated by tracheal suctioning or
tracheal tug.
Apnea Testing
Two problems occurred with the 1968 Harvard
recommendations regarding apnea testing in brain
death determination: (i) desaturation of arterial
oxygen during the period of disconnection from the
ventilator and (ii) insufficient partial pressure of
carbon dioxide in arterial blood (PaCO2) to stimulate
respirations. The first problem was effectively pre-
vented in most patients by oxygenating with 100%
oxygen for 10 min before apnea testing and then
administering 100% oxygen through a tracheal
cannula or cannula inserted to the level of the carina
at 6–8 liters/min during disconnection from the
ventilator. Respiratory movements are looked for
during the time the ventilator is stopped. In most

cases, however, an increase in PaCO2 to 460 mmHg,
generally accepted as a sufficient stimulus, can be
achieved if the PaCO2 was 4075 mmHg before
disconnection, the temperature is 436.51C and at
least 8 min of disconnection is allowed for observa-
tion of breathing movements. This should obviate
the need to administer 5% CO2, a procedure that can
lead to severe hypercarbia and respiratory acidosis.
In all but those patients with chronic chest disease
and insensitivity to PaCO2, this should serve as a
powerful stimulus to the medullary respiratory
centers for respiration.
Because apnea testing constitutes a stress and may
cause intracranial pressure to rise, it should only be
done if there is a strong suspicion of brain death and
cranial nerve areflexia. Euvolemia, preferably a
positive fluid balance, and a stable, normal blood
pressure are recommended prerequisites before the
apnea test is performed.
Respiration or spontaneous ventilation is defined
as abdominal or chest movements that produce
adequate tidal volumes. If present, respiration occurs
in the early phases of testing. Some respiratory-like
movements, despite brain death, occur as spinal cord
phenomena. These may occur at the end of testing if
oxygenation is marginal or with continued use of
continuous positive airway pressure. Such move-
ments (shoulder elevation and adduction, back
arching, and intercostal expansion) do not produce
a tidal volume; this can be confirmed by spirometry.
During apnea testing, if the systolic blood pressure
decreases to o90 mmHg, the pulse oximeter shows
marked desaturation, or cardiac arrhythmias occur,
one should immediately draw a blood gas sample
and reconnect the ventilator. Testing is considered
valid if there is apnea during the test and the PaCO2
increases to 460 mmHg, unless other exclusions
apply.
EXCLUSIONS AND CAVEATS
Occasionally, the clinical criteria cannot be ade-
quately applied for the determination of brain death.
Severe facial trauma or head trauma can preclude
assessment of cranial nerve reflexes. Hypothermia,
shock, or toxic levels of various drugs (e.g., sedatives
such as barbiturates, carbamazepine, and tricyclics)
may produce reversible unresponsiveness and depres-
sion of cranial nerve or spontaneous respirations.
Peripheral neurological syndromes can invalidate the
application of clinical criteria (e.g., the assessment of
any movements, including apnea testing, or reflexes).
BRAIN DEATH 425
These include neuromuscular transmission defects
(including the use of neuromuscular blocking
agents), polyneuropathies (including Guillain–Barré
syndrome, critical illness polyneuropathy, and por-
phyria), severe myopathies, or anterior horn cell
disorders. In these events, the clinical criteria are not
valid and one must either reverse the confounding
factors or apply ancillary tests.
ADVANCES IN CONCEPTS OF BRAIN DEATH
SINCE THE 1968 GUIDELINES
A Dead Brain and a Functional Spinal Cord
Not long after the publication of the Harvard
criteria, a number of single and collaborative studies
indicated that the spinal reflexes could be preserved
in cases that otherwise met the criteria for brain
death, with appropriate confirmation that the brain
was nonviable. These reflexes included movements of
the trunk and limbs usually related to segmental
spinal activity. It then became accepted that brain
death could occur in the presence of intact spinal
reflexes.
Brainstem Death
Three years after the publication of the Harvard
criteria, Mohandas and Chou from Minnesota
published a study that showed that most cases of
brain death could be reliably diagnosed using clinical
criteria alone. The electroencephalogram (EEG) was
thus not mandatory. Furthermore, they noted that
irreversible damage to the brainstem was ‘‘the point
of no return.’’ They also introduced the idea of
etiological preconditions—that is, that the etiology
had to be something capable of causing irreversible
structural damage or necrosis of tissue. This report
had considerable influence in the United Kingdom,
where thinking on the topic was led by Christopher
Pallis. He conceived of brainstem death as being the
essence of brain death. The physiological brainstem,
including the anatomical brainstem and the dience-
phalon, is what is meant. In other words, if the
brainstem is dead, all the conditions of the Harvard
and other criteria are met. It is then irrelevant to
ensure that all the intracranial neurons are dead. His
ideas formed the basis for the United Kingdom set of
criteria for brain death. This has subsequently been
accepted in Canada. In the United States, the current
guidelines are those of the President’s Commission
for the Study of Ethical Problems in Medicine and
Biomedical and Behavioral Research published in
426 BRAIN DEATH
1981. There is still widespread opinion in the United
States that death of the entire brain must be
ascertained and that brainstem death is inadequate.
Arguments against relying on Pallis’ set of criteria for
brainstem death include the inclusion of potentially
reversible conditions such as severe Guillain–Barré
syndrome, the Miller–Fisher variant of Guillain–
Barré syndrome (mistakenly termed brainstem en-
cephalitis) and a single case report of a fourth
ventricular hemorrhage in a premature infant. None
of these cases, however, would have been accepted if
the British criteria were properly applied. The
etiology would have precluded the first two; concerns
about prematures, neonates, and young infants
should have created extra caution in the last case.
Philosophically, it is of great comfort to the attending
physician to believe that the whole brain is dead.
However, this is most often an unobtainable goal,
when one considers the difficulties in excluding some
neuronal activity in deep cerebral structures. The
importance of excluding such activity seems unclear
when death of the brainstem is sufficient.
Improved Ancillary Testing
Angiography: Angiography is regarded as a final
determinant in the diagnosis of brain death: the
finding of blocked intracranial circulation. It is
mainly used in cases in which clinical criteria cannot
be applied: unsuitability for cranial nerve (e.g.,
enucleation of one or both eyes, swollen face, and
petrous fracture) or apnea testing (severe acute or
chronic pulmonary disease). Angiography creates
technical problems, such as moving an unstable
patient to the angiography suite and ensuring that
the patient is not hypotensive during the injection.
This type of problem would be even more proble-
matic for premature neonates. Systemic hypotension
may prevent the angiographic dye from reaching the
intracranial compartment, unless the dye is injected
under pressure with the catheter filling the lumen of
the vessel. Injection into the wall (usually deep to the
intima) will also prevent dye from reaching the
intracranial compartment. Vertebral and carotid
injections are necessary to ensure that the intracra-
nial circulation is arrested.
Radioisotope Nuclide Scanning: Conventional
scanning with technetium 99m-labeled agents is
convenient and can be done at the bedside in the
intensive care unit with adequate monitoring and
support. A major drawback is that such scanning
does not adequately assess the posterior fossa
circulation. After all, if brainstem death is the
essential element that must be proven, perfusion of
the brainstem should be the essential part of the
assessment. Brain flow studies are thus generally not
regarded as sufficient evidence of brain death, but
they are of considerable ancillary value.
Perfusion imaging with technetium 99m hexam-
ethylpropylamineoxime constitutes an advancement:
The result is independent of the adequacy of the
bolus injection, there are no problems with venous
sinus activity, and posterior fossa circulation (at least
to the cerebellum) can be better assessed. The test
can be performed at the bedside with two planar
views; the computed tomographic technique is not
required.
Nuclear Magnetic Resonance Imaging: The fol-
lowing are distinctive nuclear magnetic resonance
imaging (MRI) features of brain death: loss of the
subarachnoid spaces; slow flow in the intracavernous
and cervical internal carotid arteries; loss of flow
void in the small and large intracranial arteries and
the major intracranial venous sinuses; and relative
loss of normal gray–white differentiation on T1-
weighted images but preservation of gray–white
differentiation on T2-weighted images, producing a
‘‘supernormal’’ appearance.
MRI and MR angiography may play an important
role in the future; further study and confirmation are
needed. Nonparamagnetic ventilator equipment
must be used; transportation to the scanner and the
time involved may be problematic. Functional MRI
has not been examined. Nuclear MR spectroscopy
may also play a role in the future.
Transcranial Doppler: Transcranial Doppler flow
studies can give supportive evidence of absent flow
through middle cerebral and basilar arteries. The
latter technique is difficult, however, and one must be
certain one has insonated a vessel or feeding vessel
before one can be certain that there is no flow.
Patterns compatible with greatly increased intracra-
nial pressure include (i) absent diastolic or reverber-
ating flow, indicating flow only through systole or
retrograde diastolic flow, and (ii) small systolic peaks
in early systole with absent or reversed flow,
indicating very high vascular resistance. The pattern
of brief systolic forward flow appears to be specific
for brain death in several series. However, 10% of
patients do not have temporal insonation windows
and cannot be tested in a valid manner. An exception
might be in patients who had previously documented
transcranial Doppler signals. The sensitivity and

specificity of transcranial Doppler in brain death are
91.3 and 100%, respectively.
Transcranial Doppler velocities can be markedly
affected by significant changes in PaCO2, hematocrit,
and cardiac output. The techniques require consider-
able practice, patience, and skill. Because of such
marked operator dependence, transcranial Doppler is
not universally recommended.
Other Tests of Brain Blood Flow: These include
nitrous oxide flow studies and tests of pulsatile
midline echo on ultrasound and arteriovenous
oxygen difference. Nitrous oxide brain flow studies
can provide useful prognostic information but have
not been tested adequately in very low flow states.
Hyperoxia of jugular venous blood is characteristic
of brain death. None of these, however, have
achieved general acceptance as stand-alone criteria
or replacements for clinical criteria when the latter
cannot be applied.
EEG: Since the EEG examines only cerebral
cortical activity and not brainstem function, it
cannot be used as a sole determinant of brain death
when the clinical criteria cannot be applied. The EEG
may be of some confirmatory value in some
circumstances, but it is very limited. No electrical
activity of more than 2 mV for more than 30 min of
recording, with maximal sensitivity and long inter-
electrode distance, must be demonstrated for the
diagnosis of electrocerebral silence.
Evoked Potentials: Brainstem auditory and corti-
cal somatosensory evoked potentials are relatively
insensitive to barbiturate and other drug effects.
Their absence is an indication of very serious
disruption of the brainstem tegmentum, providing
the potentials that precede them indicate that the
signal has reached the CNS. However, they sample
only a small component of brain function in
restricted sensory pathways. Furthermore, they can
be technically difficult in the hostile electrical
environment of the intensive care unit; standardizing
the quality is more difficult than doing so for many
other diagnostic tests.
NEONATES AND VERY YOUNG CHILDREN
Early guidelines for the determination of brain death
raised caution about their application to infants and
other children younger than 5 years of age because
their brains had ‘‘increased resistance to damage’’
and a greater likelihood of recovery compared with
BRAIN DEATH 427
adults. Some early studies suggested that application
of adult criteria to children, even those younger than
3 years of age, was appropriate. Anecdotal reports of
newborns who showed no evidence of brainstem or
EEG activity but who survived added greatly to the
doubt about applying standard criteria. Recently,
British researchers concluded that brainstem death
criteria can be applied to infants older than 2 months
post-term.
Evoked responses hold promise; they have been
used in infants to predict with some accuracy an
outcome no better than persistent vegetative state
(PVS). However, they have not been adequately
tested in brain death. Sensory evoked responses can
be used to assess sensory pathways and way stations
for auditory and somatosensory pathways, but they
are specific to those anatomical locations.
Use of angiography to demonstrate the absence of
intracranial flow in the carotid and vertebrobasilar
systems is the gold standard, but the procedure is
difficult, time and labor intensive, risky, and invasive,
especially in the neonate and more so in the
premature infant.
Problems with other ancillary tests have been
recognized. Cranial sector scan using the anterior
fontanelle can detect the absence of pulsations in the
anterior and middle cerebral arteries, but the
brainstem circulation is not examined. Thus, some
neonates may show facial movements or may sur-
vive with intact respirations despite absent flow
on cranial ultrasound. Similar issues are involved
with nuclear medical scanning. Although such
infants are severely disabled, they are not brain
dead. Some of the issues can be resolved by waiting a
suitable period of time and then reapplying clinical
criteria.
In the United States, a special task force published
guidelines for the determination of brain death in
children. These were similar to previous adult criteria
except that times of observations were specified for
different ages. For infants 7 days to 2 months old
and those of gestational age 38 weeks or older, two
examinations and EEGs should be performed with
a 48-hr interval. For infants 2 months to 1 year of
age, two examinations and EEGs should be per-
formed with a 24-hr interval. A repeat exam is not
necessary if a concomitant cerebral radionuclide
angiographic study demonstrates no filling of cere-
bral arteries. For infants older than 1 year, an
observation period of at least 12 hr is recommended.
The observation period can be shortened if the
EEG shows electrocerebral silence or if cerebral
428 BRAIN DEATH
radionuclide angiographic study demonstrates no
filling of cerebral arteries.
Soon after these guidelines were published, a
number of researchers expressed concern. The cause
of coma in the neonate may be antenatal and not as
obvious as with adult cases. Hypotension is often
difficult to exclude or properly define in the new-
born. The results of ancillary tests may not be
definitive. Sufficient numbers had not been tested to
allow a high probability of certainty, especially if
there is no available a priori proof of brain death.
The validity of the EEG as a test for brain death was
questioned because approximately 20% of clinically
brain dead patients have residual EEG activity, a
finding also noted in children. The rationale for the
guidelines suggested by the task force was questioned
because supportive, scientifically validated evidence
was lacking. There were additional concerns. Toxic
screens for children are not all inclusive; some
ingested but commonly available drugs may not be
assayed. Some metabolic disorders in neonates may
not be detected in hospital laboratories. Premature
and even full-term neonates may not be very
responsive normally, which calls into quest the
validity of testing reactivity.
However, brainstem function can be adequately
assessed in neonates older than 48 weeks gestational
age. Thus, if brainstem death is used as the bench-
mark, the clinical evaluation is likely valid in
neonates, providing the other provisions of the task
force are met. The EEG seems insufficient and
unnecessary, but it may provide some support. Some
neonatologists and pediatric neurologists use a ‘‘flat’’
EEG as a screen for apnea testing.
CONCLUSIONS
For clinicians, it is vital to follow established
guidelines in the diagnosis of brain death and to
document the essential steps in arriving at the
diagnosis. Brain death should never be diagnosed
hurriedly in the emergency room. There should be an
appropriate period of observation and the clinical
examination should be repeated, mainly for con-
firmatory purposes. The diagnosis of brain death
should be clearly separated from the decisions and
exigency for organ transplantation.
The explicit legal recognition that brain death is
death varies among different countries, as do the
guidelines for making the diagnosis of brain death.
Some have no legal statutes but allow a medical
recognition of brain death. In Japan and Israel, there
is no social acceptance or full recognition of brain
death. All use clinical criteria, but some require
ancillary tests: brain flow studies, electroencephalo-
graphy, or brainstem evoked responses as options
or in various combinations. One must be aware
of the national regulations and guidelines as well
as those of the institution in which such decisions
are made.
—G. Bryan Young
See also–Anencephaly; Anoxic-Ischemic
Encephalopathy; Brain Anatomy; Cardiac Arrest
Resuscitation; Ethical Issues, Overview
Further Reading
Cairns, H. (1952). Disturbance of consciousness with lesions of the
brain-stem and diencephalon. Brain 75, 109–146.
Gloor, P. (1986). Consciousness as a neurological concept in
epileptology: A Critical review. Epilepsia 27, S14–S26.
Hubel, D. H., and Weisel, T. N. (1968). Receptive fields and the
functional architecture of monkey striate cortex. J. Physiol.
195, 215–243.
James, W. (1890). The Principles of Psychology. Macmillan,
London.
Lipowski, Z. J. (1990). Delirium: Acute Confusional States.
Oxford Univ. Press, New York.
Mesulam, M. M. (1986). Attention, confusional states and neglect.
In Principles of Behavioral Neurology (M. M. Mesulam, Ed.).
Davis, Philadelphia.
Mesulam, M. M. (1990). Large scale neurocognitive networks and
distributed processing for attention, language, and memory.
Ann. Neurol. 28, 597–613.
Mesulam, M. M. (1998). From sensation to cognition. Brain 121,
1013–1052.
Moruzzi, G., and Magoun, H. W. (1949). Brain stem reticular
formation and activation of the EEG. Electroencephalogr. Clin.
Neurophysiol. 1, 455–473.
Multi-Society Task Force on PVS (1994). Medical aspects of the
persistent vegetative state. N. Engl. J. Med. 330, 1499–1508,
1572–1579.
Pallis, C. (1996). ABC of Brainstem Death, pp. 40–44. BMJ,
London.
Plum, F., and Posner, J. B. (1980). The Diagnosis of Stupor and
Coma. Davis, Philadelphia.
President’s Commission for the Study of Ethical Problems in
Medicine and Biomedical and Behavioral Research (1981).
Defining Death: Medical, Legal and Ethical Issues in the
Determination of Death. U.S. Government Printing Office,
Washington, DC.
Watt, D. F. (1993). Delirium and the DSM-IV. J. Neuropsychiatry
5, 459–460.
Young, G. B., Bolton, C. F., Austin, T. W., et al. (1990). The
encephalopathy associated with septic illness. Clin. Invest. Med.
13, 297–304.
Young, G. B., Ropper, A. H., and Bolton, C. F. (1998). Coma and
Impaired Consciousness: A Clinical Perspective. McGraw-Hill,
New York.

Brain Development, Normal
Postnatal
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
FROM THE TIME the ovum is fertilized, there is
continuous development of the human until matura-
tion is reached. The developmental pattern, though
demonstrating some variability, is similar for all
normal humans and is a reflection of the develop-
ment and growth of the central nervous system,
progressing in cephalocaudal and proximal to distal
directions. Truncal movements are present before
those of the limbs, and controlled movements of the
upper limbs precede those of the lower limbs. To
understand development, one must be familiar with
the timetable for the normal achievement of mile-
stones that represents the average ages when the
milestones are reached (Table 1). Although human
development during the first 112 year is commonly
measured in terms of the acquisition of motor skills,
a notion of higher cortical function is better assessed
by the infant’s general level of attentiveness or
responsiveness to visual and auditory stimuli and
the later acquisition of speech and language. Valid
predictive tests of higher cortical function are usually
first obtained when the child reaches the age of 5–7
years.
PRIMITIVE REFLEXES
A variety of primitive reflexes, some of which can
be elicited in the preterm infant, are present for
relatively short periods of time after birth, and these
mass movements are replaced by volitional, more
refined movements (Table 2). The Moro reflex is
elicited in the supine infant by raising the infant’s
head from the bed or examining table to approxi-
mately 30–451 and then suddenly dropping the
infant’s head while the examiner’s hand cushions
the head from abruptly hitting the cot surface.
The reflex consists of the infant opening the hands
with arm extension and abduction, followed by
anterior flexion of the arms and sometimes asso-
ciated with a brief audible cry. The Moro reflex
should normally disappear by 3 or 4 months of
age; however, if the reflex is notably asymmetric
or there is abduction and extension of one arm
only, one should consider the possibility that the
infant has a hemiplegia, brachial plexus palsy, or a
BRAIN DEVELOPMENT, NORMAL POSTNATAL 429
clavicular or humeral fracture on the contralateral
side.
The Palmar grasp reflex is present at 28 weeks of
gestation and becomes more forceful at 32–37
weeks. It becomes less apparent and then disappears
after approximately 2 months of age, when volun-
tary grasping becomes apparent.
The rooting reflex is well established by 32
weeks of gestation and can be elicited by tactile
stimulation of the perioral region. If the superior or
inferior midline lip is stroked, the infant will move
his or her mouth in the direction of that stimulus.
This is also true if either the right or the left
lateral aspects of the lips are stroked. The infant will
follow this tactile stimulus as if in search of the
nipple. This reflex is present in the full-term new-
born, but it may be difficult to elicit unless it is done
so at approximately the normal feeding time of the
infant.
The tonic neck reflex is elicited by the rotation of
the head of a supine infant to one side followed by
extension of the upper limb on the side to which the
head is rotated, with associated flexion on the side
ipsilateral to the occiput. The reflex is usually
rudimentary in normal infants and disappears by 2
or 3 months of age. The reflex is exaggerated in
infants who have a static encephalopathy or in those
who have sustained some cerebral insult.
The placing and stepping reflex can be elicited by
approximately 37 weeks of gestation. It can be
provoked by placing the anterior tibia or dorsum of
the infant’s foot under or against the edge of a table.
The infant lifts the leg onto the table, and when
holding the infant upright over the table so that the
sole presses the table, there is reciprocal flexion and
extension of the legs, simulating walking. The reflex
disappears in normal infants by approximately 6
weeks of age.
When the normal infant is maintained in
ventral suspension by the examiner’s hand support-
ing the infant’s abdomen, the head, spine, and legs
extend. If the head is pushed downward, the hips,
knees, and elbows flex. This Landau reflex is
normally present from approximately 3 months of
age and becomes increasingly difficult to elicit
by 6–12 months. The absence of this reflex in
infants older than age 3 months is observed in those
infants who have a static encephalopathy or motor
weakness.
The parachute reflex appears at approximately 6–9
months of age and persists throughout life. To
demonstrate its presence, the infant should be held
430 BRAIN DEVELOPMENT, NORMAL POSTNATAL

Table 1 NORMAL EARLY POSTNATAL DEVELOPMENTAL MILESTONESa

Age Milestone

4 Weeks General Watches mother’s face as she speaks.

Motor When held in ventral suspension, the head is held up momentarily; the elbows are flexed, and hips
are partly extended with flexed knees.
When pulled to seated posture, there is complete head lag.
There is an asymmetric tonic neck reflex; hands are closed and grasp reflex is present.
Vision Attends to dangled object, such as a colored ring, when brought in line of vision.
Can fixate for short periods in time.
Hearing Quiets when a bell is rung.
6 Weeks General Smiles responsively at mother.
Motor When held in ventral suspension, head is held up momentarily; there is some extension of hips with
flexion of the knees and elbows; if pulled to sitting position, head is intermittently held up.
The tonic neck reflex is asymmetric.
Vision Fixates on objects and can follow moving person; in supine position will look at an object in midline
and can follow 901.
Hearing Responds to sound; may blink to brisk clap.
8 Weeks General Attends to mother and smiles responsively.
Motor In ventral suspension can maintain head in same place as torso; when pulled to seated position can
hold head up but intermittently bobs forward.
Hands are frequently open, with only slight grasp reflex present.
Tonic neck reflex continues to be asymmetric.
Vision Fixation, convergence, and focusing; can follow a moving person.
Vocalization Smiles and vocalizes when spoken to.
12 Weeks General Responsive to environment, makes sounds when spoken to—squeals of pleasure.
Motor When held in ventral suspension, can hold head for prolonged period.
When pulled to seated position, only slight head lag; hands are open and there is no grasp reflex.
Able to hold a rattle for 1 min or longer if placed in hand; does not grasp unless object placed in
hand.
Vision Typically watches his or her own hand(s); follows moving object from side to side.
Hearing Will turn head toward sound.
16 Weeks General Appears excited when food is prepared or toys are seen, demonstrating reaction involving all four
limbs; enjoys being placed in seated position.
Motor When pulled to sitting position, only slight head lag at start of movement; if held in seated position,
head is held up constantly; continues to regard hands and will pull shirt over face in play; will play
with rattle for long periods of time, shaking it, but cannot pick up rattle if dropped.
Vision Has immediate regard of dangling object.
Vocalization Will laugh aloud and can make pleasurable sounds.
24 Weeks General Will look to see where a dropped toy has gone; may become excited if hearing footsteps; smiles and
vocalizes at his or her image in mirror; stretches out arms to be taken; can show likes and dislikes;
may seem annoyed if toy taken from him or her; laughs if head hidden in towel; imitates cough or
protrusion of tongue.
Motor Sits supported in high chair; when held in standing position, has almost full weight on legs; rolls
prone to supine; can hold bottle and able to grasp feet; has palmar grasp of cube—will drop one
cube if given another; can drink from cup if it is held to lips.
Vocalization Coos, babbles, makes labial consonants.
40 Weeks General Able to put arms in front of face to prevent mother washing his face; looks around corner for
objects; pulls clothes of another to attract attention; responds to questions (e.g., ‘‘Where’s
daddy?’’); repeats performance laughed at; waves bye-bye; plays patty-cake.
Motor Crawls when on abdomen by pulling self forward with hands; can roll into prone position or change
from prone to sitting; sits well with little instability; can pull to stand by holding on to furniture—
will move toward objects with index finger.
Vocalization Imitates sounds made by others; first words—‘‘mama’’ and ‘‘dada.’’

continues
 BRAIN DEVELOPMENT, NORMAL POSTNATAL 431

Table 1 continued

Age Milestone

1 Year General May understands the meaning of some phrases (e.g., ‘‘Where is your shoe?’’); may kiss when asked—
tendency to be shy.
Motor Prone—walks on hands and feet like a bear; can walk when one hand is held; may shuffle on one
buttock and hand; mouthing has virtually ceased; will throw objects to floor.
Vocalization Can utter two or three meaningful words but knows the meaning of more words.
18 Months General Copies mother in dusting, cleaning; understands simple orders; knows body parts and common
objects; sphincter control—dry by day but occasional accidents at night.
Motor Walks, pulling toy or object; gets up and down stairs while holding railing without help; seats
himself or herself on chair; beginning to jump with both feet; manages a spoon without rotation;
takes off gloves or socks; can build tower of three or four cubes; can throw a ball without falling;
scribbles with pencil or crayon; shows sustained interest; can turn over several pages at a time;
points to pictures in a book.
Vocalization Has many intelligible words; increasing responsiveness.
2 Years General Puts on and can take off pants, socks, and shoes; pulls people to show them toys or other objects
(from 21 months).
Motor Goes up and down stairs alone, two feet per step; can walk backward in imitation; can run, kick, and
pick up object without falling; can wash hands, turn door handle, and unscrew lid; makes vertical
or circular marks with pencil or crayon and can turn pages one at a time.
Vocalization Can ask for food, drink, or toilet; repeats things said to him or her uses ‘‘I,’’ ‘‘me,’’ or ‘‘you’’; chatters
at length and can put two or three words together in a sentence.
a
Modified from Illingworth (1987).

in ventral suspension by supporting the infant under By the age of 6 months, the infant can roll from
the arms and then suddenly lowering the infant to a prone to supine, and by 9 or 10 months he or she is
bed or table. Normally, the arms extend as if to usually able to crawl, often moving forward by using
protect from falling. Infants who have a static one hand as if dragging the legs. Crawling usually
encephalopathy may demonstrate an asymmetric or will progress to a gait similar to that of a quadruped,
absent parachute reflex. The reflex can also be and by 11 months the infant is able to walk by
demonstrated by propping the infant in a seated holding onto someone’s hand. Walking indepen-
position and if the child feels unstable in this dently is commonly achieved by 15 months of age
position, the arms will extend on the appropriate and running by 2 years of age.
side to prevent falling. The use of the hands and arms also progresses
in a stepwise fashion from proximal to distal.
The primitive grasp reflex persists until approxi-
mately the age of 2 or 3 months, and between the
MOTOR SYSTEM
There is an orderly progression of developing
motor skills, from the primitive reflexes and mass
Table 2 PRIMITIVE (POSTURAL) REFLEXES
movement of the newborn period and early
infancy until the time when the infant begins to Reflex Present Absent
roll from prone to supine, assume a seated position,
Moro 28–32 gestational weeks 3–4 months
pull to a standing position, cruise, walk indepen-
Palmar grasp 28 gestational weeks 2–3 months
dently, run, and finally walk up and down steps.
Rooting 32 gestational weeks
There is no head control until approximately 6 weeks
Tonic neck Newborn 2–3 months
of age, when the infant can hold his or her head
Placing/stepping 37 gestational weeks 6 weeks
momentarily, and by 8–12 weeks the infant can
Landau 3 months 1 year
maintain the head position in the same plane as
Parachute 6–9 months Persists.
the body.
432 BRAIN DEVELOPMENT, NORMAL POSTNATAL
ages of 1 and 3 months the hands are gradually
opened. By 4 months of age, the infant attempts
to reach for an object and by 5 months can
voluntarily grasp an object. There is increasing
dexterity of hand movement so that the hands can
be brought together at approximately 4 months of
age, and at 6 months the infant can transfer an object
from one hand to the other. At approximately 5 or 6
months, there is an ulnar grasp of a cube, which is a
clumsy motion in which the fingers close against the
palm. By 6–8 months, the child will hold a cube
against the fleshy area between the thumb and wrist
that is composed of three thumb muscles located on
the palm of the hand (fat pad of the hand or thenar
eminence). By 10–12 months, there is a mature
pincer grasp with the fingertips touching the distal
thumb.
SENSORY SYSTEM
The newborn is able to recognize touch and pain,
which is evident from observing the rooting reflex
and the infant’s withdrawal from painful stimuli.
Tactile stimuli can cause the infant to become more
alert with either the initiation or the cessation of
associated motor activity, and a painful stimulus
causes withdrawal from that stimulus and is often
associated with crying. Saint-Anne Dargassies de-
monstrated that the preterm infant of 28 weeks can
differentiate touch from pain.
Since it has been demonstrated that infants can
experience pain, attempts to alleviate that pain have
proven to be beneficial. One can discern the severity
of discomfort by observing subtle findings, such as
the intensity of cry and the extent of facial grimacing.
The reliable assessment of proprioception is not
possible until later childhood.
Perception of visual stimuli occurs early in human
development. By the age of 26 gestational weeks,
the infant will blink to a light stimulus, and a
pupillary response to light can be demonstrated at
approximately 29 weeks. From 32 to 36 weeks, the
infant will turn toward a diffuse light, and at 32
weeks exposure to light will provoke lid closure as
long as the light source is present. By 32 weeks of
gestation, there is some visual fixation that improves
thereafter, and at 34 weeks most infants will track in
a small arc a red object such as a 4-in. ring. At term,
fixation and following a visual stimulus are well
developed.
Optokinetic nystagmus (OKN) is present in
some infants at approximately 36 gestational weeks
and is consistently present in term babies. By using
OKN, it is believed that the acuity of the newborn
infant is approximately 20/150. Perception of color
sensitivity can be shown at approximately 2
months, and binocular vision and depth percep-
tion are present at approximately 3–4 months. At
the age of 2–3 weeks, the infant can imitate facial
gestures, and from 12 to 20 weeks some attention is
directed to the hand(s). At approximately 4–5
months, the infant can be excited when observing
that food is being prepared, and at 6 months the
infant can adjust his or her head and body position
to gaze at an object. Normal visual function
continues to improve throughout infancy and early
childhood.
Perception of auditory stimuli also occurs in early
human development. Vibroacoustic stimulation has
been monitored by ultrasound in utero and responses
could be elicited as early as 24 or 25 weeks of
gestation. A preterm infant of 28 weeks of gestation
startles or blinks to a loud clap or noise and the
normal term infant may respond more quickly to a
similar stimulus. By the age of 3 or 4 months, the
normal infant will turn toward the source of the
sound.
Prelanguage communication begins soon after
birth when the infant watches the mother’s face,
and by 6 weeks the infant will smile responsively to
the mother. Communication is carried out by crying,
cuddling, or resisting being held. Later, the infant
communicates by laughing, screaming, or having a
temper tantrum. Soon after the infant begins to
smile, he or she begins to vocalize and by 3 or 4
months can make some consistent sounds, sometimes
squealing with delight. By the age of 7 or 8 months,
the infant can make a sound to attract attention and
by 10 months may know one meaningful sound or
word and respond to ‘‘No.’’ Between 15 and 18
months, the infant can utter some meaningful words,
and by 21–24 months he or she begins to put several
words together. One study showed that of 1824 boys
and 1747 girls, 3% said their first word at
approximately 9 months, 10% did so by 10 months,
and 90% did so by 18 months of age. With
maturation, the infant learns what effect his or her
sounds or words have on other people. The sounds
become more meaningful and the infant has under-
standing of many words before he or she can
articulate them.
Innumerable developmental processes occur dur-
ing the early postnatal period, some of which occur
simultaneously and others at different times. There is

an inexorable progression and elegant integration of
development that continues until maturation.
— Bruce Berg
See also–Brain Anatomy; Brain Evolution,
Human; Developmental Neuropsychology;
Grasp Reflex; Moro Reflex; Nervous System,
Neuroembryology of; Vertebrate Nervous
System, Development of
Further Reading
Allen, M. C., and Capute, A. J. (1986). Assessment of early
auditory and visual abilities of extremely premature infants.
Dev. Med. Child Neurol. 28, 458–466.
Hall, W. G., and Oppenheim, R. W. (1987). Developmental
psychobiology: Prenatal, perinatal and early postnatal aspects
of behavioral development. Annu. Rev. 38, 91–128.
Illingworth, R. S. (1987). The Development of the Infant and
Young Child––Normal and Abnormal, 9th ed. Churchill
Livingstone, London.
Neligan, G., and Prudham, D. (1969). Norms for four develop-
mental milestones by sex, social class and place in family. Dev.
Med. Child Neurol. 11, 413–422.
Paine, R. S., and Oppe, T. E. (1966). Neurological Examination of
Children. Spastic Society Medical Education and Information
Unit, London.
Palmer, P. G., Dubowitz, L. M., Verghote, M., et al. (1982).
Neurological and neurobehavioral differences between preterm
infants at term and full term newborn infants. Neuropediatrie
13, 183–189.
Peiper, A. (1963). Cerebral Function in Infancy and Childhood.
Consultants Bureau, New York.
Robinson, J., and Fields, A. R. (1990). Pupillary diameter and
reaction to light in preterm neonates. Arch. Dis. Child 65,
35–38.
Saint-Anne Dargassies, S. (1977). Neurological Development in
the Full Term and Preterm Neonate. Excerpta Medica.
Brain Edema
see Cerebral Edema
Brain Evolution, Human
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THIS ENTRY summarizes some of the main features of
the phylogenetic evolution of the brain in verte-
brates. It focuses largely on the anatomical and
functional organization of the ventral portion of the
cerebral hemispheres, which harbors a structure
BRAIN EVOLUTION, HUMAN 433
called the striatum. This large hemispheric nucleus
is part of the basal ganglia, a set of subcortical
structures that are directly involved in the control of
psychomotor behavior and whose study can provide
important clues as to how the entire brain evolved
along the vertebrate radiations.
FROM REPTILES TO MAMMALS
Fossil evidence of soft structures such as the brain is
generally nonexistent or incomplete, and our concept
of brain evolution is thus largely inferred. It is based
on comparisons of similarities and differences in the
organization of neuronal systems in different living
vertebrates, and these animals can no longer be
considered to represent one linear series of ever-
increasing complexity (the Scala naturae of Buffon).
Rather, living vertebrates are the result of various
distinct radiations that have evolved largely indepen-
dently and at different rates for more than 400
million years. Among these radiations, the reptiles
occupy a particularly crucial position. Indeed, early
in their evolution, the stem reptiles split into two
major groups: the sauropsid reptiles, which gave rise
to all modern reptiles and birds, and the theropsid
reptiles, which, through a series of now-extinct
intermediate forms, evolved into mammals. Thus,
the study of living reptiles is of utmost interest to
comparative neurobiology.
The cerebral hemispheres in reptiles possess a well-
characterized cerebral cortex and markedly devel-
oped basal ganglia. However, the most characteristic
feature of the reptilian brain is the so-called dorsal
ventricular ridge, a mass of neural tissue that
protrudes into the lateral ventricle (Fig. 1). The
cerebral hemispheres in birds are organized in a
pattern strikingly similar to that in reptiles, particu-
larly crocodilians. However, the dorsal ventricular
ridge in birds is even more expanded so that the
lateral ventricle is reduced to a slit, and the exact
boundaries between the ridge and other hemispheric
structures are difficult to trace. Whether the dorsal
ventricular ridge belongs to the cortex or the
striatum (basal ganglia) has been a matter of debate
for many years.
It has long been thought that the reptilian–avian
lineage is characterized by a marked increase of the
basal ganglia, whereas the reptilian–mammalian line-
age is typified by a significant increase of the cortex
at the expanse of the basal ganglia. However, studies
undertaken with histochemical methods to visualize
neurotransmitters, particularly catecholamines, have

an inexorable progression and elegant integration of
development that continues until maturation.
— Bruce Berg
See also–Brain Anatomy; Brain Evolution,
Human; Developmental Neuropsychology;
Grasp Reflex; Moro Reflex; Nervous System,
Neuroembryology of; Vertebrate Nervous
System, Development of
Further Reading
Allen, M. C., and Capute, A. J. (1986). Assessment of early
auditory and visual abilities of extremely premature infants.
Dev. Med. Child Neurol. 28, 458–466.
Hall, W. G., and Oppenheim, R. W. (1987). Developmental
psychobiology: Prenatal, perinatal and early postnatal aspects
of behavioral development. Annu. Rev. 38, 91–128.
Illingworth, R. S. (1987). The Development of the Infant and
Young Child––Normal and Abnormal, 9th ed. Churchill
Livingstone, London.
Neligan, G., and Prudham, D. (1969). Norms for four develop-
mental milestones by sex, social class and place in family. Dev.
Med. Child Neurol. 11, 413–422.
Paine, R. S., and Oppe, T. E. (1966). Neurological Examination of
Children. Spastic Society Medical Education and Information
Unit, London.
Palmer, P. G., Dubowitz, L. M., Verghote, M., et al. (1982).
Neurological and neurobehavioral differences between preterm
infants at term and full term newborn infants. Neuropediatrie
13, 183–189.
Peiper, A. (1963). Cerebral Function in Infancy and Childhood.
Consultants Bureau, New York.
Robinson, J., and Fields, A. R. (1990). Pupillary diameter and
reaction to light in preterm neonates. Arch. Dis. Child 65,
35–38.
Saint-Anne Dargassies, S. (1977). Neurological Development in
the Full Term and Preterm Neonate. Excerpta Medica.
Brain Edema
see Cerebral Edema
Brain Evolution, Human
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THIS ENTRY summarizes some of the main features of
the phylogenetic evolution of the brain in verte-
brates. It focuses largely on the anatomical and
functional organization of the ventral portion of the
cerebral hemispheres, which harbors a structure
BRAIN EVOLUTION, HUMAN 433
called the striatum. This large hemispheric nucleus
is part of the basal ganglia, a set of subcortical
structures that are directly involved in the control of
psychomotor behavior and whose study can provide
important clues as to how the entire brain evolved
along the vertebrate radiations.
FROM REPTILES TO MAMMALS
Fossil evidence of soft structures such as the brain is
generally nonexistent or incomplete, and our concept
of brain evolution is thus largely inferred. It is based
on comparisons of similarities and differences in the
organization of neuronal systems in different living
vertebrates, and these animals can no longer be
considered to represent one linear series of ever-
increasing complexity (the Scala naturae of Buffon).
Rather, living vertebrates are the result of various
distinct radiations that have evolved largely indepen-
dently and at different rates for more than 400
million years. Among these radiations, the reptiles
occupy a particularly crucial position. Indeed, early
in their evolution, the stem reptiles split into two
major groups: the sauropsid reptiles, which gave rise
to all modern reptiles and birds, and the theropsid
reptiles, which, through a series of now-extinct
intermediate forms, evolved into mammals. Thus,
the study of living reptiles is of utmost interest to
comparative neurobiology.
The cerebral hemispheres in reptiles possess a well-
characterized cerebral cortex and markedly devel-
oped basal ganglia. However, the most characteristic
feature of the reptilian brain is the so-called dorsal
ventricular ridge, a mass of neural tissue that
protrudes into the lateral ventricle (Fig. 1). The
cerebral hemispheres in birds are organized in a
pattern strikingly similar to that in reptiles, particu-
larly crocodilians. However, the dorsal ventricular
ridge in birds is even more expanded so that the
lateral ventricle is reduced to a slit, and the exact
boundaries between the ridge and other hemispheric
structures are difficult to trace. Whether the dorsal
ventricular ridge belongs to the cortex or the
striatum (basal ganglia) has been a matter of debate
for many years.
It has long been thought that the reptilian–avian
lineage is characterized by a marked increase of the
basal ganglia, whereas the reptilian–mammalian line-
age is typified by a significant increase of the cortex
at the expanse of the basal ganglia. However, studies
undertaken with histochemical methods to visualize
neurotransmitters, particularly catecholamines, have
434 BRAIN EVOLUTION, HUMAN
Figure 1
(A) Diagram comparing the pattern of distribution of
catecholaminergic nerve terminals (dots) in the cerebral
hemispheres of an amphibian (frog), a reptile (turtle), a bird
(pigeon), and a mammal (rat). In reptiles, birds, and mammals, a
dense catecholaminergic innervation characterizes the striatum,
which, in contrast to previous beliefs, occupies a relatively
constant proportion of the hemisphere in all vertebrates. (B)
Diagram summarizing the idea that the pallial thickening (PT),
which is a very active proliferating sector of the cerebral
hemispheres in reptiles, may be the origin of both the
hypertrophied dorsal ventricular ridge in birds and the cerebral
cortex in mammals. CTX, cerebral cortex; DVR, dorsal
ventricular ridge; PT, pallial thickening; STR, striatum.
led to a revision of this concept of brain evolution.
These investigations have revealed that the striatum,
as identified by its rich plexus of catecholaminergic
nerve terminals, occupies approximately the same
proportion of the hemispheres in reptiles, birds, and
mammals (Fig. 1A). This finding has led to the
hypothesis that the difference between birds and
mammals in respect to the organization of the
cerebral hemispheres may be the result of a marked
shift that occurred during embryonic development in
the migratory pathway followed by neurons pro-
duced in the so-called pallial thickening in reptiles
(Fig. 1B). On the one hand, neurons of the mitoti-
cally active pallial thickening may be genetically
instructed to follow a ventromedial migratory direc-
tion (Fig. 1B, pathway A). This would inevitably lead
to a marked hypertrophy of the dorsal ventricular
ridge, which probably occurred along the reptilian–
avian lineage. On the other hand, neurons of the
same zone may be commanded to migrate along a
dorsomedial route (Fig. 1B, pathway B). Such a shift
in the genetical instructions would cause the primi-
tive cortex to hypertrophy and transform into a
laminated neocortex, which probably occurred along
the reptilian–mammalian lineage.
Such a theory is impossible to test empirically
because living reptiles, birds, and mammals cannot
be considered ancestral to one another. However,
detailed comparative developmental studies of the
cerebral hemispheres in reptiles, birds, and mam-
mals, with new molecular markers for mitotically
active and migrating neurons, could greatly help our
understanding of the evolution of the cerebral
hemispheres in vertebrates.
BRAIN EVOLUTION IN PRIMATES
The human phylogeny, as well as that of primates in
general, is characterized by a marked tendency
toward brain enlargement (encephalization) (Table
1). As for any other vertebrates, fossil records of the
brain of extinct hominids are extremely rare.
However, the filling of fossilized crania with latex
or other flexible materials produces endocranial casts
or endocasts that can serve to determine the total
volume of the brain, the relative importance of each
hemispheric lobe, and the location of the large veins
or arteries associated with the envelops that surround
and protect the brain (meninges). Endocasts have
also been used to detect the imprint of Broca’s
language area in the frontal lobe of some extinct
hominids.
 BRAIN EVOLUTION, HUMAN 435

Table 1 CRANIAL CAPACITY FROM APES TO MAN environment. Although this type of data is not
available, significant information about primate
Mean capacity Time period
Group (cc) (millions of years) brain evolution can be derived from observations
made on the brain of living primates. This is
Living apes particularly the case for the striatum, for which
Gibbon 104 20–present
there exist detailed quantitative data from insecti-
Chimpanzee 395 20–present
Orangutan 434 20–present vores to humans. These data indicate that the volume
Gorilla 535 20–present occupied by the striatum decreases from 8.3% of the
Hominids hemispheres in insectivores to 2.7% in human.
Australopithecus 500 4.0–1.2 However, these values do not take into account the
Homo hobilis 639 2.0–1.5 enormous difference in body weight between insecti-
Homo erectus 885 1.5–0.2 vores and humans. When the data for striatal volume
erectus are correlated with those for the body weight, they
Homo erectus 1025 1.5–0.2 indicate a clear increase in striatal volume from
pekinensis insectivores to humans. The striatum in prosimians is
Homo sapiens 1470 0.2–0.1 approximately 4 times the size of that in insectivores,
neanderthalensis
whereas the mean values for simians (monkeys)
Modern human
indicate an eightfold increase. For instance, in
Homo sapiens 1370 0.1–present
animals weighing approximately 1 kg, the striatal
sapiens
volume would be 126 mm3 in insectivores, 500 mm3
in prosimians, and 1000 mm3 in simians. The human
striatum would be 14 times as large as that of an
During their relatively short evolutionary history, insectivore of equal body weight. Therefore, in
the hominids appear to have been under a strong and contrast to previous beliefs, the striatum appears to
constant selection pressure for brain enlargement. It have increased in size during primate evolution along
must be realized, however, that brain size per se does with the neocortex, although the enlargement of the
not indicate much about mental ability; many latter is approximately 4 times that of the striatum.
correction factors, such as correction for body Together, these findings indicate that primate
weight, must be used to properly assess the sig- evolution is characterized by a massive increase in
nificance of data related to brain size. For example, brain size. However, the various components of the
although the brain of Brontosaurus, one of the great brain have evolved at very different rates. For
dinosaurians that lived in the Jurassic Period, might example, the brainstem and cerebellum remain
have been relatively large, it did not represent more relatively unchanged, whereas the cerebral hemi-
than 1/100,000th of the 35-ton carcass. Such a spheres underwent an unprecedented enlargement.
brain:body weight ratio is approximately 1:45 in The diencephalon also increased markedly in size
modern human and even higher (1:12) in the squirrel during primate evolution. Such a diencephalic
monkey. Brain size does not appear to limit our enlargement is largely the result of a dramatic
ability to contribute to society, culture, and science; augmentation of the volume of the thalamus, which
some highly gifted people had very small brains. For acts as a major relay station between the sensory
example, Franz Joseph Gall and Léon Gambetta each afferent inputs and the cerebral cortex. Among the
had a brain of approximately 1000 g compared to a various thalamic nuclei, those termed associative
brain of approximately 2200 g for Lord Byron and nuclei underwent the most massive increase. This
Oliver Cromwell. It must also be recalled that the includes the pulvinar, which represents approxi-
Neanderthal man disappeared from the surface of mately one-third of the total thalamic volume in
the earth approximately 50,000 years ago despite the human. The number of thalamocortical and corti-
fact that it had a brain slightly larger than ours cothalamic fibers also increased markedly, in parallel
(Table 1). with the cerebral cortex. This augmentation most
More than information on brain weight variations, likely reflects the functional importance of these fiber
knowledge of the way the brain has developed and systems, which are involved in phenomena as crucial
matured its wiring during evolution would be of as consciousness and various state-dependent activ-
utmost importance to understanding how evolving ities. The major regression that occurs at the
primates have successfully adapted to their changing forebrain level during primate evolution concerns
436 BRAIN HERNIATION, SURGICAL MANAGEMENT
the olfactory system, which is rudimentary in hu-
mans and even completely absent in certain cetaceans
(dolphins).
Thus, the enlargement of the cerebral cortex is
probably the most significant event that occurred
during primate brain evolution. However, like the
various portions of the brain, the different cortical
regions appear to have evolved at very different rates.
For example, the occipital or visual cortex is
markedly increased in some New World monkeys,
but it is the frontal cortex that is most enlarged in
Old World monkeys. The latter tendency reaches its
peak in humans, in which the frontal lobe occupies
approximately one-third of the total hemispheric
surface. The rostral portion of the frontal lobe
(prefrontal cortex), which is particularly well devel-
oped in humans, consists of association areas whose
major function is related to the capacity of the
organism to weigh the consequences of future actions
and to plan accordingly. The development of this
unique cerebral capacity has allowed humans not
only to adapt perfectly well to their environment but
also to literally take over the environment, for the
best and the worst.
—André Parent
See also–Brain Anatomy; Brain Development,
Normal Postnatal; Communication, Nonhuman;
Instinct; Intelligence; Language, Overview;
Vertebrate Nervous System, Development of
Further Reading
Buffon, G. L., and Leclerc, Count. (1770). Histoire Naturelle.
Imprimerie Royale, Paris.
Jerisson, H. J. (1973). Evolution of the Brain and Intelligence.
Academic Press, New York.
Leakey, R. E. (1981). The Making of Mankind. Dutton, New
York.
Parent, A. (1986). Comparative Neurobiology of the Basal
Ganglia. Wiley, New York.
Tobias, P. V. (1971). The Brain in Hominid Evolution. Columbia
Univ. Press, New York.
Brain Herniation, Surgical
Management
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CLINICAL SYNDROMES of herniation and their
anatomical relationships to the tentorial edge were
elucidated at the turn of the 20th century. Clinical
syndromes of herniation mostly occur as a result of
mass lesions (i.e., tumors, hematomas, and infarc-
tions) that displace medial cerebral structures
through the tentorial edge into the brainstem. The
anatomical constraints created by the tentorial edge
and its surrounding structures lead to several clinical
syndromes depending on the location of the mass.
Lateral or uncal herniation consists of compression
of the midbrain by the medial portion of the
temporal lobe, hippocampal gyrus, and uncus from
laterally located mass lesions (Fig. 1). The herniating
brain compresses the ipsilateral cerebral peduncle,
occulomotor nerve, and posterior cerebral artery.
The associated clinical signs are dilation of the pupil
ipsilateral to the lesion from interruption of sympa-
thetic fibers, inability to move the eye in any
direction except abduction (sparing of the abducens
nerve), and loss of direct and consensual response to
light in the affected eye. In most cases, hemiparesis
contralateral to the lesion from compression of the
ipsilateral cerebral peduncle progresses to abnormal
extensor posturing. Some mass lesions compress and
shift the midbrain to the contralateral side, thereby
compressing the contralateral cerebral peduncle
against the contralateral tentorial edge. Paradoxical
motor signs ipsilateral to the hemispheric lesion
result. Mental status is altered when the reticular
activating system is compressed. Even relatively brief
compression of the posterior cerebral arteries can
lead to infarction in the occipital lobes and cortical
blindness.
Central herniation results from a downward shift
of the diencephalon through the tentorium toward
the foramen magnum with displacement, shearing,
and compression of perforating arteries to the
brainstem that arise from the basilar artery. Massive
swelling from medial structures of the frontal lobes
displaces the diencephalon posteriorly and down-
ward. This type of herniation can occur simulta-
neously with uncal herniation. In both uncal and
central herniation syndromes, alterations of con-
sciousness and eye findings precede the late and often
terminal consequences of respiratory changes and
cardiovascular instability.
Posterior or tectal herniation occurs when the
midbrain is compressed at the level of the quad-
rigeminal plate. This situation arises when anterior
mass lesions push the midbrain against the tentorial
notch or when posterior mass lesions compress the
midbrain at the level of the quadrigeminal plate.
Clinically, such patients exhibit impaired mental
436 BRAIN HERNIATION, SURGICAL MANAGEMENT
the olfactory system, which is rudimentary in hu-
mans and even completely absent in certain cetaceans
(dolphins).
Thus, the enlargement of the cerebral cortex is
probably the most significant event that occurred
during primate brain evolution. However, like the
various portions of the brain, the different cortical
regions appear to have evolved at very different rates.
For example, the occipital or visual cortex is
markedly increased in some New World monkeys,
but it is the frontal cortex that is most enlarged in
Old World monkeys. The latter tendency reaches its
peak in humans, in which the frontal lobe occupies
approximately one-third of the total hemispheric
surface. The rostral portion of the frontal lobe
(prefrontal cortex), which is particularly well devel-
oped in humans, consists of association areas whose
major function is related to the capacity of the
organism to weigh the consequences of future actions
and to plan accordingly. The development of this
unique cerebral capacity has allowed humans not
only to adapt perfectly well to their environment but
also to literally take over the environment, for the
best and the worst.
—André Parent
See also–Brain Anatomy; Brain Development,
Normal Postnatal; Communication, Nonhuman;
Instinct; Intelligence; Language, Overview;
Vertebrate Nervous System, Development of
Further Reading
Buffon, G. L., and Leclerc, Count. (1770). Histoire Naturelle.
Imprimerie Royale, Paris.
Jerisson, H. J. (1973). Evolution of the Brain and Intelligence.
Academic Press, New York.
Leakey, R. E. (1981). The Making of Mankind. Dutton, New
York.
Parent, A. (1986). Comparative Neurobiology of the Basal
Ganglia. Wiley, New York.
Tobias, P. V. (1971). The Brain in Hominid Evolution. Columbia
Univ. Press, New York.
Brain Herniation, Surgical
Management
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CLINICAL SYNDROMES of herniation and their
anatomical relationships to the tentorial edge were
elucidated at the turn of the 20th century. Clinical
syndromes of herniation mostly occur as a result of
mass lesions (i.e., tumors, hematomas, and infarc-
tions) that displace medial cerebral structures
through the tentorial edge into the brainstem. The
anatomical constraints created by the tentorial edge
and its surrounding structures lead to several clinical
syndromes depending on the location of the mass.
Lateral or uncal herniation consists of compression
of the midbrain by the medial portion of the
temporal lobe, hippocampal gyrus, and uncus from
laterally located mass lesions (Fig. 1). The herniating
brain compresses the ipsilateral cerebral peduncle,
occulomotor nerve, and posterior cerebral artery.
The associated clinical signs are dilation of the pupil
ipsilateral to the lesion from interruption of sympa-
thetic fibers, inability to move the eye in any
direction except abduction (sparing of the abducens
nerve), and loss of direct and consensual response to
light in the affected eye. In most cases, hemiparesis
contralateral to the lesion from compression of the
ipsilateral cerebral peduncle progresses to abnormal
extensor posturing. Some mass lesions compress and
shift the midbrain to the contralateral side, thereby
compressing the contralateral cerebral peduncle
against the contralateral tentorial edge. Paradoxical
motor signs ipsilateral to the hemispheric lesion
result. Mental status is altered when the reticular
activating system is compressed. Even relatively brief
compression of the posterior cerebral arteries can
lead to infarction in the occipital lobes and cortical
blindness.
Central herniation results from a downward shift
of the diencephalon through the tentorium toward
the foramen magnum with displacement, shearing,
and compression of perforating arteries to the
brainstem that arise from the basilar artery. Massive
swelling from medial structures of the frontal lobes
displaces the diencephalon posteriorly and down-
ward. This type of herniation can occur simulta-
neously with uncal herniation. In both uncal and
central herniation syndromes, alterations of con-
sciousness and eye findings precede the late and often
terminal consequences of respiratory changes and
cardiovascular instability.
Posterior or tectal herniation occurs when the
midbrain is compressed at the level of the quad-
rigeminal plate. This situation arises when anterior
mass lesions push the midbrain against the tentorial
notch or when posterior mass lesions compress the
midbrain at the level of the quadrigeminal plate.
Clinically, such patients exhibit impaired mental

Figure 1
Computed tomography scan demonstrating uncal herniation.
(A) The image demonstrates right uncal herniation (arrowhead).
The normal space between the medial right temporal lobe
and the brainstem has been ablated with obvious compression
of the midbrain. (B) The image was taken higher in the brain
and shows the large hemorrhage responsible for the
mass effect.
BRAIN HERNIATION, SURGICAL MANAGEMENT 437
status, bilateral ptosis, sunset gaze, impaired vertical
gaze, and a normal pupillary response. Subfalcine
herniation is often noted radiographically as a shift
of the cingulate gyrus under the falx from an
ipsilateral mass lesion. It is often asymptomatic.
Mass lesions in the posterior fossa can theoretically
generate enough force to lead to upward herniation
of the brainstem through the tentorium, although
this is rare.
Computed tomography (CT) is a valuable initial
screen for quickly identifying patients suspected of
having herniation syndromes. CT reveals intracranial
mass lesions, such as tumors, hematomas, or infarc-
tions, associated with obliterated basal cisterns and
midbrain compression. If clinical findings are equi-
vocal (e.g., ipsilateral motor and eye disturbances),
CT rapidly assesses and localizes the underlying
pathology.
In trauma patients, the airway must be secured and
hypotension must be prevented. Hypoxia and hypo-
tension have been associated with poor outcomes in
this patient population. A secure airway is important
in the management of all patients with suspected
herniation. If a patient with lateralizing symptoms of
herniation is hemodynamically stable, mannitol can
be used to stabilize the patient so that he or she can
be transferred to the operating room for surgical
decompression. Lasix and hypertonic saline are other
pharmacological adjuncts to the acute treatment of
herniation. When mass effect from a tumor or medial
temporal lobe infarction is responsible for a hernia-
tion, there is usually a window of opportunity during
which the medial structures can be surgically
decompressed while the underlying pathology is
treated at the same time. Usually, such patients
manifest other neurological signs for which an
imaging study is obtained. Outcomes are favorable
if the signs and symptoms of herniation are promptly
recognized before patients deteriorate from increased
intracranial pressure or midbrain shift.
The surgical goals for reversing herniation are to
decompress the mass lesion and to debulk medial
cerebral structures associated with impending mid-
brain compression. The timing of surgery depends on
the temporal sequence and precipitating events that
led to the herniation. Herniations after head injuries
tend to be associated with extra-axial lesions, such as
epidural hematomas, subdural hematomas, or in-
traparenchymal hematomas/contusions. The survival
of patients with an uncal herniation after a severe
head injury depends on the timing of surgery and the
presence of multiorgan trauma.
438 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
The surgical management of herniation requires a
thorough understanding of its pathophysiology and
clinical spectrum. Prompt identification of lateraliz-
ing signs and symptoms, such as a dilated pupil with
contralateral hemiparesis and depressed level of
consciousness, should alert the care provider to seek
proper diagnostic imaging and surgical intervention.
The functional outcome of patients with a herniation
syndrome primarily depends on the cause (head
injury results in the worst outcome) and timing of
surgical decompression.
—Juan Bartolomei, Richard E. Clatterbuck,
and Robert F. Spetzler
See also–Herniation; Midbrain
Further Reading
Andrews, B. T., Pitts, L. H., Lovely, M. P., et al. (1986). Is
computed tomographic scanning necessary in patients with
tentorial herniation? Results of immediate surgical exploration
without computed tomography in 100 patients. Neurosurgery
19, 408–414.
Jefferson, G. (1938). The tentorial pressure cone. Arch. Neurol.
Psychiatry 40, 857–876.
Meyer, A. (1920). Herniation of the brain. Arch. Neurol.
Psychiatry 4, 387–400.
Brain Injury, Traumatic:
Epidemiological Issues
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RESEARCHERS studying the incidence and prevalence
of traumatic brain injury (TBI) agree that it is a
major cause of death and disability in the United
States. However, reliable estimates of the total
incidence and prevalence of TBI have not been
possible. Descriptive epidemiological studies of brain
injury in the civilian population of the United States
began in 1980, but problems in the development of
standard case definitions of brain injury (particularly
less severe brain injury), the difficulty of counting
nonhospitalized brain injury cases, the relative
neglect of brain injury due to falls in the elderly,
and changing care practices have hampered the
development of these needed estimates. Epidemiolo-
gical measurements do not develop in isolation from
research, policy, and clinical care. Estimates of
incidence and prevalence, clinical trials, public
policy, and practice guidelines continue to inform
each other in the area of TBI.
With a recent accumulation of large studies
utilizing standardized measurements and with good
follow-up, and Centers for Disease Control and
Prevention (CDC) efforts in the measurement of TBI
in statewide systems, progress is being made in
estimating the incidence and prevalence of moderate
and severe TBI. However, reliable estimates of the
incidence and prevalence of mild TBI remain difficult
to obtain. Part of the challenge has been the
development of valid definitions of severity classes
in TBI. Traditionally, patients in a coma (i.e., patients
with a Glasgow Coma Scale [GCS] score of 3 to 8)
were classified as severely injured; patients with
generally good motor response, verbal response, and
eye opening to stimulus (GCS score of 13 to 15) were
classified as mildly injured; and patients with
responsiveness between mild and severe were classi-
fied as moderately injured. However, severity based
solely on GCS has not correlated highly with
patients’ long-term outcome, thus definitions have
been enriched in recent years with the addition of
other measures of severity, including length of loss of
consciousness and length of post-traumatic amnesia
(PTA). The American Congress of Rehabilitation
Medicine defines mild TBI as a traumatically induced
physiological disruption of brain function that
includes one or more of the following:
1. Any period of loss of consciousness lasting 30
minutes or less
2. An initial GCS score of 13 to 15 after 30
minutes
3. PTA lasting no more than 24 hours
4. Any loss of memory for events immediately
before or after the incident
5. Any alteration of mental state at the time of
injury
6. Focal neurological deficits that may or may not
be transient
Severe TBI almost always results in prolonged
unconsciousness lasting at least one hour and usually
longer. Persons with severe TBI will often be left with
permanent impairments.
INCIDENCE, CAUSE OF INJURY, AND
CORRELATES OF TBI
Thurman and Guerrero utilized hospital discharge
information collected by the CDC’s National Center
438 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
The surgical management of herniation requires a
thorough understanding of its pathophysiology and
clinical spectrum. Prompt identification of lateraliz-
ing signs and symptoms, such as a dilated pupil with
contralateral hemiparesis and depressed level of
consciousness, should alert the care provider to seek
proper diagnostic imaging and surgical intervention.
The functional outcome of patients with a herniation
syndrome primarily depends on the cause (head
injury results in the worst outcome) and timing of
surgical decompression.
—Juan Bartolomei, Richard E. Clatterbuck,
and Robert F. Spetzler
See also–Herniation; Midbrain
Further Reading
Andrews, B. T., Pitts, L. H., Lovely, M. P., et al. (1986). Is
computed tomographic scanning necessary in patients with
tentorial herniation? Results of immediate surgical exploration
without computed tomography in 100 patients. Neurosurgery
19, 408–414.
Jefferson, G. (1938). The tentorial pressure cone. Arch. Neurol.
Psychiatry 40, 857–876.
Meyer, A. (1920). Herniation of the brain. Arch. Neurol.
Psychiatry 4, 387–400.
Brain Injury, Traumatic:
Epidemiological Issues
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
RESEARCHERS studying the incidence and prevalence
of traumatic brain injury (TBI) agree that it is a
major cause of death and disability in the United
States. However, reliable estimates of the total
incidence and prevalence of TBI have not been
possible. Descriptive epidemiological studies of brain
injury in the civilian population of the United States
began in 1980, but problems in the development of
standard case definitions of brain injury (particularly
less severe brain injury), the difficulty of counting
nonhospitalized brain injury cases, the relative
neglect of brain injury due to falls in the elderly,
and changing care practices have hampered the
development of these needed estimates. Epidemiolo-
gical measurements do not develop in isolation from
research, policy, and clinical care. Estimates of
incidence and prevalence, clinical trials, public
policy, and practice guidelines continue to inform
each other in the area of TBI.
With a recent accumulation of large studies
utilizing standardized measurements and with good
follow-up, and Centers for Disease Control and
Prevention (CDC) efforts in the measurement of TBI
in statewide systems, progress is being made in
estimating the incidence and prevalence of moderate
and severe TBI. However, reliable estimates of the
incidence and prevalence of mild TBI remain difficult
to obtain. Part of the challenge has been the
development of valid definitions of severity classes
in TBI. Traditionally, patients in a coma (i.e., patients
with a Glasgow Coma Scale [GCS] score of 3 to 8)
were classified as severely injured; patients with
generally good motor response, verbal response, and
eye opening to stimulus (GCS score of 13 to 15) were
classified as mildly injured; and patients with
responsiveness between mild and severe were classi-
fied as moderately injured. However, severity based
solely on GCS has not correlated highly with
patients’ long-term outcome, thus definitions have
been enriched in recent years with the addition of
other measures of severity, including length of loss of
consciousness and length of post-traumatic amnesia
(PTA). The American Congress of Rehabilitation
Medicine defines mild TBI as a traumatically induced
physiological disruption of brain function that
includes one or more of the following:
1. Any period of loss of consciousness lasting 30
minutes or less
2. An initial GCS score of 13 to 15 after 30
minutes
3. PTA lasting no more than 24 hours
4. Any loss of memory for events immediately
before or after the incident
5. Any alteration of mental state at the time of
injury
6. Focal neurological deficits that may or may not
be transient
Severe TBI almost always results in prolonged
unconsciousness lasting at least one hour and usually
longer. Persons with severe TBI will often be left with
permanent impairments.
INCIDENCE, CAUSE OF INJURY, AND
CORRELATES OF TBI
Thurman and Guerrero utilized hospital discharge
information collected by the CDC’s National Center
 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
for Health Statistics from 1980 through 1995 to
estimate the incidence of TBI that resulted in
patients being hospitalized. The incidence of TBI
cases that resulted in hospitalization during this time
period (identified by diagnostic codes 800.0–801.9,
803.0–804.9, and/or 850.0–854.1 present in one or
more of seven diagnostic code fields) declined 51%
from 199 to 98 per 100,000 per year. Most of this
decline was among mild TBI cases, which declined
61% over that time period. The number of moderate
TBI cases declined 19%, and hospitalizations for
severe TBI increased 90%. Severity of TBI was
estimated with ICDMAP-90 from ICD-9-CM codes.
In the last period studied (1994–1995), 51% of cases
were characterized as mild, 21% moderate, and
19% severe. The severity of 7% of the cases could
not be determined. Similar distributions of TBI cases
by severity have been found in other studies.
Thurman and Guerrero conclude that the decline
in the overall incidence of TBI cases that result in
hospitalization is likely due to a combination of
improved prevention and changing practice patterns,
especially regarding the outpatient treatment of mild
TBI. The increased proportion of patients with
severe TBI treated in hospitals could be due in part
to better diagnostic tools (magnetic resonance
imaging, etc.) and to improvements in trauma care
that result in the survival of more severely injured
TBI persons.
National estimates of individuals treated in emer-
gency departments, clinics, doctors’ offices, etc. and
those not receiving treatment are not available
because there are no national surveillance systems
or periodic national surveillance systems in place for
these injuries. Studies estimating the number of
individuals with TBI treated in nonhospital settings
or not treated at all have had to rely on state
surveillance systems when available or on special
research studies of particular communities. Estimates
of total TBI incidence (TBI patients treated in the
hospital, treated in other care settings, and not treated
at all) vary considerably among community- and
state-based epidemiological studies. Surveys of the
general population such as the National Health
Interview Survey (NHIS), that include all self-
reported TBI, report higher incidence rates.
Despite differences in the definition of brain
injury, and the different populations studied in
community- and state-based studies, findings are
generally consistent with respect to risk factors and
causation. Males are consistently found to have a
higher TBI incidence rate than females and the
439
incidence rate is highest for the aged (75 and older)
and the 15–24 age group.
Most studies of TBI that resulted in hospitalization
find that transportation-related injuries are the
leading cause of TBI. Using data from CDC-
supported TBI surveillance programs in seven U.S.
states (Arizona, Colorado, Minnesota, Missouri,
Oklahoma, New York, and South Carolina), Thur-
man and associates estimated that transportation-
related crashes (including pedestrians, bicycles,
automobiles, and recreational vehicles) accounted
for 49% of the cases of TBI that resulted in death or
hospitalization in the seven states combined in 1994,
although others have reported a lower proportion.
The difference may be due in part to the different
time periods examined by the studies and also to the
fact that motor vehicle accidents can result in more
severe injuries, which are likely to result in hospita-
lization. Thus, studies that rely on hospitalization
data may place motor vehicle crashes as a more
predominant cause of injury than studies relying on
surveys of more inclusive populations (nonhospita-
lized, nontreated, as well as hospitalized).
Many community studies of hospitalized patients
find falls to be the second leading cause of TBI. Also,
assault has been found to be an important cause of
TBI, particularly in U.S. inner cities. Inner cities also
tend to have an overall higher rate of TBI than other
communities studied.
Alcohol has been found in many TBI patients
tested for its presence. However, estimates of the
percentage of TBI patients with relatively high levels
of alcohol are not precise because generally only
selected patients are tested for the presence of
alcohol.
Safety equipment also appears to be an important
factor affecting TBI incidence rates because many
TBI patients have been found to not be using
helmets, seat belts, and other safety equipment at
the time of injury. The absence of comparable data
on non-TBI individuals makes it problematic to
conclude that failure to use safety equipment resulted
in injury. It is possible that nonuse of safety
equipment is typical of all people and not just those
who suffer TBI.
TBI IN MILITARY POPULATIONS
Prior to the Korean War, many patients with
survivable injuries perished. Improvements in eva-
cuation of the injured, resuscitation, and surgical
care resulted in better survival in Korea and Vietnam.
440 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
Approximately 40% of the 58,000 U.S. combat
fatalities in the Vietnam War were due to head and
neck wounds and 14% of those who survived their
wounds suffered head injury. The survival of more
severely wounded men in that conflict compared to
prior wars was due to early field care, helicopter
evacuation, and the presence of neurosurgical teams
close to the battlefront. Some of these innovations in
care were adopted in civilian medical care practices
after the war. The long-term outcome of active duty
military personnel suffering penetrating head injury
in the Vietnam War has been intensively studied in a
sample of 520 head-injured veterans and 86 unin-
jured Vietnam veterans evaluated 14 years after
injury. Approximately two-thirds of the head injured
could be classified as having a good outcome on the
Glasgow Outcome Scale. Fifty-six percent were
gainfully employed 14 years postinjury, with occupa-
tions similar to those of the age-matched population
of the United States.
The percent of active duty personnel with TBI in
peacetime is not very different from the percent of
individuals with TBI in the civilian population. Men
in the age category 18–24 years are more likely than
women of those ages to have TBI. Closed TBI is the
predominant type of TBI, and many patients have
associated injuries.
MILD TBI
Diagnosis
Mild TBI (MTBI) has been poorly defined, and the
limits of what constitutes mild TBI are controversial.
Some head injuries are so mild that it is unlikely
brain injury has resulted. For example, a bump on
the head that does not result in altered consciousness
of any sort may not produce lasting neurological
sequelae. Some period of time with any altered
consciousness has recently been used by some
researchers to define the lower limit of MTBI. Others
use any of a series of features of brain injury,
including LOC, PTA, or altered mental state (such as
being dazed, confused, or ‘‘seeing stars’’). Research
studies have not reliably determined the rate of
MTBI or the percentage of persons suffering MTBI
who show symptoms or become disabled afterwards.
Sequelae
MTBI, even without loss of consciousness, has been
repeatedly associated with measurable abnormalities
in cognition, attention, and behavior as well as
documented quantitative electroencephalogram
microvascular and neuropathological changes.
Abnormalities on cognitive tasks have been repeat-
edly documented following MTBI and typically
include disturbances of attention, information pro-
cessing, and memory. As might be expected, MTBI
also has psychosocial impact for some patients.
Many MTBI patients report some somatic and/or
cognitive symptoms during the first several weeks
postinjury; these can have important functional,
social, and economic implications. Symptoms in-
clude headache, dizziness or vertigo, blurred vision,
fatigue, sleep disturbance, irritability, depression,
anxiety, and poor memory and concentration.
Typically, these symptoms improve markedly during
the first 3 months postinjury. The term postconcus-
sive syndrome is often applied when this complex of
symptoms is persistent.
Since MTBI constitutes the majority of TBI, even
small percentages of cases with brain injury sequelae
may have a significant socioeconomic impact. Well-
designed, longitudinal studies are needed to account
for the natural history and outcome of patients with
MTBI.
SPORTS-RELATED TBI
Using data from the Injury Supplement to the 1991
NHIS, Thurman and associates estimated that
306,000 (20%) of the TBIs that occurred in the
12-month period referenced by the NHIS resulted
from sports or other physical activity. This repre-
sented an annual incidence of 124 per 100,000. Most
of these injuries appeared to be mild. Approximately
one-third of these injuries were not treated by a
physician. An additional 55% were treated on an
outpatient basis and approximately 12% of the
injuries resulted in hospitalization. Basketball, base-
ball, and football accounted for 58% of all sports-
related TBI reported in the Consumer Product Safety
Commission’s National Electronic Injury Surveil-
lance System. This was attributed to the popularity
of these sports as well as the TBI risks inherent in
them.
Nationwide estimates of the total number of
deaths from TBI that resulted from sports and
recreation activities are problematic. The few sources
of national level population-based mortality data do
not indicate whether a fatality was related specifi-
cally to sports and recreation. This forces researchers
to make assumptions about whether the injury was
related to recreational activities. For example, a fatal
 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
TBI sustained by a bicyclist who is struck by a motor
vehicle could be classified as a recreational injury or
a traffic-related injury. This determination affects the
estimate of recreational injuries or fatalities. For
example, Thurman et al (1998) estimated that TBI
caused by sports and recreation activities resulted in
approximately 900 deaths in the United States in
1995. However, if deaths from bicycle-related TBI
were excluded, the estimate would have decreased
nearly 45% to 500. There are other sources of
sports-related mortality data, such as the National
Center for Catastrophic Sports Injury Research
(NCCSIR); however, the data maintained by these
types of organizations are limited to specific sports at
the high-school and college level and are not
designed to provide comprehensive population-based
fatality estimates.
Research on the Consequences of Multiple
Sports-Related TBI
Researchers and clinicians are beginning to focus
their attention on the consequences of multiple
sports-related TBI. Boxing studies show that ap-
proximately one-fifth of retired professional boxers
have some form of chronic traumatic brain injury or
dementia pugilistica, a condition that includes
significant motor, cognitive, and behavioral impair-
ments. Professional-level soccer players have received
attention because of the possibility that frequently
heading a soccer ball over a period of time may cause
neurological and neuropsychological impairments.
However, the results of neurological and neuropsy-
chological studies conducted to date are inconclu-
sive.
There is also concern about the possibility of
catastrophic consequences if an athlete returns to
play prematurely after suffering a mild TBI. Increas-
ing evidence suggests that athletes may be at risk for
second-impact syndrome (SIS), a rare but cata-
strophic condition. SIS has been diagnosed in several
deaths and permanent disabilities among athletes
who sustained TBI. It is thought to occur within
minutes after an athlete suffers a second, often mild
TBI before a prior TBI has healed. Research has not
clearly demonstrated whether or not SIS is a result of
a second TBI or a late effect of the prior TBI.
Nevertheless, the catastrophic consequences of SIS
should be a major cause for concern for everyone
involved in sports and have led to the development of
simple specialized cognitive batteries that may be
especially useful in this population and can be used
by coaches and trainers. The American Academy of
441
Neurology has promulgated guidelines for return to
play after various grades of TBI severity.
TBI MORTALITY
In 1994, the overall annual death rate due to TBI in
the United States was estimated to be 19.8 per
100,000 population. Between 1980 and 1994, the
annual TBI death rate declined 20%, although this
was not as much as the decease in the incidence of
TBI cases resulting in hospitalization, which de-
creased 51% during the same time interval. In 1994,
the death rate from TBI for females was 9.3 per
100,000. The death rate for males (30.7 per
100,000) was 3.3 times higher than the death rate
of females. Interestingly, when age was considered,
the people most likely to die from TBI were 75 years
old or older. The death rate from TBI among persons
who were 75 years old or older was 46.3 per 100,000
in 1994. The death rate for persons between the ages
of 15 and 24 years was 32.8 per 100,000.
Death rates for people with TBI also differ by race.
In 1994, the overall death rate from TBI for
Caucasians in the United States was 19 per
100,000. The death rate for African Americans was
25.5 per 100,000. The combined death rate for all
other racial groups was 15.3 per 100,000. Race
differences in mortality rates from TBI are likely due
to a combination of income, age, and urban/rural
residence patterns that vary by race.
The cause of TBI deaths differs across the age
spectrum. Firearm-related TBIs were the leading
cause of TBI death for males aged 15–84. TBI deaths
associated with firearms outnumbered TBI deaths
associated with motor vehicle crashes from 1990
through 1994, the last year included in the study.
Transportation-related injuries were the leading
cause of TBI death among males younger than age
15, whereas falls were the leading cause among
males older than age 84. However, firearm-related
TBIs were also an important cause of TBI death in
elderly men. For females, transportation-related
injuries were the leading cause of TBI death from
birth to age 74 and falls were the leading cause after
age 74.
PREVALENCE
A number of studies have followed individuals with
moderate or severe TBI and documented continued
symptomatology or disabilities in many patients for
months or years after their injury. The CDC has
442 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
estimated that approximately 5.3 million U.S.
citizens live with disability as a result of TBI.
However, this certainly underestimates disability
due to TBI since it does not count persons treated
in emergency departments, outpatient clinics, or
those who did not seek treatment at all. The
prevalence of TBI due to injuries in the civilian and
military populations has not been given the attention
it requires. Also, because diagnostic tools were not as
effective in the past as they are now, disabilities from
past TBI may be more underdiagnosed and under-
treated than is the case for more recent TBI.
METHODOLOGICAL ISSUES AND
IMPLICATIONS FOR CLINICAL PRACTICE
In the past, researchers and policymakers largely
relied on counts of patients hospitalized with TBI to
estimate the prevalence and severity of brain injury.
These counts often excluded the large number of
cases treated outside the hospital, not treated at all,
or who died before reaching the hospital. However,
as long as the ‘‘other things being equal’’ assumption
held, researchers could at least approximately
estimate trends in TBI over time. With changes in
managed care during the past decade, hospitalization
for nonsevere brain injury has declined, necessitating
a reexamination of methodologies used to estimate
trends in TBI. More emphasis has necessarily been
placed on developing more accurate counts of brain
injury treated outside the hospital. Patients with mild
to moderate TBIs are often treated in physician
offices or outpatient clinics and sometimes not
treated at all. These cases are the most difficult to
count because they are not routinely entered into
databases.
Data from general population surveys can supple-
ment information gathered in hospital databases but
are subject to their own biases and problems with
over- and undercounts. Not surprisingly, given the
lack of consensus in the expert community of what
constitutes brain injury (especially mild brain injury),
survey respondents will not always respond in
expected ways to questions about prior brain injury.
For instance, in an ongoing self-administered survey
of paratroopers at Fort Bragg, 11.3% of more than
2300 respondents reported that they could not recall
whether or not they had suffered a head injury in the
past. When asked about loss of consciousness,
patients may combine some or all of a period of
post-traumatic amnesia into their estimate (since
both conditions result in failure to record memory).
Patients injured in solo accidents may have had an
unrecorded period of unconsciousness. Patients also
may misspecify the time period in which their TBI
occurred. Also, patients may change their reported
length of unconsciousness at follow-up evaluation,
adding further uncertainty to questionnaire surveys.
Even counts of patients hospitalized for TBI
contain error. The use of International Classification
of Diseases codes permits the identification of TBI
cases at hospital discharge. However, these codes are
often assigned by nonmedical staff who depend on
written clinician descriptions of cases. Some cases are
misclassified in regard to TBI diagnoses at discharge
and admission. Other sources of error result from
‘‘double counting’’ patients who receive treatment in
more than one hospital, are hospitalized more than
once in 1 year for the same head injury, or who live in
the community or state described but who received
their injury and hospitalization outside the area
studied. Some patients with other life-threatening
injuries may have their head injury undiagnosed until
after their hospitalization, or clinicians may list it
toward the end of a long list of diagnoses.
GCS scores have more serious measurement
difficulties. Many hospital staff are not trained to
accurately record GCS or are unable to take the time
to record GCS in busy, chaotic treatment settings.
Patients who are intubated, have bandaged eyes, or
have chemically induced comas present complex
measurement issues for GCS. Also, the time since the
patient’s injury affect GCS measurement. For exam-
ple, GCS can vary depending on whether it was
recorded at the scene of an injury or after patient
resuscitation, or whether minimum or maximum
GCS was recorded within the first 24 hours.
Measurement of risk factors involves similar issues
and some unique issues. For instance, accurate
measurement of alcohol and drug involvement can
be thwarted by confidentiality rules in hospitals, by
patients’ efforts to remain outside the judicial
process, by the difficulties of accurate measurement
in busy clinical settings in which the primary purpose
is saving lives rather than developing accurate data
sets, and by differences across hospitals regarding
which patients get laboratory tests and which do not.
Continuing research on the reliable and valid
measurement of TBI will eventually provide further
guidance for the appropriate identification of cases.
Studies thus far have not resolved difficult issues
regarding the definition of TBI because they generally
lack uniformity in definition, vary in entry criteria,
follow patients for too short a time, do not include
 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES
control groups, fail to evaluate premorbid condi-
tions, fail to document associated problems such as
chronic pain that may confound findings, and/or lack
comparable neuroimaging and neuropsychological
testing. Few studies of patients with MTBI have been
population based, so it is difficult to determine
whether patients seen in clinics with complaints are
typical of this population.
These measurement issues also relate to the
establishment of good practice guidelines for TBI.
What are the predictors of poor outcome in
individuals after TBI? Which patients benefit from
treatment in the hospital and which do not? What
evaluation is needed to distinguish these patients?
What kind of monitoring is needed? Which patients
need to be counseled to refrain from activity that
could result in reinjury, and for how long? These
issues all depend on clarification of measurement
issues in brain injury and continued research into the
sequelae of injury and their effective treatment.
Continued improvements in proper case identifica-
tion of TBI patients needing monitoring will result in
better allocation of scarce treatment dollars, the
saving of lives, and return of survivors to a good
quality of life.
PREVENTION
Primary prevention efforts include improved road
design, lower speed limits, increased use of safety
equipment, changes in driver education, and pro-
grams designed to improve anger management in
families. Some measures, such as seat belts, airbags,
and helmets, reduce injury after a crash rather than
prevent or reduce the chances of a crash. Some of
these measures have been controversial at their
inception since they require the expenditure of scarce
tax dollars and, when mandated by law, limit
individual choice. Research has been an important
component of the debate surrounding the effective-
ness of prevention strategies aimed at reducing TBI
and other injury. Relevant questions include the
following: Does a measure effectively reduce the
frequency and/or severity of TBI? What is the ratio of
benefit versus costs? Dannenberg and Fowler, in their
review of various research approaches used to
evaluate the effectiveness of TBI prevention mea-
sures, strongly recommend that any new injury
intervention contains an evaluation component,
including cost–benefit analysis. Some prevention
strategies have been found to be effective in reducing
death and disability from TBI.
443
Although bicycle helmet use is associated with a
reduction in the number of patients hospitalized with
TBI, motorcycle and bicycle rider use of helmets has
been controversial, resulting in the passage, with-
drawal, and repassage of mandated use laws in
several jurisdictions. These changes provided a type
of natural experiment with which researchers could
examine the correlation of changes in law with
helmet use. Indeed, the rate of helmet use increased
with legal mandates and then decreased to preman-
date levels of use when helmet laws were repealed.
Although TBI resulting from falls is the most
important cause of TBI among the elderly, relatively
little research has been done on the prevention of
these injuries. One randomized study of elderly
persons living in the community who presented to
the emergency department after a fall found that a
program of patient evaluation, referrals, and home
visits by occupational therapists provided to 183
patients resulted in significant improvements in
outcome at 12-month follow-up compared to the
usual treatment given to 213 patients. The risk of
further falls was significantly reduced, odds of
hospital admission were lowered, and the Barthel
score declined less.
ACUTE PROGNOSIS IN SEVERE TBI
A relatively few features of TBI appear to contain the
most significant prognostic information. Prognostic
factors such as age, clinical indices indicating severity
of brain injury (GCS), and results of computed
tomography scans or ICP monitoring have been
found to be the most useful. A working group
convened by the Brain Trauma Foundation, the
American Association of Neurological Surgeons,
the Neuro-Trauma Committee of the World Health
Organization, and the Brain Injury Association
evaluated the literature on prognostic indicators in
head injury and developed recommendations while
adhering to the concepts of evidence-based practice
(www.braintrauma.org). The study group evaluated
GCS score, patient age, pupillary diameter and light
reflex, the presence of hypotension, and computed
tomography scan features as possible prognostic
indicators for outcome. The findings are summarized
in Table 1.
CONCLUSION
TBI surveillance needs to be expanded in order to
determine the total number of persons with TBI
444 BRAIN INJURY, TRAUMATIC: EPIDEMIOLOGICAL ISSUES

Table 1 PROGNOSTIC INDICATORS OF TBIa

Indicator evaluated Comments

Glasgow Coma Scale score The probability of poor outcome increased with a low GCS.
GCS should be measured in a standardized way after resuscitation.
GCS should be measured by trained medical personnel.
Patient age The probability of poor outcome increases with age.
Pupillary diameter/light Bilaterally absent pupillary light reflex worsens prognosis.
reflex Pupillary measurement parameters
A measured pupil difference of 1 mm defines asymmetry.
A fixed pupil has no response to bright light.
A dilated pupil has a size 44 mm.
Measure pupils after pulmonary and hemodynamic resuscitation.
Exclude orbital trauma.
Pupils should be measured by trained medical personnel.
Hypotension Systolic blood pressure o90 mmHg has a 67% PPV for poor outcome and, when combined with hypoxia,
a 79% PPV.
Accurate monitoring by arterial line is the method of choice.
Blood pressure should be measured as frequently as possible and hypotension duration should be
documented.
Computed tomography Compression of basal cisterns worsens prognosis.
Traumatic subarachnoid hemorrhage worsens prognosis.
Midline shift 45 mm worsens prognosis over age 45.
Intracranial mass lesions worsen prognosis.
Hematoma volume correlates with outcome.
Prognosis is worse with acute subdural than with epidural hematoma.
a
Abbreviations used: GCS, Glasgow Coma Scale; PPV, positive predictive value.

(incidence and prevalence). Good follow-up studies
with carefully designed evaluations need to be
conducted on the full range of TBI in order to
determine the kinds and severity of injuries result-
ing in disability. More effective prevention in the
types of TBI that have been relatively neglected,
such as falls in the elderly, will require efficacy
studies of various prevention and treatment ap-
proaches. Many survivors of TBI are unable to
fully participate in work life, family relationships,
and community activities that they engaged in
prior to their injuries. More complete TBI surveil-
lance combined with expanded research on outcomes
and treatments are needed to reduce future mortality
and disability after injuries. Substantial progress
has been made since the Vietnam War in identify-
ing individuals and situations associated with brain
injury, improving treatment effectiveness, and edu-
cating clinicians, survivors, and family members
about steps they can take to improve the quality
of life for survivors. However, until we under-
stand the full scope of TBI and its long-term
consequences, we will not and cannot apply
resources appropriately to provide effective preven-
tion and treatment.
—Karen A. Schwab, Brian J. Ivins,
and Andres M. Salazar
See also–Brain Trauma, Overview; Epidemiology,
Overview; Head Trauma, Overview;
Neuroepidemiology, Overview of Incidence and
Prevalence Rates
Further Reading
Annegers, J., Grabow, J., Kurland, L., et al. (1980). The
incidence, causes, and secular trends of head trauma in
Olmstead County, Minnesota, 1935–1974. Neurology 30,
912–919.
Barth, J., Alves, W., Ryan, T., et al. (1989). Mild head injury
in sports: Neuropsychological sequelae and recovery of
function. In Mild Head Injury (H. Levin, H. Eisenberg,
and A. Benton, Eds.), pp. 257–275. Oxford Univ. Press,
New York.
Close, J., Ellis, M., Hooper, R., et al. (1999). Prevention of falls in
the elderly trial (PROFET): A randomised controlled trial.
Lancet 353, 93.

Dannenberg, A., and Fowler, C. (1998). Evaluation of interven-
tions to prevent injuries: An overview. Injury Prev. 4,
141–147.
Dikmen, S., Temkin, N., and Armsden, G. (1989). Neuropsycho-
logical recovery, relationship to psychosocial function and
postconcussional complaints. In Mild Head Injury (H. Levin,
H. Eisenberg, and A. Benton, Eds.), pp. 229–240. Oxford Univ.
Press, New York.
Frankowski, R., Annegers, J., Whitman, S., et al. (1985).
Epidemiological and descriptive studies part I: The descriptive
epidemiology of head trauma in the United States. In Central
Nervous System Trauma Status Report (P. Becker and J.
Povlishock, Eds.). National Institute of Neurological and
Communicative Disorders and Stroke, National Institutes of
Health, Bethesda, MD.
George, D., and Dagi, T. (1995). Military penetrating craniocer-
ebral injuries: Applications to civilian triage and management.
Neurosurg. Clin. North Am. 6, 753–759.
Jordan, B., Relkin, N., Ravdin, L., et al. (1997). Aplipoprotein E
epsilon 4 associated with chronic traumatic brain injury in
boxing. J. Am. Med. Assoc. 278, 136–140.
Kraft, J. F., Schwab, K., Salazar, A. M., and Brown, H. R. (1993).
Occupational and educational achievements of head injured
Vietnam veterans at 15 year follow-up. Arch. Phys. Medicine
Rehab. 74, 596–601.
Kraus, J., and McArthur, D. (1996). Epidemiolgic aspects of brain
injury. Neuroepidemiology 14, 435–450.
Levin, H., Mattis, S., Ruff, R., et al. (1987). Neurobehavioral
outcome following minor head injury: A three-center study. J.
Neurosurg. 66, 234–243.
Ommaya, A., and Ommaya, A. (1996). Causation, incidence and
costs of traumatic brain injury in the U.S. military medical
system. J. Trauma 40, 211–217.
Salazar, A., Schwab, K., and Grafman, J. H. (1995). Penetrating
injuries in the Vietnam War. Neurosurg. Clin. North Am. 6,
715–726.
Schwab, K., Grafman, J., Salazar, A., et al. (1993). Residual
impairments and work status 15 years after penetrating head
injuries: Report from the Vietnam head injury study. Neurology
43, 95–103.
Sosin, D., Sniezek, E., and Thurman, D. J. (1996). Incidence of
mild and moderate brain injury in the United States, 1991.
Brain Injury 10, 47–54.
Thurman, D., and Guerrero, J. (1999). Trends in hospitalization
associated with traumatic brain injury. J. Am. Med. Assoc. 282,
954–957.
Thurman, D., Branche, C., and Sniezek, J. E. (1998). The
epidemiology of sports-related traumatic brain injuries in the
United States: Recent developments. J. Head Trauma Rehab.
13, 1–8.
Brain Ischemic Edema
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN EDEMA represents an increase in brain
tissue water. Because the increase occurs within a
closed cranium and is accompanied by brain swel-
BRAIN ISCHEMIC EDEMA 445
ling, it often produces a clinical syndrome manifested
by intracranial hypertension, papilledema, and
neurological symptoms characteristic of progressive
brain compression (headache, nausea, vomiting,
disturbances of consciousness, and coma). Edema-
tous brain may displace and compress brain
structures, reducing cerebral perfusion and ulti-
mately leading to brain herniation and infarction
and death.
Brain edema can be produced by acutely decreas-
ing plasma tonicity (osmotic edema), interfering with
brain cell metabolism (cytotoxic edema), or disturb-
ing the integrity of cerebral capillaries (vasogenic
edema). Ischemia, the condition of a reduced,
inadequate brain blood flow, can cause cytotoxic
and vasogenic edema as well as infarction (cell
death). Vasogenic edema involves accumulation of
plasma ultrafiltrate in the brain extracellular space,
whereas cytotoxic edema arises from fluid accumula-
tion within brain cellular elements. In animal studies,
increased brain water can be quantified by compar-
ing weights or specific gravities of edematous and
intact tissue. In the clinic, brain edema is identified as
a reduced density on computer-assisted tomography,
a prolonged relaxation time on T1- or T2-weighted
magnetic resonance imaging (MRI), or by diffusion-
weighted MRI.
Brain capillaries, the site of the blood–brain
barrier, are the first line of defense against vasogenic
brain edema. Their lumen is lined by a continuous
layer of endothelial cells that are connected by
complete rings of tight junctions (zonulae occludens).
This layer does not support vesicular transport, it is
very poorly permeable to proteins and salts, and it
has a very low hydraulic conductivity (high resis-
tance) to fluid flow. In contrast, capillary endothe-
lium in tissues outside the central nervous system
(except at the retina, peripheral nerve, and testes) has
multiple interendothelial discontinuities. Due to these
discontinuities, plasma ultrafiltrate constantly drains
into the tissue, driven by the difference between
hydrostatic and osmotic pressures across the capil-
lary wall (Starling’s law). Edema is prevented because
the ultrafiltrate is returned to the bloodstream by
lymphatics, which are absent in brain.
The low permeability and low hydraulic con-
ductivity of the normal cerebrovascular endothe-
lium limit fluid accumulation in brain. Plasma
fluid that might be forced into brain by increased
intravascular hydrostatic pressure would enter
slowly and be essentially salt- and protein-free,
diluting brain extracellular fluid and setting up

Dannenberg, A., and Fowler, C. (1998). Evaluation of interven-
tions to prevent injuries: An overview. Injury Prev. 4,
141–147.
Dikmen, S., Temkin, N., and Armsden, G. (1989). Neuropsycho-
logical recovery, relationship to psychosocial function and
postconcussional complaints. In Mild Head Injury (H. Levin,
H. Eisenberg, and A. Benton, Eds.), pp. 229–240. Oxford Univ.
Press, New York.
Frankowski, R., Annegers, J., Whitman, S., et al. (1985).
Epidemiological and descriptive studies part I: The descriptive
epidemiology of head trauma in the United States. In Central
Nervous System Trauma Status Report (P. Becker and J.
Povlishock, Eds.). National Institute of Neurological and
Communicative Disorders and Stroke, National Institutes of
Health, Bethesda, MD.
George, D., and Dagi, T. (1995). Military penetrating craniocer-
ebral injuries: Applications to civilian triage and management.
Neurosurg. Clin. North Am. 6, 753–759.
Jordan, B., Relkin, N., Ravdin, L., et al. (1997). Aplipoprotein E
epsilon 4 associated with chronic traumatic brain injury in
boxing. J. Am. Med. Assoc. 278, 136–140.
Kraft, J. F., Schwab, K., Salazar, A. M., and Brown, H. R. (1993).
Occupational and educational achievements of head injured
Vietnam veterans at 15 year follow-up. Arch. Phys. Medicine
Rehab. 74, 596–601.
Kraus, J., and McArthur, D. (1996). Epidemiolgic aspects of brain
injury. Neuroepidemiology 14, 435–450.
Levin, H., Mattis, S., Ruff, R., et al. (1987). Neurobehavioral
outcome following minor head injury: A three-center study. J.
Neurosurg. 66, 234–243.
Ommaya, A., and Ommaya, A. (1996). Causation, incidence and
costs of traumatic brain injury in the U.S. military medical
system. J. Trauma 40, 211–217.
Salazar, A., Schwab, K., and Grafman, J. H. (1995). Penetrating
injuries in the Vietnam War. Neurosurg. Clin. North Am. 6,
715–726.
Schwab, K., Grafman, J., Salazar, A., et al. (1993). Residual
impairments and work status 15 years after penetrating head
injuries: Report from the Vietnam head injury study. Neurology
43, 95–103.
Sosin, D., Sniezek, E., and Thurman, D. J. (1996). Incidence of
mild and moderate brain injury in the United States, 1991.
Brain Injury 10, 47–54.
Thurman, D., and Guerrero, J. (1999). Trends in hospitalization
associated with traumatic brain injury. J. Am. Med. Assoc. 282,
954–957.
Thurman, D., Branche, C., and Sniezek, J. E. (1998). The
epidemiology of sports-related traumatic brain injuries in the
United States: Recent developments. J. Head Trauma Rehab.
13, 1–8.
Brain Ischemic Edema
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN EDEMA represents an increase in brain
tissue water. Because the increase occurs within a
closed cranium and is accompanied by brain swel-
BRAIN ISCHEMIC EDEMA 445
ling, it often produces a clinical syndrome manifested
by intracranial hypertension, papilledema, and
neurological symptoms characteristic of progressive
brain compression (headache, nausea, vomiting,
disturbances of consciousness, and coma). Edema-
tous brain may displace and compress brain
structures, reducing cerebral perfusion and ulti-
mately leading to brain herniation and infarction
and death.
Brain edema can be produced by acutely decreas-
ing plasma tonicity (osmotic edema), interfering with
brain cell metabolism (cytotoxic edema), or disturb-
ing the integrity of cerebral capillaries (vasogenic
edema). Ischemia, the condition of a reduced,
inadequate brain blood flow, can cause cytotoxic
and vasogenic edema as well as infarction (cell
death). Vasogenic edema involves accumulation of
plasma ultrafiltrate in the brain extracellular space,
whereas cytotoxic edema arises from fluid accumula-
tion within brain cellular elements. In animal studies,
increased brain water can be quantified by compar-
ing weights or specific gravities of edematous and
intact tissue. In the clinic, brain edema is identified as
a reduced density on computer-assisted tomography,
a prolonged relaxation time on T1- or T2-weighted
magnetic resonance imaging (MRI), or by diffusion-
weighted MRI.
Brain capillaries, the site of the blood–brain
barrier, are the first line of defense against vasogenic
brain edema. Their lumen is lined by a continuous
layer of endothelial cells that are connected by
complete rings of tight junctions (zonulae occludens).
This layer does not support vesicular transport, it is
very poorly permeable to proteins and salts, and it
has a very low hydraulic conductivity (high resis-
tance) to fluid flow. In contrast, capillary endothe-
lium in tissues outside the central nervous system
(except at the retina, peripheral nerve, and testes) has
multiple interendothelial discontinuities. Due to these
discontinuities, plasma ultrafiltrate constantly drains
into the tissue, driven by the difference between
hydrostatic and osmotic pressures across the capil-
lary wall (Starling’s law). Edema is prevented because
the ultrafiltrate is returned to the bloodstream by
lymphatics, which are absent in brain.
The low permeability and low hydraulic con-
ductivity of the normal cerebrovascular endothe-
lium limit fluid accumulation in brain. Plasma
fluid that might be forced into brain by increased
intravascular hydrostatic pressure would enter
slowly and be essentially salt- and protein-free,
diluting brain extracellular fluid and setting up
446 BRAIN ISCHEMIC EDEMA
Figure 1
Diagrams of capillary and surrounding tissue of intact brain with normal capillary and normal plasma hydrostatic pressure (left); intact brain
with normal capillary and increased plasma hydrostatic pressure (Pplasma), leading to minimal flow of solute-free ultrafiltrate in brain across
vascular endothelium (center); and swollen edematous brain with damaged endothelial cells and extravasated plasma proteins and salts
(right). Stippling represents plasma salts, and large dots represent plasma protein. t.j., tight junction.
an osmotic gradient to immediately counteract
the hydrostatic pressure change and prevent
significant edema. If the brain capillaries are
damaged by ischemia, however, plasma ultra-
filtrate will rapidly enter the brain extracellular
space, separate the cells, and accumulate and spread
as a function of time while tissue compliance
increases (Fig. 1).
Many biological substances whose concentrations
increase during brain ischemia can increase the
accompanying cytotoxicity and promote edema.
They include histamine, serotonin, substance P,
adenosine nucleotides, free oxygen radicals, nitric
oxide, bradykinin, 5-hydroxytryptamine, cytokines
(interleukins, tumor necrosis factor-a, and platelet-
activating factor), metalloproteinases, endothelin-1,
and tumor-secreted vascular permeability factor.
Ischemia also initiates phospholipase activation,
releasing long-chain fatty acids (particularly arachi-
donic acid) from brain membrane phospholipids.
The fatty acids and their metabolites (leukotrienes,
prostaglandins, hydroxyeicosanoic acid, and reac-
tive oxygen species), platelet-activating factor, and
the lysophospholipids formed by fatty acid release
have multiple cytotoxic effects. For brain tissue
to recover, the excess fatty acids must be reincorpo-
rated into the phospholipids, which requires two
molecules of ATP per fatty acid molecule. This
places an extra energy demand on the metaboli-
cally compromised tissue and can extend the
infarcted edematous region. Glucocorticoids may
be clinically effective against brain edema by
inhibiting phospholipase A2 and thus arachi-
donate release. Other drugs that interfere with
the ‘‘arachidonate cascade,’’ such as lithium, lipox-
ygenase inhibitors, thromboxane A2 antagonists,
and free radical scavengers, may also prove clinically
useful.
—Stanley I. Rapoport
See also–Cerebral Edema; Cerebral Metabolism
and Blood Flow; Ischemic Cell Death,
Mechanisms
Further Reading
Ito, U., Baethmann, A., Hossmann, K.-A., et al. (1993).
Brain edema IX. Proceedings of the Ninth International
Symposium, Tokyo, May 16–19, 1993. Acta Neurochir. Suppl.
60, 1–589.
Purdon, A. D., and Rapoport, S. I. (1998). Energy requirements for
two aspects of phospholipid metabolism in mammalian brain.
Biochem. J. 335, 313–318.
Rapoport, S. I. (1997). Brain edema and the blood–brain barrier.
In Primer on Cerebrovascular Diseases (K. M. A. Welch, L. R.
Caplan, D. J. Reis, B. K. Seisjö, and B. Weir, Eds.), pp. 25–28.
Academic Press, New York.
Winkler, A. S., Baethmann, A., Peters, J., et al. (2000). Mechanism
of arachidonid acid induced swelling. Brain Res. Mol. Brain
Res. 76, 419–423.

Brain Mapping and
Quantitative EEG
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE HUMAN BRAIN functions by exchanging elec-
trical signals continuously among its many regions.
Through technology, one can eavesdrop on these
electrical signals through recording electrodes placed
on the scalp. Spontaneous scalp recordings of brain
electrical activity are termed electroencephalography
(EEG). EEG has been viewed traditionally on a
continuous paper printout, which displays voltages
recorded from approximately 20 standardized scalp
sites.
In traditional visual EEG analysis, an expert
physician views a 30-min long recording of these
voltage tracings. This recording takes up approxi-
mately 200 pages. The expert can identify various
brain state changes such as falling asleep. He or she
can also identify clinically relevant abnormal brain
discharges. One common abnormality is epileptic
spikes, which are brief, fast voltage changes typically
seen in patients with epileptic seizures. The expert
can also identify regions with slowing of the usual
brain wave patterns, typical of regions with brain
damage.
Research scientists have long sought to automate
the process of EEG analysis. They have also sought
to extract from these signals additional information
too subtle to be identified by simple expert visual
analysis of tracings. To accomplish this analysis, EEG
can be digitized and analyzed in the computer. A
variety of techniques are available for analyzing and
displaying digitally processed EEG.
TECHNIQUES
Digital EEG is the paperless recording of EEG with
digital storage and display on a computer monitor.
Recordings are made with amplifiers and electronic
filters similar to those used for traditional paper
EEG. The monitor display mimics the look of paper
EEG but provides much more flexibility for the
reader. For example, the reader visually interpreting
a digital EEG can adjust the display gain to magnify
small features for a better view. The reader can also
apply filters to eliminate certain unwanted fast or
slow contaminating artifacts. Digital signals can be
easily transmitted to remote sites. Overall, the digital
BRAIN MAPPING AND QUANTITATIVE EEG 447
display of EEG has many advantages over traditional
paper displays.
Quantitative EEG (QEEG) is the analysis of the
digital EEG. It includes a variety of computer graphics
displays as well as several types of signal analysis.
Table 1 shows several types of QEEG techniques.
Automated event detection uses mathematical
algorithms to detect or identify interesting events or
important abnormalities. This is especially helpful in
long recordings because it spares the human reader
the monotonous task of reviewing enormous EEG
files. For example, an EEG can be recorded for 24 hr
to seek signs of brief epileptic seizures. Automated
spike and seizure detectors can search through this
prolonged recording and flag any possible epileptic
EEG abnormalities. However, the mathematical
algorithms are very imperfect and also flag many
other nonepileptic transient voltage changes. To use
this clinically, one common approach is to have a
human expert review each event flagged by the
computer. The expert can then identify which events
are of clinical interest. This approach combines the
screening ability of QEEG with the ability of the
expert to separate important clinical events from
meaningless voltage transients.
Monitoring and trending of EEG uses mathema-
tical algorithms to extract simple measurements
from the EEG. Repeated measurements are then
displayed in graphs showing the changes over hours
or days. For example, measurement of overall EEG
amplitude can be monitored during surgery. If the
surgeon accidentally interferes with brain blood
supply, EEG monitoring and trending shows a
decline in the EEG amplitude. This change can warn
the surgical team to quickly correct the problem.
Similarly, in the intensive care unit (ICU), EEG
monitoring and trending can show changes that
Table 1 NOMENCLATURE FOR DIGITAL AND
QUANTITATIVE EEG
Digital EEG
Quantitative EEG (QEEG)
Signal analysis
Automated event detection
Monitoring and trending
Source analysis
Frequency analysis
Topographic displays (EEG brain maps)
Statistical analysis
Comparisons to normative values
Diagnostic discriminant analysis
448 BRAIN MAPPING AND QUANTITATIVE EEG

warn of complications. In surgery or the ICU, these

EEG trends can show when a change occurs and
give a general indication of its cause. When trends
raise the alarm of adverse changes, physicians and
surgeons then evaluate the patient to diagnose the
actual complication and decide on a treatment.
Source analysis tries to identify the brain location
responsible for generating abnormal brain waves.
It does so by comparing the distribution of voltages
across the scalp to those expected if the voltages
were caused by a single electrical dipole at a specific
site in the brain. This analysis may specify the
location, orientation, strength, and number of
possible intracranial sources of the EEG features
analyzed.
Frequency analysis converts the original EEG
tracing into its frequency content. Such analysis
shows how much energy occurred at each frequency.
Frequencies are expressed as cycles per second or
hertz (Hz). Frequency analysis is typically used to
measure the amount of fast or slow activity in an
EEG. Frequency analysis can be reported as a
continuous graph across the spectrum of frequencies,
usually 0.1–30.0 Hz. More often, the frequency
content is averaged into a few traditional EEG
frequency bands, such as delta (0.1–3.9 Hz), theta
(4.0–7.9 Hz), alpha (8.0–12.9 Hz), and beta (higher
frequencies). These can give the reader an estimate of
the overall energy content of EEG in the typical
frequency bands. This estimate can alert a reader to
an excess of abnormal slow activity.
EEG brain maps are visual computer graphical
displays for presenting EEG. They can help commu-
nicate to nonspecialists the locations of certain EEG
Figure 1
features. The stylized maps superficially resemble a Example of a frequency analysis EEG brain map. (A) The
computed tomography (CT) scan image of the brain, scalp distribution of the slow delta band EEG brain waves
but the resemblance is purely superficial. EEG brain (in the 0.1- to 4.0-Hz frequency range). Abnormally increased
maps actually have relatively few real data points, so delta activity is shown in yellow and red. Blue and green represent
areas without much delta activity. The brain map shows that
most of the image is just an extrapolation among the
the delta is maximal in the left posterior temporal region of the
few real points. In EEG brain maps, the EEG voltage brain. (See color plate section.) (B) A corresponding computed
is often color coded to represent intensities of some tomogram (CT scan). In the CT, the outer white oval is the skull.
feature (e.g., to represent the scalp locations where The symmetrical black interior areas are the fluid-filled ventricles
slow EEG waves are seen). in the brain. The darkened area in the lower right corner of the
scan is the area of damage in this patient. It also shows damage
Figure 1 shows an example of a frequency
in the left posterior temporal region. (Radiologists plot the left
analysis EEG brain map. Figure 1A is a graphical body on the right side of scans.) This 57-year-old man had the
representation of the slow brain waves in the 0.1- to sudden onset of inability to understand spoken language (fluent
4.0-Hz (cycles per second) frequency range known aphasia). The EEG brain map showed damage in the area of
as the delta band in EEG. In this case, the delta the brain known to serve speech understanding functions.
The CT scan confirmed the region of damage from this stroke.
is maximal in the left parietal region of the brain.
However, the CT scan does not become diagnostic until 1 day or
Figure 1B shows a corresponding CT scan. The more after such a stroke, whereas the EEG shows the areas of
area of damage shown in the CT corresponds to damage immediately (illustrations and case courtesy of Sheldon
the area of delta slowing on the brain map. Jordan).

Radiologists plot CT scans with the left brain
on the right side of the scan, whereas EEG
brain maps plot the left brain on the left side. In
this example, frequency analysis is used to calculate
the delta activity, and then an EEG brain map is
used to diagram the delta’s distribution across the
scalp.
Statistical analysis compares a patient to a group
of normal subjects or a group of patients. These
comparisons can be carried out on frequency
analysis, such as alpha wave activity, or other EEG
features. Statistical analysis can be summarized and
displayed in tables of statistical values or on EEG
brain maps.
Group statistics are used to compare an individual
to other age-matched normal subjects. Statistical
techniques are used to identify a patient’s EEG
features that are outside the normal range. For
example, a particular patient might be shown to have
an excess of slow EEG waves over a certain brain
region.
Diagnostic discriminant analysis compares EEG
features from a patient to those from a group of
patients with a particular disorder. In theory, this
may help match EEG changes for that individual to
the pattern of EEG changes typical for a particular
disorder. Implementing this in practice has been
difficult. In theory, one might develop discriminant
patterns for a variety of diseases and submit the EEG
to testing to determine which disease the EEG most
closely matches.
PROBLEMS
A variety of problems have occurred in the imple-
mentation of QEEG. Some applications have devel-
oped well and are described later. In other areas,
enthusiasm for theoretical uses of these techniques
has far outstripped the actual clinical benefit or even
the science.
Contaminating factors such as the voltages caused
by eye movements, heartbeats, and sweat have
hampered clinical use of QEEG. It has also been
hampered by technical factors such as poor electrode
contact with the scalp. Signals from scalp muscles
easily contaminate most EEGs. When visually
analyzed by an expert, these contaminating signals
can be factored out. The computer, however, accepts
all data as if they were real EEGs and proceeds to
process the whole signal through its analysis and into
its displays. Often, these contaminating factors
thoroughly confuse the results of such QEEGs.
BRAIN MAPPING AND QUANTITATIVE EEG 449
EEG differs among normal individuals. Just as
outward appearance or fingerprints differ among
individuals, EEGs have considerable variation
among individuals. This makes it difficult to establish
a true normal range for clinical purposes. EEGs
from an individual could have tall alpha waves, but
these can easily be nonpathological, just as an
individual person could be tall. Therefore, sophisti-
cated statistical analysis to identify tall or short brain
waves of particular frequencies does no more than
profile the brain waves recorded from an individual
and does not necessarily reflect any underlying
pathology.
The processing techniques for EEG, especially
advanced statistical processing, are particularly
fraught with difficulties. Many of these have not
been satisfactorily resolved. Clinicians need to be
very wary of changes flagged by QEEG. Traditional
real clinical EEG abnormalities include epileptic
spikes and regions of excess slow waves. When
QEEG does flag such well-known abnormalities,
they can draw a reader’s attention to them much
like a second opinion. However, QEEG often has
false-positive features, so it should not be solely
relied on. Instead, its findings should be considered
as flags or alarm features that cause an expert to go
back and visually analyze the EEG, searching for the
causes of the features seen and flagged. Sometimes
this can alert the visual reader to a previously
overlooked epileptic spike or region of slow EEG.
CLINICAL SETTINGS
Epilepsy
QEEG is used in epilepsy for detecting spikes and
seizures in EEG recordings. Spikes may be a sign of
epilepsy and can help determine the type of epilepsy
in a patient. QEEG searches through long EEG
records and is sometimes used to aid in the diagnosis
of epilepsy. For example, a patient may present to a
physician complaining of episodes of loss of con-
sciousness. The physician may question whether
these are due to cardiac arrhythmia, fainting spells,
epileptic seizures, hypoglycemia, or other causes. If
routine 30-min EEGs and other testing fail to clarify
the diagnosis, a 24-hr EEG can be conducted. QEEG
is used to help search through this recording,
searching for brief epileptic spikes or seizures that
may have occurred. Potential events are flagged by
the computer for later evaluation by an expert EEG
reader. If epileptic spikes or seizures are found, they
450 BRAIN MAPPING AND QUANTITATIVE EEG
could help confirm the specific diagnosis for the
patient.
When patients are under evaluation for epilepsy
surgery, it is key to capture EEG during the epileptic
seizures. Only in this way can precise localization of
the seizure focus be achieved before surgery. Record-
ings are often undertaken for many days. QEEG
screening of these prolonged recordings can help
identify subtle epileptic seizures. This can speed the
process of evaluation and help determine whether
surgery is indicated to cure the patient’s epileptic
seizures.
When a patient does have epileptic spikes, QEEG
source localization can help determine where in the
brain these spikes occurred. This can be used in a
presurgical evaluation to help determine the area of
the brain responsible for the patient’s seizures. Source
localization can also be used to help identify which
epileptic spikes are associated with particular known
epileptic syndromes, such as benign Rolandic epi-
lepsy. Spike analysis can be helpful in clarifying the
measurements of a spike, such as its amplitude,
width, and electrical polarity at onset, or how
stereotyped (identical) each spike is compared to
the others. The clinician can use this information to
make specific diagnoses and to advise the patient
about medication use and prognosis.
Figure 2 shows an example of dipole source
localization for an epileptic spike. The figure shows
the correspondence between the spike and the
most likely place in the brain from which that spike
arose.
Figure 2
Source localization of an epileptic spike. The spike’s wave shape is
shown on the left. The three graphic head displays show the
intracranial site at which the spike most likely arose. In this case, it
probably arose from the deep right temporal lobe (courtesy of John
Ebersole).
Operating Room and ICU Monitoring
Certain surgical procedures put the brain at risk for
intraoperative complications. Continuous EEG mon-
itoring can help identify certain complications,
leading to prompt intervention to correct them.
QEEG can supplement routine EEG by tracking
changes across time. This tracking can help identify
gradual changes that might be overlooked in routine
visual EEG reading. Trending can graphically de-
monstrate physiological changes in a way that draws
attention to potential clinical problems. Digital EEG
can also provide a way to transmit the EEG and
trending to a remote site. This allows a physician to
monitor EEG trending changes without having to be
present in the operating room (OR).
An example of OR monitoring is in carotid
endarterectomy. In this procedure, the surgeon
clamps shut the carotid artery, which is a main
artery to the brain. Monitoring can indicate whether
the patient’s brain is tolerating this adequately or
whether the surgeon must change his or her
approach to performing the surgery.
In the ICU, monitoring EEG continuously can help
identify EEG trends and warn of complications in a
way similar to its use in the OR. In addition, in ICU
patients there is an ever-present risk of epileptic
seizures. Some seizures are nonconvulsive (i.e., are
accompanied by little or no outward sign of the
brain’s seizures). EEG can easily detect these seizures
as well as flag possible epileptic spikes. Slow brain
waves can be a sign of brain injury or dysfunction. In
the ICU, monitoring can measure the slow waves and
help show that a patient is stable or improving. If it
show deterioration, physicians should evaluate the
patient and find ways to halt the deterioration. By
identifying such complications, QEEG continuous
ICU monitoring can provide early warnings for
clinicians to alter therapy. It can also provide
additional information contributing to a better
diagnosis or prognosis.
Figure 3 shows an example of continuous ICU
EEG monitoring. In these six EEG channels, each
trend graph shows EEG activity during a 5-hr
window of time. On three occasions, there is a brief
burst of EEG activity, each corresponding to a
nonconvulsive epileptic seizure.
Another ICU use is in regulating therapy. Some-
times medications are given to deliberately induce
suppression of brain function. This can be a
preventative therapy in some critical care situations.
EEG is critical in determining when a sufficient

Figure 3
EEG detection of three nonconvulsive seizures using monitoring
and trending of continuous ICU EEG. The monitoring is displayed
a 5-hr period. For each of the six recording locations, the amount
of alpha EEG activity is shown by the height of the vertical bars.
The nonconvulsive seizures appear as sudden bursts of activity
(arrows) (courtesy UCLA EEG Laboratory).
amount of medication has been given—typically
enough to cause brief suppressions of the EEG
known as burst suppression. Continuous monitoring
can determine when suppressions are occurring or if
more medicine is needed. EEG monitoring can also
determine if sufficient seizure medication has been
administered to prevent repetitive epileptic seizures
or if enough diuretic or other therapy has been given
to treat severely increased intracranial pressure.
Dementias and Other Encephalopathies
In dementia and other diffuse brain impairment
known as encephalopathy, the EEG often shows
excess slow waves instead of background alpha
waves. Routine visual EEG reading identifies most
such changes. However, when the changes are
particularly mild, visual EEG reading may miss
certain abnormalities. QEEG has been proposed as
a technique to identify subtle degrees of slowing. In
this way, it can help supplement the visual inter-
pretation of EEG. For example, if a patient presents
to a physician with complaints of memory impair-
ment, diagnoses considered include dementia (such
as Alzheimer’s disease) as well as depression and
other disorders. EEG abnormalities can heavily
weigh in favor of a dementia as opposed to
BRAIN MAPPING AND QUANTITATIVE EEG 451
depression as the cause of a patient’s memory
problem. QEEG frequency analysis may help to
grade the degree of impairment in Alzheimer’s
disease or to predict the rapidity of deterioration.
In other patients, finding specific regions of increased
slow EEG activity can point to abnormality in a
specific region of the brain. In the latter case, the
physician will use neuroimaging techniques, such as
CT or magnetic resonance imaging, for further
evaluation of the abnormal region.
Other Clinical Disorders
A considerable amount of research and opinion have
been published on the use of QEEG in many other
disorders, including concussion and head injury,
learning and attention disorders, schizophrenia,
alcoholism, and drug abuse. In each case, authors
have suggested that QEEG is useful in the clinical
diagnosis of these disorders. Recent studies have
shown reproducible differences between groups of
patients and groups of normal subjects, such as the
finding of EEG increased frontal alpha waves in
depression. However, these general studies have not
provided sufficient scientific information to warrant
the use of QEEG in these clinical conditions. Many
of these scientific observations are not necessarily
directly relevant for clinical diagnosis in an indivi-
dual patient’s care. The clinical use of QEEG tests in
these patients remains a matter of research rather
than of established clinical value.
CONCLUSION
The microelectronics revolution has brought the
digital world to EEG analysis, in the same way as
microelectronics has affected so many other aspects
of medical care and daily life. For EEG, this has been
a mixed blessing. For the visual analysis of digital
EEG, the computer-based recording and reading
stations have allowed great flexibility for the reader.
Such digital EEG techniques are now well established
and widely used.
QEEG is routinely used in epilepsy for flagging
possible epileptic spikes and seizures in long record-
ings. QEEG techniques also measure epileptic spikes,
indicate possible intracranial locations from which
the spikes arise, and match the spikes to character-
istics of spikes from known epileptic syndromes. In
the OR and ICU, monitoring and trending of EEG
can help identify potential complications and warn
clinicians to avert possible long-term harm. Mon-
itoring can be helpful in regulating some ICU
452 BRAINSTEM AUDITORY EVOKED POTENTIALS
therapies. In dementia and other encephalopathies,
QEEG can flag subtle EEG slowing that makes a
diagnosis of depression less likely.
On the other hand, QEEG has not lived up to
some of its promises. Overly enthusiastic statements
by some research scientists have resulted in confusion
by suggesting that there are clinical uses when
data are still lacking. A major problem in using
EEG to diagnose many specific illnesses is its relative
lack of specificity. EEGs tend to change in a very few
specific ways. EEGs can show epileptic spikes or
other specific brief wave patterns. EEGs can also
show excess slowing as a sign of pathology or
occasionally a focal loss of fast activity as a sign of a
localized problem. However, similar changes can
occur in a wide variety of disorders, so QEEG and
routine EEG suffer the disadvantage of a limited
repertoire.
QEEG and EEG brain mapping can process EEGs
in interesting ways. Some of these are certain to
result in new or novel uses of QEEG in the future.
Just as the microelectronics revolution continues to
foster many changes in medical care and daily life, so
too does it offer hope of many fascinating and
insightful advances in QEEG in the future.
—Marc R. Nuwer
See also–Electroencephalogram (EEG);
Electroencephalographic Spikes and Sharp
Waves; Electromyography (EMG);
Neuroimaging, Overview
Further Reading
American Psychiatric Association (1991). Quantitative electro-
encephalography: A report on the present state of computerized
EEG techniques. Am. J. Psychiatry 148, 961–964.
Duffy, F. H., Hughes, J. R., Miranda, F., et al. (1994). Status of
quantitative EEG (QEEG) in clinical practice, 1994. Clin.
Electroencephalogr. 25, vi–xxii.
Ebersole, J. S., and Wade, P. B. (1991). Spike voltage topography
identifies two types of frontotemporal epileptic foci. Neurology
41, 1425–1433.
Gotman, J. (1990). Automatic seizure detection: Improvements
and evaluation. Electroencephalogr. Clin. Neurophysiol. 76,
317–324.
Jordan, K. G. (1999). Continuous EEG monitoring in the intensive
care unit and emergency department. J. Clin. Neurophysiol. 16,
14–39.
Nuwer, M. R. (1997). Assessment of digital EEG, quantitative
EEG and EEG brain mapping: Report of the American
Academy of Neurology and American Clinical Neurophysiol-
ogy Society. Neurology 49, 277–292.
Nuwer, M. R. (1998). Assessing digital and quantitative EEG in
clinical settings. J. Clin. Neurophysiol. 15, 458–463.
Rodriguez, G., Nobili, F., Arrigo, A., et al. (1999). Prognostic
significance of quantitative electroencephalography in Alzhei-
mer patients. Electroencephalogr. Clin. Neurophysiol. 99,
123–128.
Vespa, P. M., Nenov, V., and Nuwer, M. R. (1999). Continuous
EEG monitoring in the intensive care unit: Early findings and
clinical efficacy. J. Clin. Neurophysiol. 16, 1–13.
Brainstem Auditory Evoked
Potentials (BAEPs)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAINSTEM auditory evoked potentials (BAEPs) are
the electrical signals produced by the nervous system
within the first 10 msec following a transient acoustic
stimulus. They are quite small (typically o1 mV in
amplitude) but are typically easily to record, highly
reproducible across subjects and in multiple record-
ings in the same subject, and only minimally affected
by surgical anesthesia. Therefore, they have been
widely used for neurodiagnostic testing, hearing
screening, intraoperative monitoring, and neurophy-
siological research.
RECORDING TECHNIQUES
BAEPs are usually recorded between the scalp at the
vertex and the earlobe or mastoid, and the vertex-
positive peaks are typically labeled with Roman
numerals according to the convention of Jewett and
Williston (Fig. 1A). Waves IV and V are often fused
into a IV–V complex of variable morphology. BAEPs
are usually assessed in a vertex-to-ipsilateral ear
recording channel, but additional recording channels
incorporating the contralateral ear recording elec-
trode may be useful in identifying components and
tend to separate overlapping waves IV and V (Fig. 1).
Most of the BAEP components are far-field poten-
tials, recorded at a large distance from their
intracranial generators and widely distributed over
the scalp. Wave I, however, is a near-field potential
around the stimulated ear, and it is thus absent in the
vertex-to-contralateral ear recording channel
(Fig. 1B).
BAEPs are typically elicited by brief transient
acoustic stimuli, such as clicks or tone pips, that are
delivered monaurally. A click is generated by passing
an electrical square pulse through the earphone or
other transducer. If the initial movement of the
460 BRAIN TRAUMA, CONTRECOUP
mesencephalic (Parinaud’s) syndrome (with rostral
tectal plate bleed), a vertical gaze palsy, skew
deviation, bilateral or unilateral Horner’s syndrome,
as well as bilateral trochlear nerve palsies.
Top of the Basilar Syndrome
Occlusive vascular disease of the rostral basilar artery,
usually embolic, frequently results in the top of the
basilar syndrome due to infarction of the midbrain,
thalamus, and portions of the temporal and occipital
lobes. This syndrome variably includes disorders of
eye movements, such as unilateral or bilateral
paralysis of upward or downward gaze, disordered
convergence, pseudoabducens palsy, convergence–
retraction nystagmus, ocular abduction abnormal-
ities, elevation and retraction of the upper eyelids
(Collier’s sign), skew deviation, and lightning-like eye
oscillations; pupillary abnormalities—small and re-
active, large or midposition and fixed, corectopia, and
occasionally oval pupils; behavioral abnormalities,
such as somnolence, peduncular hallucinosis, memory
difficulties, and agitated delirium; visual defects, such
as hemianopia, cortical blindness, and Balint’s syn-
drome; and motor and sensory deficits.
—Paul W. Brazis
See also–Locked-In Syndrome
Further Reading
Bassetti, C., Bogousslavsky, J., Barth, A., et al. (1996). Isolated
infarcts of the pons. Neurology 46, 165–175.
Bassetti, C., Bogousslavsky, J., Mattle, H., et al. (1997). Medial
medullary stroke: Report of seven patients and review of the
literature. Neurology 48, 882–890.
Bertholon, P., Michel, D., Convers, P., et al. (1996). Isolated body
lateropulsion caused by a lesion of the cerebellar peduncles. J.
Neurol. Neurosurg. Psychiatry 60, 356–357.
Brazis, P. W., Masdeu, J. C., and Biller, J. (1996). Localization in
Clinical Neurology, 3rd ed. Little, Brown, Boston.
Brochier, T., Ceccaldi, M., Milandre, L., et al. (1999). Dorsolateral
infarction of the lower medulla: Clinical–MRI study. Neurology
52, 190–193.
Kataoka, S., Hori, A., Shirakawa, T., et al. (1997). Paramedian
pontine infarction. Neurological/topographical correlation.
Stroke 28, 809–815.
Kim, J. S., and Choi-Kwon, S. (1999). Sensory sequelae of
medullary infarction. Differences between lateral and medial
medullary syndrome. Stroke 30, 2697–2703.
Kim, J. S., Kim, H. G., and Chung, C. S. (1995). Medial medullary
syndrome. Report of 18 patients and a review of the literature.
Stroke 26, 1548.
Kim, J. S., Lee, J. H., Im, J. H., et al. (1995). Syndromes of pontine
base infarction. A clinical–radiological correlation study. Stroke
26, 950.
Kim, J. S., Lee, J. H., and Lee, M. C. (1997). Patterns of sensory
dysfunction in lateral medullary infarction. Clinical–MRI
correlation. Neurology 49, 1557–1563.
Kim, J. S., Lee, J. H., and Choi, C. G. (1998). Patterns of lateral
medullary infarction. Vascular lesion–magnetic resonance
imaging correlation of 34 cases. Stroke 29, 645–652.
Tatu, L., Moulin, T., Bogoisslavsky, J., et al. (1996). Arterial
territories of human brain: Brainstem and cerebellum. Neurol-
ogy 47, 1125–1135.
Terao, S., Izumi, M., Takatsu, S., et al. (1998). Serial magnetic
resonance imaging shows separate medial and lateral medullary
infarctions resulting in the hemimedullary syndrome. J. Neurol.
Neurosurg. Psychiatry 65, 134–135.
Vaudens, P., and Bogousslavsky, J. (1998). Face–arm–trunk–leg
sensory loss limited to the contralateral side in lateral medullary
infarction: A new variant. J. Neurol. Neurosurg. Psychiatry 65,
255–257.
Vuilleumier, P., Bogousslavsky, J., and Regli, F. (1995). Infarction
of the lower brainstem. Clinical, aetiological, and MRI–
topographical correlation. Brain 118, 1013.
Brain Trauma, Contrecoup
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE WORD CONTRECOUP is French, meaning ‘‘coun-
ter blow,’’ and refers to a traumatic brain injury
contralateral to the site of impact. These injuries
result when the force of an impact moves the
intracranial contents away from the blow. The
intracranial contents (e.g., brain) are then stopped
by the skull opposite the site of the impact.
Contrecoup injuries often occur at the floors of the
frontal and temporal fossae, which have many bony
protuberances. The resulting traumatic injury can
include contusions and subarachnoid hemorrhage.
Surgical evacuation of hematomas may be required if
significant mass effect or increased intracranial
pressure result.
—Wendy Elder and Robert F. Spetzler
See also–Brain Injury, Traumatic:
Epidemiological Issues; Brain Trauma, Overview;
Head Trauma, Overview
Brain Trauma, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN INJURY is the major cause of death and
disability among trauma patients worldwide. Trau-
matic brain injury particularly affects younger
patients and imposes an enormous socioeconomic
460 BRAIN TRAUMA, CONTRECOUP
mesencephalic (Parinaud’s) syndrome (with rostral
tectal plate bleed), a vertical gaze palsy, skew
deviation, bilateral or unilateral Horner’s syndrome,
as well as bilateral trochlear nerve palsies.
Top of the Basilar Syndrome
Occlusive vascular disease of the rostral basilar artery,
usually embolic, frequently results in the top of the
basilar syndrome due to infarction of the midbrain,
thalamus, and portions of the temporal and occipital
lobes. This syndrome variably includes disorders of
eye movements, such as unilateral or bilateral
paralysis of upward or downward gaze, disordered
convergence, pseudoabducens palsy, convergence–
retraction nystagmus, ocular abduction abnormal-
ities, elevation and retraction of the upper eyelids
(Collier’s sign), skew deviation, and lightning-like eye
oscillations; pupillary abnormalities—small and re-
active, large or midposition and fixed, corectopia, and
occasionally oval pupils; behavioral abnormalities,
such as somnolence, peduncular hallucinosis, memory
difficulties, and agitated delirium; visual defects, such
as hemianopia, cortical blindness, and Balint’s syn-
drome; and motor and sensory deficits.
—Paul W. Brazis
See also–Locked-In Syndrome
Further Reading
Bassetti, C., Bogousslavsky, J., Barth, A., et al. (1996). Isolated
infarcts of the pons. Neurology 46, 165–175.
Bassetti, C., Bogousslavsky, J., Mattle, H., et al. (1997). Medial
medullary stroke: Report of seven patients and review of the
literature. Neurology 48, 882–890.
Bertholon, P., Michel, D., Convers, P., et al. (1996). Isolated body
lateropulsion caused by a lesion of the cerebellar peduncles. J.
Neurol. Neurosurg. Psychiatry 60, 356–357.
Brazis, P. W., Masdeu, J. C., and Biller, J. (1996). Localization in
Clinical Neurology, 3rd ed. Little, Brown, Boston.
Brochier, T., Ceccaldi, M., Milandre, L., et al. (1999). Dorsolateral
infarction of the lower medulla: Clinical–MRI study. Neurology
52, 190–193.
Kataoka, S., Hori, A., Shirakawa, T., et al. (1997). Paramedian
pontine infarction. Neurological/topographical correlation.
Stroke 28, 809–815.
Kim, J. S., and Choi-Kwon, S. (1999). Sensory sequelae of
medullary infarction. Differences between lateral and medial
medullary syndrome. Stroke 30, 2697–2703.
Kim, J. S., Kim, H. G., and Chung, C. S. (1995). Medial medullary
syndrome. Report of 18 patients and a review of the literature.
Stroke 26, 1548.
Kim, J. S., Lee, J. H., Im, J. H., et al. (1995). Syndromes of pontine
base infarction. A clinical–radiological correlation study. Stroke
26, 950.
Kim, J. S., Lee, J. H., and Lee, M. C. (1997). Patterns of sensory
dysfunction in lateral medullary infarction. Clinical–MRI
correlation. Neurology 49, 1557–1563.
Kim, J. S., Lee, J. H., and Choi, C. G. (1998). Patterns of lateral
medullary infarction. Vascular lesion–magnetic resonance
imaging correlation of 34 cases. Stroke 29, 645–652.
Tatu, L., Moulin, T., Bogoisslavsky, J., et al. (1996). Arterial
territories of human brain: Brainstem and cerebellum. Neurol-
ogy 47, 1125–1135.
Terao, S., Izumi, M., Takatsu, S., et al. (1998). Serial magnetic
resonance imaging shows separate medial and lateral medullary
infarctions resulting in the hemimedullary syndrome. J. Neurol.
Neurosurg. Psychiatry 65, 134–135.
Vaudens, P., and Bogousslavsky, J. (1998). Face–arm–trunk–leg
sensory loss limited to the contralateral side in lateral medullary
infarction: A new variant. J. Neurol. Neurosurg. Psychiatry 65,
255–257.
Vuilleumier, P., Bogousslavsky, J., and Regli, F. (1995). Infarction
of the lower brainstem. Clinical, aetiological, and MRI–
topographical correlation. Brain 118, 1013.
Brain Trauma, Contrecoup
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE WORD CONTRECOUP is French, meaning ‘‘coun-
ter blow,’’ and refers to a traumatic brain injury
contralateral to the site of impact. These injuries
result when the force of an impact moves the
intracranial contents away from the blow. The
intracranial contents (e.g., brain) are then stopped
by the skull opposite the site of the impact.
Contrecoup injuries often occur at the floors of the
frontal and temporal fossae, which have many bony
protuberances. The resulting traumatic injury can
include contusions and subarachnoid hemorrhage.
Surgical evacuation of hematomas may be required if
significant mass effect or increased intracranial
pressure result.
—Wendy Elder and Robert F. Spetzler
See also–Brain Injury, Traumatic:
Epidemiological Issues; Brain Trauma, Overview;
Head Trauma, Overview
Brain Trauma, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN INJURY is the major cause of death and
disability among trauma patients worldwide. Trau-
matic brain injury particularly affects younger
patients and imposes an enormous socioeconomic

burden. Based on estimates from the Centers for
Disease Control National Center for Injury Preven-
tion, 1.5 million people sustain a traumatic head
injury each year in the United States alone, with
nearly 300,000 people requiring hospitalization. In
the United States, more than 50,000 people die and
more than 80,000 people are left permanently
disabled each year as a result of severe head injury.
The cumulative burden of traumatic brain injury is
also high, with an estimated 5.3 million people in the
United States having a disability related to brain
trauma, accounting for more than 30 million days of
work lost annually at an estimated cost of $38 billion
per year.
Epidemiologically, motor vehicle and violence-
related injuries are the most common causes of brain
trauma-related death and disability among adoles-
cents and young adults. Men are twice as likely to
suffer a traumatic brain injury compared to women.
Falls are the leading cause of traumatic brain injury
in people older than 65 years.
Traumatic brain injury is graded as mild, moder-
ate, or severe based on the level of consciousness and
the Glasgow Coma Scale (GCS) after initial resusci-
tation from the head injury. Patients with severe head
injury, defined as a GCS of 3–8, are at significant risk
from the initial injury as well as for the development
of brain swelling and ischemia, which result in
secondary brain injury. Importantly, neurological
outcomes have improved with early prehospital
resuscitation and aggressive management of in-
creased intracranial pressure and cerebral perfusion
pressure during acute hospitalization.
PATHOPHYSIOLOGY
Primary Brain Injury
The mechanism of injury after head trauma results
from both the primary insult directly from the
trauma and secondary insults from the development
of brain swelling, increased intracranial pressure,
and subsequent cerebral ischemia. Primary brain
injury can cause focal and diffuse abnormalities.
Blunt head trauma causes a concussive injury in
which rotational shear forces from abrupt accelera-
tion or deceleration lead to the disruption of axons
and myelin sheaths resulting in diffuse axonal injury.
Diffuse axonal injury causes predominantly cortical
disruption, but it may also affect subcortical struc-
tures. The shear forces are maximal at the brain
surface and near bony or dural protrusions. Focal
BRAIN TRAUMA, OVERVIEW 461
cerebral contusions and lacerations can also occur
under areas of extreme impact or from penetrating
injuries due to stab, puncture, and missile wounds.
Acute vascular injury can lead to extracranial or
intracranial hematoma formation or ischemic stroke.
Identification of primary injury is essential to early
therapeutic and neurosurgical intervention after head
trauma (Table 1).
Secondary Brain Injury
Secondary brain injury accounts for the majority of
deaths after hospitalization for traumatic brain
injury. Severe head injury usually produces vasogenic
edema causing brain swelling within hours of injury.
The resultant increase in intracranial pressure (ICP)
and subsequent decrease in cerebral perfusion
pressure (CPP) can lead to ischemia. Cerebral
perfusion pressure is equal to the inflow pressure,
or mean systemic arterial blood pressure (MAP),
minus the outflow pressure, or ICP (CPP ¼ MAP

ICP), and is inversely proportional to cerebrovascu-
lar resistance. In the early hours after traumatic brain
injury, there is a global decrease in cerebral blood
flow (CBF). CBF is further compromised by the loss
of autoregulation after severe head injury. With the
loss of autoregulation, cerebrovascular resistance can
no longer adjust and CBF becomes entirely depen-
dent on CPP. Poor outcomes are associated with CPP
less than 60 mmHg, and the presence of either early
or late hypotension significantly worsens outcome,
presumably from exacerbating secondary ischemic
brain injury.
The injured brain is particularly vulnerable to
ischemia. The changes in cellular homeostasis and
metabolism after traumatic brain injury may explain
this vulnerability to secondary insults. The initial
Table 1 MECHANISMS OF BRAIN INJURY IN SEVERE
HEAD TRAUMA
Primary
Intracranial hematoma
Subdural, epidural, intraparenchymal, subarachnoid
Contusion
Laceration
Vascular injury
Diffuse axonal injury
Secondary
Ischemia
Cerebral edema
Elevated intracranial pressure
Seizure
462 BRAIN TRAUMA, OVERVIEW
mechanical injury triggers a cascade of cellular
injury that begins with abnormal depolarization
and release of neurotransmitters leading to activation
of excitotoxicity via glutamate and N-methyl-d-
aspartate receptors and release of intracellular
calcium. In addition, oxygen radicals, lipid perox-
idation, and inflammatory mediators are also acti-
vated. Apoptotic cell death may also occur. Many of
these cellular mechanisms have been targeted in
neuroprotection strategies. Unfortunately, none of
these strategies has yet proven effective in human
clinical trials.
MANAGEMENT PRINCIPLES
Prehospital Guidelines
Studies have demonstrated that establishing emer-
gency medical systems and designated trauma centers
improves outcome after traumatic brain injury,
particularly when the system provides 24-hr brain
imaging [usually with computed tomography (CT)],
neurosurgical care, and the ability to monitor and
manage ICP. The prehospital phase is critical to
outcome after severe head injury and new guidelines
for prehospital treatment of head trauma have been
established by the Brain Trauma Foundation. The
fundamental initial treatment of patients with severe
head injury involves resuscitation of blood pressure,
establishment of adequate ventilation and oxygena-
tion, and transport to a trauma center with resources
to manage traumatic brain injury.
Early endotracheal intubation of patients with
isolated severe brain injury decreases the risk of
death. With the establishment of a secure airway, the
goal is to maintain oxygen saturation above 90%
and normal ventilation (often a respiratory rate of 10
breaths per minute). Transient hyperventilation
(respiratory rate of 20 breaths per minute) during
transport to the hospital is advocated if there are
clinical signs of cerebral herniation, such as fixed,
dilated pupils or extensor posturing. Prophylactic
hyperventilation in the absence of signs of cerebral
herniation may actually worsen outcome, presum-
ably by exacerbating secondary ischemic injury
through a reduction in CBF.
Hypotension, defined as systolic blood pressure
less than 90 mmHg, is a significant predictor of
poor outcome in the prehospital period. Early
aggressive hemodynamic support is advocated in
the prevention and treatment of hypotension asso-
ciated with traumatic brain injury. Intravascular fluid
resuscitation is the first line of therapy since the
major cause of hypotension in trauma patients is
hemorrhage. Standard fluid resuscitation with Ring-
er’s lactate or normal saline is acceptable; however,
some studies have shown benefit with the use of
hypertonic saline in severe head injury. In cases in
which head injury is accompanied by penetrating
truncal trauma, there is controversy regarding the
benefit of aggressive resuscitation since fluid resusci-
tation in severe truncal injury has been shown to
worsen outcome.
Hospital Guidelines
Guidelines for the management of traumatic brain
injury have been established in Europe and the
United States. Management strategies address both
primary and secondary mechanisms of injury. Once
the patient has been stabilized with adequate blood
pressure, oxygenation, and ventilation, CT of the
head should be obtained so that lesions requiring
neurosurgical evacuation can be identified. Early
evacuation of subdural and epidural hematomas
that are causing significant mass effect improves
outcomes. In addition, removal of intraparenchy-
mal hematomas may be necessary in cases with
radiographic and clinical evidence of cerebral
herniation.
Elevated ICP, defined as greater than 20 mmHg, is
associated with poor outcome after severe traumatic
brain injury. Current recommendations advocate ICP
monitoring in all patients with severe injury (GCS
3–8) who have radiographic abnormalities on head
CT or the presence of any of the following risk
factors: age 440 years, hypotension, or unilateral or
bilateral posturing. Although no definitive rando-
mized trial has compared outcomes with the use of
ICP monitors, direct measurement of ICP is a
fundamental aspect of the critical care management
of the head trauma patient and knowledge of the ICP
is necessary to ensure that an appropriate CPP is
being maintained. Ventricular catheters are preferred
over parenchymal monitors, if possible, because of
the ability to drain cerebrospinal fluid as a treatment
for elevated ICP.
In the prevention of secondary brain injury after
hospitalization, aggressive treatment of increased
ICP and maintenance of CPP is recommended. There
is evidence that mortality decreases if a CPP of 70
mmHg is maintained with normal blood volume and
vasopressors; however, there may be no added
benefit from higher CPP levels. Also, mortality
benefit is seen with lowering of ICP to less than
 BRAIN TRAUMA, OVERVIEW 463

20 mmHg. In cases in which ICP remains elevated

despite ventricular drainage, mannitol can be used to
decrease ICP. Mannitol should be administered as a
0.25- to 1.0-g/kg bolus intravenously. Intermittent
boluses are effective to a serum osmolarity of 320
mmol/liter, but hypotension from osmotic diuresis
should be avoided. Likewise, hyperventilation is very
effective in lowering ICP. Hyperventilation to de-
crease arterial CO2 to 30 mmHg causes cerebral
vasoconstriction and decreased cerebral blood vo-
lume and thereby lowers ICP. Because prolonged
prophylactic hyperventilation has been demonstrated
to worsen outcome, hyperventilation is best reserved
for use as a transient therapy until a more definitive
intervention, such as cerebrospinal fluid drainage or
mass lesion evacuation, can be implemented. Other
medical therapies for refractory elevations in ICP
include sedation, neuromuscular blockade, and
barbiturate coma. Glucocorticoids do not improve
outcome after traumatic brain injury and should not
be administered for this indication.
When persistent elevation in ICP is refractory to
first-line medical treatments, barbiturates can be
initiated to lower ICP by decreasing the cerebral Figure 1
metabolic activity. However, systemic cardiovascular Axial noncontrast head CT scan of a 45-year-old man who
complications need to be addressed to avoid com- suffered a closed head injury after a motor vehicle accident. He
promise of CPP. Induced hypothermia was recently underwent emergent drainage of a right subdural hematoma,
studied in acute brain injury. Although there was no followed by hemicraniectomy for severe brain swelling. A brain
tissue oxygen monitor (arrow) was placed in the left cerebral white
significant effect on overall outcome, hypothermia matter adjacent to a parenchymal ICP monitor (tip not shown).
may still have a role in selected patient populations.
Other second-line therapies include aggressive hy-
perventilation to an arterial CO2 less than 30 mmHg
FUTURE DIRECTIONS
and hemicraniectomy. None of these interventions
have been definitively demonstrated to improve The most important recent advance in traumatic
outcome, but they do offer additional treatment brain injury is the development of standardized
options for salvageable patients with refractory evidence-based guidelines for the prehospital and
intracranial hypertension (Fig. 1). in-hospital management of patients with head
Additional intensive care unit (ICU) management trauma. Increased adoption of these guidelines has
issues include early extubation when appropriate, the potential to significantly improve head injury
adequate early nutritional support, prevention of care worldwide. These guidelines also form a frame-
hyperglycemia, treatment of fever, and infection work whereby future advances can be integrated into
control. Seizure prophylaxis, usually with phenytoin, the care of the head-injured patient. Additionally,
is indicated for the first 7 days after severe traumatic advances in the understanding of the pathophysiol-
brain injury and may help to prevent increased ICP ogy of primary and secondary brain injury have led
and elevated cerebral metabolic rate associated with to the development of new monitoring tools for early
seizures. However, prophylactic use of anticonvul- detection of brain ischemia. Tools such as jugular
sants is not recommended for the prevention of late venous oxygen catheters, parenchymal brain tissue
seizures or neurological disability. Early institution of oxygen monitors, and cerebral microdialysis may
rehabilitation services, even passive range of motion allow critical care management to be individualized
in comatose patients, should be considered in the based on the presence of markers of secondary brain
ICU setting for patients who can tolerate these injury in specific patients. It is hoped that integration
interventions. of these new ICU monitoring approaches with
464 BRAIN TUMORS, BIOLOGY
existing treatment guidelines, perhaps with the
addition of pharmacological interventions for cellu-
lar mechanisms of brain injury, will lead to continued
improvements in the treatment of traumatic brain
injury.
—Nerissa U. Ko and J. Claude Hemphill, III
See also–Brain Injury, Traumatic; Brain Trauma,
Contrecoup; Intracranial Pressure; Intracranial
Pressure Monitoring
Further Reading
Baxt, W. G., and Moody, P. (1987). The impact of advanced
prehospital emergency care on the mortality of severely brain-
injured patients. J. Trauma 27, 365–369.
Brain Trauma Foundation, American Association of Neurological
Surgeons, Joint Section on Neurotrauma and Critical Care
(1996). Guidelines for the management of severe head injury.
J. Neurotrauma 13, 641–734.
Bullock, M. R., Lyeth, B. G., and Muizelaar, J. P. (1999). Current
status of neuroprotection trials for traumatic brain injury:
Lessons from animal models and clinical studies. Neurosurgery
45, 207–217.
Chesnut, R. M., Marshall, S. B., Piek, J., et al. (1993). Early and
late systemic hypotension as a frequent and fundamental source
of cerebral ischemia following severe brain injury in the
Traumatic Coma Data Bank. Acta Neurochir. Suppl. 59, 121–
125.
Chesnut, R. M., Carney, N., Maynard, H., et al. (1999). Summary
report: Evidence for the effectiveness of rehabilitation for
persons with traumatic brain injury. J. Head Trauma Rehab. 14,
176–188.
Clifton, G. L., Miller, E. R., Choi, S. C., et al. (2001). Lack of
effect of induction of hypothermia after acute brain injury. N.
Engl. J. Med. 344, 556–563.
Muizelaar, J. P., Marmarou, A., Ward, J. D., et al. (1991). Adverse
effects of prolonged hyperventilation in patients with severe
head injury: A randomized clinical trial. J. Neurosurg. 75,
731–739.
Brain Tumors, Biology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MULTIPLE TYPES of tumors that occur in the
central nervous system (CNS) are distinguished by
their histological criteria and named by their
similarities to cell types that are normally found in
the brain and spinal cord. Substantial effort has been
invested recently into documenting genetic altera-
tions found in these tumors, primarily in gliomas,
and inferring their role in tumorigenesis. Analysis of
these tumors demonstrates many mutations and
alterations in gene expression. However, determin-
ing which of these are causally related to tumor
formation and which are epiphenomena of the
tumor progression process requires genetic modeling
of tumorigenesis in animals. These experiments have
demonstrated that a subset of these alterations are
capable of inducing tumors with very similar
characteristics as those found in humans. Many of
these mutations that are casually related to tumor
formation are in genes encoding proteins that
control the differentiation process of the cell type
from which the tumor arises. Therefore, CNS tumor
etiology may be viewed as dysregulation of commu-
nication pathways that normally occur between cells
in the control of development and cell proliferation.
The two CNS tumor types that have been most
extensively analyzed are gliomas and medulloblas-
tomas.
GLIOMAS
The development of differentiated astrocytes or
oligodendrocytes from CNS stem cells is regulated
by a number of growth factors and their receptors.
Platelet-derived growth factor (PDGF), for example,
causes proliferation of the oligodendroglial progeni-
tor population and cooperates with basic fibroblast
growth factor (bFGF) in preventing further differ-
entiation into mature oligodendrocytes. In contrast,
the epidermal growth factor (EGF) forces glial
progenitors toward astrocytic differentiation. Upon
binding of their respective ligands, these growth
factor receptors activate a number of signaling
pathways, including those involving Ras and Akt.
The net effect of these pathways enhances cell
proliferation, progression of the cell through the cell
cycle, and inhibition of apoptosis.
Analysis of glioblastoma samples demonstrates
that mutations and gene expression alterations occur
frequently. These alterations can be classified into
two functional categories, those that activate signal
transduction pathways and those that disrupt the cell
cycle arrest machinery. Activation of signaling path-
ways is achieved by alterations leading to over-
expression of many of the growth factors that
control glial cell differentiation, such as PDGF or
EGF and their receptors, and by loss of the tumor
suppressor PTEN, resulting in further activation of
the Akt pathway downstream of these receptors.
Disruption of the cell cycle arrest in malignant
gliomas is usually achieved by either loss of INK4a-
ARF, which encodes p16INK4a and p14ARF, or
464 BRAIN TUMORS, BIOLOGY
existing treatment guidelines, perhaps with the
addition of pharmacological interventions for cellu-
lar mechanisms of brain injury, will lead to continued
improvements in the treatment of traumatic brain
injury.
—Nerissa U. Ko and J. Claude Hemphill, III
See also–Brain Injury, Traumatic; Brain Trauma,
Contrecoup; Intracranial Pressure; Intracranial
Pressure Monitoring
Further Reading
Baxt, W. G., and Moody, P. (1987). The impact of advanced
prehospital emergency care on the mortality of severely brain-
injured patients. J. Trauma 27, 365–369.
Brain Trauma Foundation, American Association of Neurological
Surgeons, Joint Section on Neurotrauma and Critical Care
(1996). Guidelines for the management of severe head injury.
J. Neurotrauma 13, 641–734.
Bullock, M. R., Lyeth, B. G., and Muizelaar, J. P. (1999). Current
status of neuroprotection trials for traumatic brain injury:
Lessons from animal models and clinical studies. Neurosurgery
45, 207–217.
Chesnut, R. M., Marshall, S. B., Piek, J., et al. (1993). Early and
late systemic hypotension as a frequent and fundamental source
of cerebral ischemia following severe brain injury in the
Traumatic Coma Data Bank. Acta Neurochir. Suppl. 59, 121–
125.
Chesnut, R. M., Carney, N., Maynard, H., et al. (1999). Summary
report: Evidence for the effectiveness of rehabilitation for
persons with traumatic brain injury. J. Head Trauma Rehab. 14,
176–188.
Clifton, G. L., Miller, E. R., Choi, S. C., et al. (2001). Lack of
effect of induction of hypothermia after acute brain injury. N.
Engl. J. Med. 344, 556–563.
Muizelaar, J. P., Marmarou, A., Ward, J. D., et al. (1991). Adverse
effects of prolonged hyperventilation in patients with severe
head injury: A randomized clinical trial. J. Neurosurg. 75,
731–739.
Brain Tumors, Biology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MULTIPLE TYPES of tumors that occur in the
central nervous system (CNS) are distinguished by
their histological criteria and named by their
similarities to cell types that are normally found in
the brain and spinal cord. Substantial effort has been
invested recently into documenting genetic altera-
tions found in these tumors, primarily in gliomas,
and inferring their role in tumorigenesis. Analysis of
these tumors demonstrates many mutations and
alterations in gene expression. However, determin-
ing which of these are causally related to tumor
formation and which are epiphenomena of the
tumor progression process requires genetic modeling
of tumorigenesis in animals. These experiments have
demonstrated that a subset of these alterations are
capable of inducing tumors with very similar
characteristics as those found in humans. Many of
these mutations that are casually related to tumor
formation are in genes encoding proteins that
control the differentiation process of the cell type
from which the tumor arises. Therefore, CNS tumor
etiology may be viewed as dysregulation of commu-
nication pathways that normally occur between cells
in the control of development and cell proliferation.
The two CNS tumor types that have been most
extensively analyzed are gliomas and medulloblas-
tomas.
GLIOMAS
The development of differentiated astrocytes or
oligodendrocytes from CNS stem cells is regulated
by a number of growth factors and their receptors.
Platelet-derived growth factor (PDGF), for example,
causes proliferation of the oligodendroglial progeni-
tor population and cooperates with basic fibroblast
growth factor (bFGF) in preventing further differ-
entiation into mature oligodendrocytes. In contrast,
the epidermal growth factor (EGF) forces glial
progenitors toward astrocytic differentiation. Upon
binding of their respective ligands, these growth
factor receptors activate a number of signaling
pathways, including those involving Ras and Akt.
The net effect of these pathways enhances cell
proliferation, progression of the cell through the cell
cycle, and inhibition of apoptosis.
Analysis of glioblastoma samples demonstrates
that mutations and gene expression alterations occur
frequently. These alterations can be classified into
two functional categories, those that activate signal
transduction pathways and those that disrupt the cell
cycle arrest machinery. Activation of signaling path-
ways is achieved by alterations leading to over-
expression of many of the growth factors that
control glial cell differentiation, such as PDGF or
EGF and their receptors, and by loss of the tumor
suppressor PTEN, resulting in further activation of
the Akt pathway downstream of these receptors.
Disruption of the cell cycle arrest in malignant
gliomas is usually achieved by either loss of INK4a-
ARF, which encodes p16INK4a and p14ARF, or

mutations in p53 associated with either CDK4
overexpression or Rb loss. These pathways control
cell cycle arrest in G1 and G2 and promote
apoptosis, and p53 helps to maintain genomic
integrity.
Demonstration that these alterations are actually
causally related to glioma formation is provided by
experiments modeling gliomagenesis in mice. Exam-
ples include the expression of viral oncogenes that
activate combinations of signal transduction path-
ways, such as v-src driven as a transgene from the
glial fibrillary acetic protein (GFAP) promoter and
inducing astrocytomas. In addition, viral transfer of
PDGF gene expression to mixed cell types in vivo
induces a number of glioma types, including glio-
blastoma multiforme (GBM). PDGF gene transfer
specifically to glial progenitors leads to the formation
of oligodendrogliomas.
Cooperative effects between signaling pathways in
tumorigenesis have also been demonstrated by
combined viral gene transfer of activated forms of
Akt and Ras to glial progenitor cells, resulting in
the formation of GBMs. However, in this cell
type neither Ras nor Akt alone is sufficient for
gliomagenesis. In these experiments, the combina-
tion of Ras and Akt induces GBMs from nestin-
expressing progenitor cells but not from GFAP-
expressing astrocytes, implying that undifferentiated
cells are more sensitive to the oncogenic effects of
these signaling pathways. Another example of
cooperation between signal transduction and cell
cycle arrest pathways is the combined loss of the
tumor suppressors NF-1 and p53 leading to the
formation of gliomas. Mice with a p53
/
, NF-1
/

genetic background develop frequent high-grade
gliomas, whereas mice with either deletion alone
do not.
MEDULLOBLASTOMAS
The molecular machinery underlying the formation
of medulloblastomas is less well understood than
that for gliomas; however, the pathways leading to
these tumors are beginning to be identified. These
primitive neuroectodermal tumors are believed to
originate from external granular cells prior to their
migration through the molecular layer during cere-
bellar development, and eventual they residence in
the internal granular layer. The proliferation of these
cells and their differentiation into mature granular
neurons are controlled by Sonic Hedgehog (SHH)
binding to its receptor, Patched (PTCH). Mechan-
BRAIN TUMORS, BIOLOGY 465
istically, PTCH exerts a tonic inhibitory effect on the
signaling pathway that is released by the binding of
SHH. Therefore, PTCH acts as a tumor suppressor,
and loss of PTCH expression has an oncogenic
effect. Humans with inactivating germline muta-
tions in PTCH (Gorlin’s syndrome) develop a
number of tumor types including medulloblastomas.
Furthermore, inactivating mutations in PTCH
have been demonstrated in some sporadic medullo-
blastomas.
Consistent with the previously mentioned findings
in humans, mice heterozygous for targeted deletions
of PTCH develop several tumor types, including a
modest amount of medulloblastomas. Homozygous
deletion of PTCH is embryonically lethal due in part
to cardiac abnormalities. Interestingly, the medullo-
blastomas arising in PTCH þ /
mice do not show
loss of the remaining wild-type PTCH allele, and
there is still some detectable expression of PTCH,
indicating a potential effect of haploinsufficiency or
signaling dosage through this pathway. There are no
other known signaling pathways that contribute to
the formation of these tumors.
Far less molecular detail is known about other
tumors that arise within the CNS. Part of the
difficulty is the inability to obtain sufficient tissue
for analysis and an adequate number of tumor
samples to identify potential candidate causal path-
ways. Once such candidate pathways and mutations
are identified, they will need to be tested in animal
models to demonstrate what role, if any, they play in
the formation of these tumors.
—Eric C. Holland
See also–Brain Tumors, Clinical Manifestations
and Treatment; Brain Tumors, Genetics; Central
Nervous System Tumors, Epidemiology;
Childhood Brain Tumors; Glial Tumors;
Metastases, Brain; Nerve Sheath Tumors;
Pituitary Tumors; Primary Central Nervous
System Lymphoma and Germ Cell Tumors; Spinal
Cord Tumors, Biology of
Further Reading
Goodrich, L. V., Milenkovic, L., Higgins, K. M., et al. (1997).
Altered neural cell fates and medulloblastoma in mouse patched
mutants. Science 277, 1109–1113.
Holland, E. C. (2001). Gliomagenesis: Genetic alterations and
mouse models. Nature Rev. Genet. 2, 120–129.
Kleihues, P., and Cavenee, W. (2000). Pathology and Genetics of
Tumors of the Nervous System. IARC, Lyon, France.
Rajan, P., and McKay, R. D. (1998). Multiple routes to astrocytic
differentiation in the CNS. J. Neurosci. 18, 3620–3629.
466 BRAIN TUMORS, CLINICAL MANIFESTATIONS AND TREATMENT
Brain Tumors, Clinical
Manifestations and Treatment
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE OVERALL INCIDENCE of primary brain tumors in
the United States is 13.8 per 100,000. Glioblastoma
multiforme is the most frequently reported histology
(29.6%) in the National Cancer Data Base. This
entry focuses on the clinical manifestations and
surgical management of the most common brain
tumors (i.e., supratentorial glial tumors in adults).
SIGNS AND SYMPTOMS
Signs and symptoms related to brain tumors are
either general symptoms associated with increased
intracranial pressure (ICP) or focal symptoms related
to the location of the tumor. It is important to obtain
a history, a physical examination, and a thorough
neurological examination preoperatively to obtain
relevant details and information about the patient’s
general medical condition. Due to better health care
systems and advanced diagnostic technology, pa-
tients are now diagnosed at an earlier stage of the
disease.
The general group of symptoms are headache,
nausea, vomiting, personality changes, and altered
psychomotor function. Headaches are not always
present and may vary in severity and quality; they
often occur in the early morning hours and some
patients complain of an uncomfortable feeling rather
than of a headache. Nausea and, occasionally,
vomiting may occur in all patients but are most
common in children and in patients with infratentor-
ial tumors. Personality changes and alterations in
mental capacity and concentration may be the only
signs observed and can easily be confused with
psychological problems.
Seizures are a presenting symptom in approxi-
mately 20% of patients with supratentorial brain
tumors, and the association increases with increasing
patient age. Relatively slow-growing tumors (e.g.,
astrocytomas, gangliogliomas, and oligodendroglio-
mas) may manifest with a history of generalized
seizures. Rapidly growing lesions are likely to
produce complex partial motor or sensory seizures,
although grand mal seizures are also common.
The location most often involved in the cerebrum
is the frontal lobe, followed by the parietal,
temporal, and occipital lobes. Frontal lobe tumors
may be asymptomatic or may produce mild slowing
of contralateral hand movements, contralateral
spastic hemiplegia, mood changes, loss of initiative,
and aphasia if the dominant lobe is involved. In
patients with bifrontal involvement, bilateral hemi-
paresis, severe impairment of intellect, and dementia
may be observed. Parietal lobe tumors may become
symptomatic with hemianesthesia or other hemisen-
sory abnormalities as well as with hemiparesis and
homonymous hemianopsia. Dominant parietal lobe
lesions can cause alexia or dysgraphia. Nondominant
parietal lobe tumors may manifest with anosognosia
or apraxia. The most common presenting symptom
of patients with temporal lobe tumors is seizures.
One-half to two-thirds of patients with low-grade
gliomas become symptomatic with seizures. Ap-
proximately 50% of patients have headaches. In
larger series and community-based studies, the
presence of a brain tumor was detected in 8–30%
of patients who presented with partial seizures. The
risk of epilepsy being caused by a tumor increases
with age. Together with gangliogliomas, low-grade
astrocytomas and oligodendrogliomas constitute the
gliomas that are most commonly associated with
intractable epilepsy. This fact is attributed to the
characteristics of the tumors’ growth pattern: A
higher incidence of seizures is associated with
relatively slow-growing tumors.
Focal neurological deficits caused by direct tumor
infiltration or local pressure depend on the extension
of the lesion. Depending on the location of the lesion,
disinhibition, irritability, apathy, motor and sensory
loss, aphasia, anosognosia, impairment of recent
memory, auditory hallucinations, quadrantanopsia,
homonymous hemianopsia, or, in cases with bilateral
involvement, cortical blindness may be present.
SURGICAL TREATMENT
Surgical resection or biopsy is the initial therapeutic
modality in the management of patients with brain
tumors. Diagnostic biopsy is most often accom-
plished by a closed stereotactic procedure performed
with local anesthesia. By using image-guided stereo-
tactic biopsy techniques, optimal acquisition of
diagnostic tissue material can be obtained with a
low rate of morbidity and mortality. In series from
Toronto, Bernstein and colleagues found that stereo-
tactic brain biopsies are associated with a 6% overall
complication rate, a 2% mortality rate, an 8%
risk of failed biopsy due to inadequate material
 BRAIN TUMORS, CLINICAL MANIFESTATIONS AND TREATMENT
for diagnosis, and a high rate of clinically silent
hemorrhage postoperatively.
In addition to potentially removing the tumor and
providing a tissue diagnosis to guide further therapy,
resection permits management of increased ICP and
decompression of adjacent brain structures. Con-
temporary neurosurgical methods, including ultra-
sonography, functional mapping, frameless
navigational resection devices, and intraoperative
imaging techniques, enable neurosurgeons to achieve
more extensive resections with less morbidity.
Intraoperative ultrasonography provides real-time
intraoperative data and is helpful in detecting the
tumor, delineating its margins, and differentiating
tumor from peritumoral edema, cyst, necrosis, and
adjacent normal brain. Although its use is limited by
artifact from blood and surgical trauma at the
margin of resection, postresection tumor volumes
based on intraoperative ultrasound are significantly
correlated with those determined by postoperative
magnetic resonance imaging (MRI). Stimulation
mapping techniques are essential to minimize com-
plications and to achieve radical resections of tumors
located in or around functionally eloquent cortical
and subcortical sites. Frameless navigation systems
are very helpful in planning incisions and bone
flaps as well as in guiding the initial phases of
resection. Shifting of the brain will necessarily
limit the utility of these methods when resecting
gliomas because localization is based on images.
However, stealth images correlated with real-time
sononavigation data may allow surgeons to account
for the shift.
Brain shifting is not a factor when intraoperative
imaging techniques are used. Unlike frameless and
frame-based systems, which are limited by their
reliance on preoperative imaging, both intraopera-
tive computed tomography and MRI provide in-
traoperative updates of data sets for navigational
systems. Intraoperative reregistration of target anat-
omy eliminates the problem of brain shift caused by
resection or brain retractors and allows surgeons to
control more precisely resection and to modify the
planned surgical approach if necessary. Use of
intraoperative MRI requires MR-compatible instru-
ments (i.e., titanium or ceramic) to minimize artifact.
Surgical instruments can be tracked with the use of
light-emitting diode sensors to provide image gui-
dance during movements and interactive feedback on
corresponding images.
The operative position depends on the exposure
needed. Patients are positioned appropriately for the
467
operation, with limbs partially flexed and all pressure
points padded. The incision and underlying bone flap
should be generous to permit a radical tumor
resection, swelling during the procedure, and func-
tional mapping if necessary. When a previous
incision is present, care must be taken to extend the
scalp opening by making incisions perpendicular to
the scar lines to create a wide base for each new
portion of the scalp flap. The tumor may be localized
with intraoperative ultrasonography or surgical
navigation systems. Because the dura is pain sensi-
tive, the area around the middle meningeal artery
should be infiltrated with a lidocaine–marcaine
mixture to alleviate the patient’s discomfort while
awake.
For patients with an intractable seizure disorder,
preresection electrocorticography is often performed.
Strip electrodes are used to record from mesiobasal
structures. In addition, recording along the hippo-
campus is obtained in appropriate patients after
removal of the lateral temporal cortex and entry into
the temporal horn of the lateral ventricle. Strip
electrodes may also be used for the orbitofrontal
cortex or under the bone flap if the cortical exposure
is inadequate. The preresection recording requires
5–15 min. An intravenous infusion of methohexital
(Brevital, 0.5–1 mg/kg) may be used to induce ictal
discharges if epileptiform activity is sparse.
Stimulation mapping begins by identifying the
motor cortex. Using multichannel electromyographic
recordings in addition to visual observation of motor
movements increases sensitivity, allowing the use of
lower stimulation levels to evoke motor activity.
After the motor cortex has been identified, the
descending tracts may be found using similar
stimulation parameters. Descending motor and
sensory pathways may be followed into the internal
capsule and inferiorly to the brainstem and spinal
cord. This process is especially important during
resection of infiltrative glial tumors because func-
tioning motor, sensory, or language tissue can be
located within macroscopically obvious tumor or
surrounding infiltrated brain.
A final postresection stimulation of cortical sites
should be performed to confirm that the pathways
are intact. It will also ensure that the underlying
functional tracts have been preserved if subcortical
responses have not been obtained. Even if the
patient’s neurological status is worse postoperatively,
the presence of intact cortical and subcortical motor
pathways implies that the deficit will be transient and
will resolve in days to weeks.
468 BRAIN TUMORS, CLINICAL MANIFESTATIONS AND TREATMENT
Although somatosensory evoked potentials may
help identify the central sulcus, they do not help
localize descending subcortical motor and sensory
white matter tracts. Determination of the subcortical
pathways is important when removing a deep tumor
within or adjacent to the corona radiata, internal
capsule, insula, supplementary motor area, and
thalamus. Because current spread from the electrode
contacts is minimal during bipolar stimulation,
resection is stopped when movement occurs or
paresthesia is evoked.
If the tumor involves the dominant temporal, mid-
to posterior frontal, and mid- to anterior inferior
parietal lobes, identification of language sites is
essential before the tumor is removed to minimize
morbidity. After bone removal under propofol
anesthesia, the patient is kept awake during language
mapping. The electrocorticography equipment is
placed on the field and attached to the skull after
the motor pathways have been identified. The
recording electrode–cortex contact point is stimu-
lated using the bipolar electrode with the electro-
corticogram in progress.
This stimulation may cause afterdischarge poten-
tials to appear on the monitor. The presence of such
afterdischarge potentials indicates that the stimula-
tion current is too high and must be decreased 1 or
2 mA until no afterdischarge potentials follow
stimulation. At this point, the patient is asked to
count from 1 to 50 while the bipolar stimulation
probe is placed near the inferior aspect of the motor
strip to identify Broca’s area. Interruption of count-
ing (i.e., complete speech arrest without orophar-
yngeal movement) localizes Broca’s area. Speech
arrest (e.g., complete interruption of counting) is
usually localized to the area directly anterior to the
portion of the motor cortex devoted to the face.
Using this ideal stimulation current, object-naming
slides are presented and changed every 4 sec. The
patient is expected to name the object correctly
during stimulation mapping. The answers are care-
fully recorded. To ensure that there are no stimula-
tion-induced errors in the form of anomia and
dysnomia, each cortical site is checked three times.
All cortical sites essential for naming are marked
on the surface of the brain with sterile numbered
tickets.
A negative stimulation mapping may not provide
the necessary security to proceed confidently with
resection. Therefore, it is essential to document
where language is and is not located, if feasible.
This is also the reason for a generous exposure. Not
only must the extent of resection be maximized but
also the possibility of obtaining negative data must
be minimized. The distance of the resection margin
from the nearest language site is the most important
factor in determining improvement in preoperative
language deficits, the duration of postoperative
language deficits, and whether the latter are perma-
nent. Significantly fewer permanent language deficits
occur if the distance from the resection margin to the
nearest language site is more than 1 cm.
Based on ultrasonographic and navigational find-
ings, gross inspection, and frozen section analysis of
resection margins, a gross total tumor resection is
usually attempted. After the tumor is removed,
electrocorticography is always performed in patients
who had an identifiable seizure foci before resection.
Although obvious epileptiform foci persistent on
postresection electrocorticogram are resected, occa-
sional spike activity is not pursued, especially when it
involves functional cortex. New discharging areas on
postresection recordings are regarded as postresec-
tion activation phenomena unless they are indepen-
dent or clearly epileptiform. Resected seizure foci are
documented in terms of their relationship with the
tumor nidus and routinely submitted for histopatho-
logical analysis. Preoperative insertion of a subdural
grid electrode array, which provides ictal and
interictal information, may be necessary in children
younger than 11 or 12 years old.
OUTCOME
In evaluating the efficiency of surgery for brain
tumors, seizure outcome, quality of life, and survival
rates appear to be the most important criteria. In
most cases, including patients with malignant glio-
mas, seizures are infrequent and easily controlled
with one antiepileptic drug. In such cases, removal of
the tumor alone usually controls the epilepsy, with or
without the need for additional anticonvulsants.
However, younger patients with indolent tumors
may have seizure activity that is refractory to medical
therapy.
The literature suggests that acceptable seizure
control may be achieved with lesionectomy alone in
patients with tumor-associated epilepsy. Serial elec-
troencephalographic analysis has documented that
independent seizure foci may lose their epileptogenic
activity after various lesions are excised. However,
the seizures of most patients in earlier series were not
‘‘intractable’’ according to contemporary criteria.
Continued use of antiepileptic drugs is usually
 BRAIN TUMORS, CLINICAL MANIFESTATIONS AND TREATMENT
necessary, and some patients may require an addi-
tional operation for persistent seizure activity.
Results of published studies do not support the use
of electrocorticography during tumor resection to
maximize control of epilepsy associated with a
tumor. However, in these studies, in addition to the
tumor, brain adjacent to the lesion was also included
in the resection. In our experience, epilepsy is
controlled optimally without the need for post-
operative anticonvulsants when perioperative (i.e.,
extraoperative or intraoperative) electrocortico-
graphic mapping of separate seizure foci accompanies
the tumor resection. When mapping is not used and a
radical tumor resection includes adjacent brain tissue,
the occurrence of seizures will decrease but most
patients will have to remain on antiepileptic drugs.
The degree of cytoreduction achieved, as measured
by the extent of resection, appears to correlate with
outcome and quality of life. Patients with gross total
resection live longer than those with partial resec-
tion, who in turn live longer than those who have
undergone a biopsy only. A further consideration is
that partial resection is often associated with
significant postoperative edema surrounding residual
tumor tissue along with an increased rate of
neurological morbidity.
Similar to low-grade gliomas for which the
prognostic effect of extensive surgery is poorly
defined but appears to have a positive effect on
outcome, the association between the extent of
resection and longer survival for patients with high-
grade malignant gliomas is also controversial. In a
recent retrospective study of preoperative and post-
operative tumor volumes in 92 patients with a
glioblastoma multiforme, the extent of tumor re-
moval and residual tumor volume were significantly
correlated with the median time to tumor progres-
sion and median survival. In this study, greater
resections did not compromise the quality of life.
Patients with no residual disease had a better
postoperative performance status than patients who
received less than total resections. However, the
literature on the prognostic impact of surgery is
controversial. The controversy mainly reflects the
lack of randomized studies addressing the issue and
the inconsistent and less-than-objective methodology
used to determine the extent of resection.
—G. Evren Keles, Chih-Ju Chang, and Mitchel S. Berger
See also–Brain Tumors, Biology; Brain Tumors,
Genetics; Central Nervous System Tumors,
Epidemiology; Childhood Brain Tumors;
469
Metastases, Brain; Spinal Cord Tumors,
Treatment of
Further Reading
Berger, M. S., and Wilson, C. B. (1999). Extent of resection and
outcome for cerebral hemispheric gliomas. In The Gliomas (M.
S. Berger and C. B. Wilson, Eds.), pp. 660–679. Saunders,
Philadelphia.
Bernstein, M., and Parrent, A. G. (1994). Complications of CT-
guided stereotactic biopsy of intra-axial brain lesions. J.
Neurosurg. 81, 165–168.
Bourgeois, M., Sainte-Rose, C., Lellouch-Tubiana, A., et al.
(1999). Surgery of epilepsy associated with focal lesions in
childhood. J. Neurosurg. 90, 833–842.
Ciric, I., Ammirati, M., Vick, N., et al. (1987). Supratentorial
gliomas: surgical considerations and immediate postoperative
results. Gross total resection versus partial resection. Neuro-
surgery 21, 21–22.
Davis, F. G., Kupelian, V., Freels, S., et al. (2001). Prevalence
estimates for primary brain tumors in the United States by
behavior and major histology groups. Neuro-Oncology 3,
152–158.
Hammond, M. A., Ligon, B. L., Souki, R., et al. (1996). Use of
intraoperative ultrasound for localizing tumors and determining
the extent of resection: A comparative study with magnetic
resonance imaging. J. Neurosurg. 84, 737–741.
Keles, G. E., and Berger, M. S. (2000). Functional mapping. In
Neuro-Oncology Essentials (M. Bernstein and M. S. Berger,
Eds.), pp. 130–134. Thieme, New York.
Keles, G. E., and Berger, M. S. (2001). Epilepsy associated with
brain tumors. In Brain Tumors: An Encyclopedic Approach (A.
H. Kaye and E. R. Laws, Jr., Eds.), 2nd ed., pp. 273–279.
Churchill Livingstone, London.
Keles, G. E., Anderson, B., and Berger, M. S. (1999). The effect of
extent of resection on time to tumor progression and survival in
patients with glioblastoma multiforme of the cerebral hemi-
sphere. Surg. Neurol. 52, 371–379.
Keles, G. E., Lamborn, K. R., and Berger, M. S. (2001). Low-grade
hemispheric gliomas in adults: A critical review of extent of
resection as a factor influencing outcome. J. Neurosurg. 95,
735–745.
Kulkarni, A. V., Guha, A., Lozano, A., and Bernstein, M. (1998).
Incidence of silent hemorrhage and delayed deterioration after
stereotactic brain biopsy. J. Neurosurg. 89, 31–35.
Pignatti, F., van den Bent, M., Curran, D., et al. (2002). Prognostic
factors for survival in adult patients with cerebral low-grade
glioma. J. Clin. Oncol. 20, 2076–2084.
Soo, T. M., Bernstein, M., Provias, J., et al. (1995). Failed
stereotactic biopsy in a series of 518 cases. Stereotact. Funct.
Neurosurg. 64, 183–196.
Steinmaier, R., Fahlbusch, O., Ganslandt, O., et al. (1998).
Intraoperative magnetic resonance imaging with the mag-
netom open scanner: Concepts, neurosurgical indications,
and procedures: A preliminary report. Neurosurgery 43, 739–
748.
Surawicz, T. S., Davis, F., Freels, S., et al. (1998). Brain tumor
survival: Results from the National Cancer Data Base. J. Neuro-
Oncol. 40, 151–160.
Zakhary, R., Keles, G. E., and Berger, M. S. (1999). Intraoperative
imaging techniques in the treatment of brain tumors. Curr.
Opin. Oncol. 11, 152–156.
470 BRAIN TUMORS, GENETICS
Brain Tumors, Genetics
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
PRIMARY BENIGN and malignant brain tumors are
common and occur with an incidence of 12.8 cases
per 100,000 according to the Central Brain Tumor
Registry of the United States. The relative incidence
of brain tumors is age dependent. Intracranial
neoplasms, or new tissue growths, represent the
most common solid tumors in children younger than
age 15. In this age group, primary tumors of the
nervous system comprise approximately 20% of all
cancers, making them the second most common form
of childhood cancer after leukemias.
SPORADIC BRAIN TUMORS
The initiation and progression of brain tumors is
associated with a variety of molecular genetic
alterations. Most brain tumors result from sporadic
genetic alteration. The most common of these
include glial tumors, primitive neuroectodermal
tumors (PNETs), meningiomas, and schwannomas.
Glial Tumors
Gliomas are a heterogeneous group of mostly
sporadic neoplasms derived from glial cells. They
account for approximately 40–45% of all intracra-
nial tumors and thus are the most common tumors
among the primary central nervous system (CNS)
neoplasms. Depending on morphology and histology,
gliomas are classified into several subgroups, the
most important being astrocytic tumors (including
the glioblastoma), oligodendroglial tumors, mixed
gliomas (oligoastrocytomas), and ependymal tumors.
Astrocytomas, or astrocytic gliomas, may be
subdivided into two major groups: the more common
group of diffusely infiltrating tumors, comprising
astrocytoma, anaplastic astrocytoma, and glioblas-
toma, and the less common group of tumors with
more circumscribed growth, consisting of pilocytic
astrocytoma, pleomorphic xanthoastrocytoma, and
subependymal giant cell astrocytoma of tuberous
sclerosis. Astrocytomas are slow-growing tumors
that tend to infiltrate surrounding brain. Genetic
alterations causing astrocytomas have been mapped
to chromosomes 9p, 10, 11p, 17p, 19, and 22 in
addition to mutations in the TP53 gene, and
amplification of protooncogenes such as EGFR.
Pilocytic astrocytomas constitute a separate clinical
and histopathological entity and are the most
common astrocytic tumors in children. In contrast
to adult astrocytomas, allelic losses on chromosomes
10, 17p, and 19q are not found in pilocytic
astrocytomas nor are alterations in the EGFR gene.
Oligodendrogliomas are tumors composed predo-
minantly of neoplastic oligodendrocytes. Oligoden-
drogliomas are typically slow growing and usually
occur during adulthood. They are most commonly
located in the cerebral white matter and deep gray
structures. Oligodendrogliomas have a lesser ten-
dency to malignant transformation than do astro-
cytomas.
Ependymoma is a tumor composed predominantly
of neoplastic ependymal cells. Ependymomas are
moderately cellular with low mitotic activity. They
are thought to arise from the ependymal or
subependymal cells surrounding the ventricles, the
central canal, or within the filum terminale. Ependy-
momas occasionally occur in patients with neurofi-
bromatosis 2 (NF-2). Loss of chromosome 6p is
common in the pediatric ependymoma, in addition to
17p and 22q abnormalities.
Primitive Neuroectodermal Tumors
PNETs are small-cell, malignant tumors of childhood
with predominant location in the cerebellum and a
noted capacity for divergent differentiation, includ-
ing neuronal, astrocytic, ependymal, muscular, and
melanotic. Molecular abnormalities on chromosome
9, 11, and 17 have been linked to the development of
PNETs. Medulloblastomas represent a subcategory
of PNETs. Common genetic abnormalities in medul-
loblastomas are gains of portions of chromosome 1
and deletion of 1q, 6q, 11p, and 16q. Mutations in
the genes encoding Wnt signaling pathway proteins
APC and b-catenin occur rarely in sporadic medullo-
blastomas. Familial medulloblastoma is very rare.
Meningiomas
The meningioma is a tumor composed of neoplastic
meningothelial (arachnoid) cells. Several histological
variants are recognized, such as meningothelial,
fibrous (fibroblastic), transitional, and psammoma-
tous meningioma. Meningiomas are the most com-
mon benign brain tumors and account for
approximately 15% of all intracranial tumors and
25% of intraspinal tumors. The frequency of
meningioma increases with advancing age, and
meningiomas are more common in women.
Although meningiomas are frequently attached to
the dural membranes, they may occur in unusual

sites, such as within the ventricular space. Menin-
giomas frequently occur in patients with NF-2 and
less frequently in those with Werner’s and Gorlin’s
syndrome. Genetic linkage studies provide further
evidence for the existence of a meningioma locus on
chromosome 22 centromeric to the NF-2 gene.
Schwannomas
Schwannomas are encapsulated and sometimes cystic
tumors composed of spindle-shaped neoplastic
Schwann cells. Schwannomas account for 8% of
intracranial tumors and 29% of intraspinal tumors.
Vestibular schwannomas are also referred to as
acoustic schwannomas or neuromas and commonly
occur as single tumors on the vestibular branch of the
eighth cranial nerve. Schwannomas are caused by
mutation in the NF-2 gene. Schwannomatosis
describes a condition of multiple schwannomas and
represents a unique class of NF that may or may not
involve NF-2 gene mutations.
BRAIN TUMORS AND INHERITED
TUMOR SYNDROMES
Brain tumors may occur as part of known inherited
cancer syndromes. The most common inherited
cancer syndromes are described here.
Neurofibromatosis 1 (NF-1) is a common auto-
somal dominant disease affecting approximately 1 in
3500 individuals. The NF-1 gene is located on the
long arm of chromosome 17 and was identified in
1990. The NF-1 protein neurofibromin is large and
functions as a Ras GTPase-activating protein. Neu-
rofibromin action as a tumor suppressor is through
its stimulation of GTP hydrolysis on normal but not
oncogenic Ras and regulation of the Ras–MAP
kinase signaling pathway. Patients with NF-1 typi-
cally develop multiple neurofibromas of the periph-
eral nervous system. Most neurofibromas are benign.
Patients with NF-1 may also develop gliomas. These
typically involve the optic nerves or optic chiasm and
may occur in up to 15% of patients if detailed
neuroimaging is used for detection. However, the
majority of these tumors are asymptomatic and show
little progression. The histology is typically that of a
pilocytic astrocytoma. Gliomas may also occur less
frequently in the brainstem and hypothalamus, and
they rarely occur in the cerebellum or spinal cord.
Reports of meningiomas in NF-1 most likely
represent the chance association of a common brain
tumor with a common genetic disease.
BRAIN TUMORS, GENETICS 471
Neurofibromatosis 2 (NF-2) is less common than
NF-1 and affects approximately 1 in 40,000
individuals. NF-2 is inherited as an autosomal
dominant trait and caused by germline mutation of
the NF-2 gene. The NF-2 gene is located at
chromosome 22q12 and was identified in 1993.
NF-2 patients are characterized by bilateral vestib-
ular schwannomas, a hallmark feature of the disease.
Commonly, NF-2 patients have other cranial and
spinal schwannomas and meningiomas. Gliomas are
also found in patients with NF-2, most commonly in
the spinal cord. Approximately 80% of gliomas in
NF-2 patients are intramedullary spinal or cauda
equina tumors, and the vast majority of these are
ependymomas.
Von Hippel–Lindau (VHL) disease is the result of
loss of function mutations in the VHL gene on
chromosome 3p, which was identified in 1993.
Hemangioblastomas are found in the majority of
VHL patients and are frequently a cause of death.
The majority of hemangioblastomas in VHL disease
occur in the cerebellum, followed by locations in
spinal cord and brainstem. Approximately one-half
of the tumors are asymptomatic. Capillary heman-
gioblastomas tend to manifest in younger VHL
patients than do sporadic capillary hemangioblasto-
mas and are more often multifocal.
Tuberous sclerosis (TS) is the second most frequent
hereditary tumor syndrome of the nervous system
after NF-1. Two different genes have been linked to
onset of TS: TSC1 located at chromosome 9q34 and
TSC2 located at 16p13.2. Neuroimaging studies
show CNS lesions in the majority of patients with
TS, including hamartomas such as cortical tubers
and subependymal nodules. However, only approxi-
mately one-fourth of the lesions are tumorous and
represent giant cell astrocytomas. Giant cell astro-
cytomas, in contrast to subependymal nodules, show
marked enhancement. There are no major differences
in the TS phenotypes associated with mutations in
TSC1 or TSC2, with the possible exception of mental
retardation, which may be more frequent in patients
with TSC2 mutations.
The Li–Fraumeni syndrome is a rare domi-
nantly inherited syndrome associated with germline
mutations in the TP53 gene. Although soft tissue
sarcomas and breast cancers predominate, approxi-
mately 13% of patients develop brain tumors
that typically show the histology of astrocytic
glioma, followed by PNETs. In addition to
patients with the Li–Fraumeni syndrome, TP53
germline mutations have occasionally been identified
472 BRAIN TUMORS, GENETICS
in patients with nonfamilial malignancies with
early onset or multifocality. First-degree relatives
of these patients are also at an increased risk of
gliomas.
Gorlin’s syndrome, also called nevoid basal cell
carcinoma syndrome, is an autosomal dominant
disorder leading to the development of multiple
basal cell carcinomas of the skin and palmar and
plantar pits, odontogenic keratocysts, and skeletal
anomalies. Childhood medulloblastoma, meningio-
ma, craniopharyngioma, and neurofibroma have
been described in patients with Gorlin’s syndrome.
This syndrome has been linked to mutations in the
tumor-suppressor gene PTCH, which is the human
ortholog of Drosophila patched. Somatic mutations
in PTCH have been detected in sporadic basal cell
carcinomas, PNETs, medulloblastomas, and certain
types of sporadic tumors.
Ataxia telangiectasia is a recessive trait mapped to
the ATM gene on chromosome 11q. Lymphoid
malignancies are frequently seen in patients with
ataxia telangiectasia. Although solid tumors occur,
primary CNS tumors are infrequent.
Cowden’s syndrome, also known as multiple
hamartoma syndrome, is an autosomal dominant
cancer syndrome that predisposes to a variety of
hamartomas and neoplasms. The major CNS
lesion associated with the disease is the dysplastic
gangliocytoma of the cerebellum. Additional asso-
ciated CNS lesions include megaencephaly and gray
matter heterotopias. Occasional cases of meningio-
mas in patients with Cowden’s disease have also
been documented. Peripheral manifestations include
multiple trichilemmomas of the skin, cutaneous
keratoses, oral papillomatosis, gastrointestinal
polyps, hamartomas of soft tissues, thyroid tumors,
as well as benign and malignant breast tumors.
Germline mutations in the PTEN tumor-suppressor
gene at 10q23 have been linked to Cowden’s
disease.
Werner’s syndrome is a recessive trait with clinical
symptoms resembling premature aging. The respon-
sible gene maps to the short arm of chromosome 8
and has been identified by positional cloning. In
addition to premature aging, some individuals with
Werner’s syndrome develop tumors, including CNS
tumors such as meningiomas and, less frequently,
astrocytomas.
Turcot’s syndrome describes a rare heterogeneous
disorder characterized by the association of colonic
polyposis and malignant primary neuroepithelial
tumors of the CNS. Colonic polyposis in patients
with Turcot’s syndrome appears to be the result of
mutations in genes encoding Wnt signaling pathway
proteins (APC and b-catenin). Turcot’s syndrome has
also been linked to mutations in the mismatch repair
genes hPMS2 and hMLH1.
KNUDSON’S TWO-HIT MODEL AND LOSS
OF HETEROZYGOSITY
Inherited cancer syndromes are often characterized
by loss of two alleles at a disease-causing locus. This
is known as the Knudson two-hit model of tumor-
igenesis and is most commonly observed in syn-
dromes caused by loss of function of a recessive
tumor-suppressor gene. When observed, the patient
is heterozygous at the disease-causing locus, posses-
sing one normal and one mutated allele. Sporadic
loss of the normal allele at that locus leaves only the
mutated recessive allele. When sporadic deletion or
chromosomal rearrangement cause the second ‘‘hit,’’
the resulting tumor is said to have undergone loss of
heterozygosity.
—Daniel R. Scoles and Stefan M. Pulst
See also–Brain Tumors, Biology; Brain Tumors,
Clinical Manifestations and Treatment;
Childhood Brain Tumors; Genetic Testing,
Molecular; Glial Tumors; Meningiomas;
Migraine, Genetics of; Nerve Sheath Tumors;
Neurogenetics, Overview; Tuberous Sclerosis
Complex (TSC); Von Hippel-Lindau Disease
Further Reading
Bernstein, M., and Berger, M. S. (Eds.) (2000). Neuro-oncology,
the Essentials. Thieme, New York.
Kleihues, P., Burger, P. C., and Scheithauer, B. W. (1993).
Histological Typing of Tumours of the Central Nervous
System., 2nd ed. Springer-Verlag, Heidelberg.
Pulst, S. M., and Reifenberger, G. (2000). Primary tumors of the
nervous system. In Neurogenetics (S. M. Pulst, Ed.). Oxford
Univ. Press, New York.
Riccardi, V. M. (1992). Neurofibromatosis: Phenotype, Natural
History and Pathogenesis, 2nd ed. Johns Hopkins Univ. Press,
Baltimore.
Russell, D., and Rubinstein, L. J. (1989). Pathology of Tumors of
the Nervous System, 5th ed. Arnold, London.
Brancher Deficiency
see Glycogen Storage Diseases
452 BRAINSTEM AUDITORY EVOKED POTENTIALS
therapies. In dementia and other encephalopathies,
QEEG can flag subtle EEG slowing that makes a
diagnosis of depression less likely.
On the other hand, QEEG has not lived up to
some of its promises. Overly enthusiastic statements
by some research scientists have resulted in confusion
by suggesting that there are clinical uses when
data are still lacking. A major problem in using
EEG to diagnose many specific illnesses is its relative
lack of specificity. EEGs tend to change in a very few
specific ways. EEGs can show epileptic spikes or
other specific brief wave patterns. EEGs can also
show excess slowing as a sign of pathology or
occasionally a focal loss of fast activity as a sign of a
localized problem. However, similar changes can
occur in a wide variety of disorders, so QEEG and
routine EEG suffer the disadvantage of a limited
repertoire.
QEEG and EEG brain mapping can process EEGs
in interesting ways. Some of these are certain to
result in new or novel uses of QEEG in the future.
Just as the microelectronics revolution continues to
foster many changes in medical care and daily life, so
too does it offer hope of many fascinating and
insightful advances in QEEG in the future.
—Marc R. Nuwer
See also–Electroencephalogram (EEG);
Electroencephalographic Spikes and Sharp
Waves; Electromyography (EMG);
Neuroimaging, Overview
Further Reading
American Psychiatric Association (1991). Quantitative electro-
encephalography: A report on the present state of computerized
EEG techniques. Am. J. Psychiatry 148, 961–964.
Duffy, F. H., Hughes, J. R., Miranda, F., et al. (1994). Status of
quantitative EEG (QEEG) in clinical practice, 1994. Clin.
Electroencephalogr. 25, vi–xxii.
Ebersole, J. S., and Wade, P. B. (1991). Spike voltage topography
identifies two types of frontotemporal epileptic foci. Neurology
41, 1425–1433.
Gotman, J. (1990). Automatic seizure detection: Improvements
and evaluation. Electroencephalogr. Clin. Neurophysiol. 76,
317–324.
Jordan, K. G. (1999). Continuous EEG monitoring in the intensive
care unit and emergency department. J. Clin. Neurophysiol. 16,
14–39.
Nuwer, M. R. (1997). Assessment of digital EEG, quantitative
EEG and EEG brain mapping: Report of the American
Academy of Neurology and American Clinical Neurophysiol-
ogy Society. Neurology 49, 277–292.
Nuwer, M. R. (1998). Assessing digital and quantitative EEG in
clinical settings. J. Clin. Neurophysiol. 15, 458–463.
Rodriguez, G., Nobili, F., Arrigo, A., et al. (1999). Prognostic
significance of quantitative electroencephalography in Alzhei-
mer patients. Electroencephalogr. Clin. Neurophysiol. 99,
123–128.
Vespa, P. M., Nenov, V., and Nuwer, M. R. (1999). Continuous
EEG monitoring in the intensive care unit: Early findings and
clinical efficacy. J. Clin. Neurophysiol. 16, 1–13.
Brainstem Auditory Evoked
Potentials (BAEPs)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAINSTEM auditory evoked potentials (BAEPs) are
the electrical signals produced by the nervous system
within the first 10 msec following a transient acoustic
stimulus. They are quite small (typically o1 mV in
amplitude) but are typically easily to record, highly
reproducible across subjects and in multiple record-
ings in the same subject, and only minimally affected
by surgical anesthesia. Therefore, they have been
widely used for neurodiagnostic testing, hearing
screening, intraoperative monitoring, and neurophy-
siological research.
RECORDING TECHNIQUES
BAEPs are usually recorded between the scalp at the
vertex and the earlobe or mastoid, and the vertex-
positive peaks are typically labeled with Roman
numerals according to the convention of Jewett and
Williston (Fig. 1A). Waves IV and V are often fused
into a IV–V complex of variable morphology. BAEPs
are usually assessed in a vertex-to-ipsilateral ear
recording channel, but additional recording channels
incorporating the contralateral ear recording elec-
trode may be useful in identifying components and
tend to separate overlapping waves IV and V (Fig. 1).
Most of the BAEP components are far-field poten-
tials, recorded at a large distance from their
intracranial generators and widely distributed over
the scalp. Wave I, however, is a near-field potential
around the stimulated ear, and it is thus absent in the
vertex-to-contralateral ear recording channel
(Fig. 1B).
BAEPs are typically elicited by brief transient
acoustic stimuli, such as clicks or tone pips, that are
delivered monaurally. A click is generated by passing
an electrical square pulse through the earphone or
other transducer. If the initial movement of the

Figure 1
Normal BAEPs to monaural stimulation, recorded from electrodes
at the vertex (Cz), the earlobe ipsilateral to the stimulus (Ai), and
the contralateral earlobe (Ac). (A) Cz–Ai waveforms, with vertex-
positive peaks shown as upward deflections and labeled with
Roman numerals according to the convention of Jewett and
Williston. (B) Cz–Ac waveforms. Note that wave I is absent, and
the peak latency of wave IV has decreased, whereas that of wave V
has increased (dotted lines).
transducer diaphragm is toward the subject’s ear, a
propagating wave of increased air pressure, called a
compression click, is produced. Reversing the polar-
ity of the electrical square pulse produces a rarefac-
tion click, in which the initial portion of the acoustic
stimulus is a wave of decreased air pressure and the
movements of the tympanic membrane and of
structures in the inner ear are the opposite of those
produced by compression clicks. BAEPs to rarefac-
tion and compression clicks may differ, and a single
click polarity (usually rarefaction) is preferable for
clinical diagnostic BAEP studies. During extraopera-
tive diagnostic BAEP studies, the nonstimulated ear
is masked with continuous white noise at an intensity
30–40 dB below that of the BAEP stimulus to prevent
acoustic cross talk (stimulation of the ear that is
supposed to be unstimulated due to air and bone
conduction of the acoustic stimulus from the other
side). During intraoperative monitoring, alternating
stimulus polarity may be useful by helping to reduce
the stimulus artifact; also, stimulus trains consisting
of interleaved left- and right-sided stimuli are often
used to permit assessment of both ears simulta-
neously, although this protocol precludes white noise
masking.
Far-field BAEPs are too small to be visible in
unaveraged raw data, and signal averaging is
BRAINSTEM AUDITORY EVOKED POTENTIALS 453
required to extract them from electroencephal-
graphic, electromyographic, and other electrical
signals picked up by the recording electrodes. The
averaging epoch duration (sometimes called the
analysis time) is typically 10 msec for diagnostic
BAEP studies in adults; a longer analysis time of
15 msec may be required to record pathologically
delayed BAEPs, BAEPs to lowered stimulus inten-
sities (such as when recording a threshold study),
BAEPs in children, and BAEPs during intraoperative
monitoring.
INTERPRETATION OF BAEPs
Waves I, III, and V are the most consistent BAEP
peaks, and interpretation of diagnostic BAEP
studies is based on measurements of the absolute
latencies of these components and on the I–III, III–V,
and I–V interpeak intervals, which are calculated
from the absolute latencies. The absolute latency
of wave I has also been labeled the peripheral
transmission time, and the I–V interpeak interval
has been called the central transmission time. Right–
left differences of the absolute component latencies
and of the interpeak intervals are also calculated.
Examination of right–left differences increases the
sensitivity of BAEPs for detection of abnormalities
within the auditory pathways because the inter-
subject variability of these asymmetry measures is
less than that of the absolute component latencies
and interpeak intervals from which they were
derived.
By themselves, the absolute amplitudes of the
components are not useful criteria for BAEP inter-
pretation. However, the ratio between the amplitude
of the IV–V complex (measured from the highest
peak within it to the trough that follows) and the
amplitude of wave I (measured from the peak to the
following trough) has proven to be a clinically useful
measure. An abnormally small IV–V:I amplitude
ratio can identify as abnormal some BAEP wave-
forms in which the absolute component latencies,
interpeak intervals, and asymmetry measures are all
normal (Fig. 2F).
Wave I arises from the distal eighth nerve, at its
cochlear end. Subsequent BAEP peaks represent
composites of contributions from multiple genera-
tors. However, in the interpretation of clinical BAEP
studies, wave III can be interpreted as a predomi-
nantly reflecting activity in the lower pons and wave
V as a predominantly reflecting activity in the
auditory pathways at the level of the mesencephalon.
454 BRAINSTEM AUDITORY EVOKED POTENTIALS

Figure 2
BAEPs from a normal subject and from patients with diseases affecting the auditory system. (A) Normal BAEPs. (B) BAEPs from a patient
with a peripheral hearing loss; wave I is abnormally prolonged, but the I–V interpeak interval is normal. (C) BAEPs from a patient with an
eighth nerve tumor that has abnormally prolonged the I–III interpeak interval. (D) BAEPs from a patient with a large eighth nerve tumor,
showing loss of all components after wave I. (E) BAEPs from a patient with multiple sclerosis in whom the I–III and III–V interpeak intervals
are both abnormally prolonged, reflecting multilevel demyelination. (F) BAEPs from a patient with multiple sclerosis in whom the IV–V:I
amplitude ratio is abnormally small (0.28; lower limits of normal ¼ 0.5), but the interpeak intervals are all within normal limits. Voltage
calibration bar: A, 0.2 mV; B, 0.1 mV; C, 0.1 mV; D, 0.2 mV; E, 0.1 mV; F, 0.4 mV.

Wave VI may be absent in normal subjects, and
wave VII is more frequently absent. Thus, the
absence of these components does not necessarily
signify dysfunction within the auditory pathways.
Also, these components are in part generated within
the mesencephalon and may persist in patients who
suffer damage to more rostral portions of the
auditory system. Therefore, waves VI and VII do
not provide clinically useful information about the
status of the auditory pathways, and BAEPs cannot
be used to assess the auditory pathways rostral to the
mesencephalon.

CLINICAL APPLICATIONS
A peripheral (i.e., conductive or cochlear) hearing
loss typically causes a delay or absence of wave I and
subsequent components (Fig. 2B); thus, BAEPs can
also detect peripheral auditory dysfunction. When
the stimulus intensity is decreased, the BAEPs show
progressive latency and amplitude changes and
eventually disappear, permitting measurement of a
threshold. Such BAEP audiometry permits hearing
assessment in subjects in whom conventional audio-
metry is not feasible. Frequency-limited stimuli and
masking noise can be used to confer some frequency
specificity on the threshold measurements.
BAEPs are also highly sensitive for the detection of
eighth nerve and brainstem tumors (Figs. 2C and 2D)
as well as demyelinating disease affecting the infra-
tentorial auditory pathways (Figs. 2E and 2F). Abnor-
mal neural conductions within the eighth nerves or the
brainstem auditory pathways typically cause prolon-
gation of the interpeak intervals or loss of BAEPs
generated rostral to the area of abnormality (Figs. 2C–
2E) and/or an abnormally small IV–V:I amplitude
ratio (Fig. 2F). The ascending auditory pathways
rostral to the cochlear nuclei are bilateral; each ear
activates auditory pathways on both sides of the
brainstem. However, the BAEPs appear to predomi-
nantly reflect activity in the ipsilateral ascending
pathways. Unilateral brainstem lesions that produce
unilateral BAEP abnormalities involving either the I–
III or the III–V interpeak interval usually do so upon
stimulation of the ear ipsilateral to the lesion.
BAEPs are highly resistant to anesthetic effects and
are useful for monitoring the ears, eighth nerves, and
brainstem auditory pathways during posterior fossa
surgery. Cerebellar retraction can stretch the eighth
nerve and cause hearing loss even when surgery does
not directly affect the auditory pathways, and BAEP
monitoring has been shown to lead to improved
hearing outcomes during operations such as poster-
ior fossa microvascular decompression.
—Alan D. Legatt
See also–Auditory System, Central; Auditory
System, Peripheral; Event-Related Potentials
(ERPs); Evoked Potentials (EPs); Hearing Loss;
Somatosensory Evoked Potentials; Visual
Evoked Potentials
Further Reading
American Electroencephalographic Society (1994). Guideline nine:
Guidelines on evoked potentials. J. Clin. Neurophysiol. 11,
40–73.
BRAINSTEM SYNDROMES 455
Chiappa, K. H. (1997). Evoked Potentials in Clinical Medicine,
3rd ed. Lippincott-Raven, Philadelphia.
Jewett, D. L., and Williston, J. S. (1971). Auditory-evoked far
fields averaged from the scalp of humans. Brain 94, 681–696.
Legatt, A. D. (1999). Brainstem auditory evoked potentials:
Methodology, interpretation, and clinical application. In
Electrodiagnosis in Clinical Neurology (M. J. Aminoff, Ed.),
4th ed., pp. 451–484. Churchill Livingstone, New York.
Legatt, A. D., Arezzo, J. C., and Vaughan, H. G., Jr (1988). The
anatomical and physiological bases of brainstem auditory
evoked potentials. Neurol. Clin. 6, 681–704.
Brainstem Syndromes
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRAINSTEM contains both long tracts of the
nervous system, which travel in a rostrocaudal plane,
and cranial nerve nuclei and fascicles, which
originate at distinct levels in the brainstem. Lesions
affecting the brainstem can thus be exquisitely
localized based on the findings of the neurological
history and examination. Often, lesions of the
brainstem cause ‘‘crossed’’ syndromes in which signs
of damage to cranial nerve nuclei or fascicles on one
side are associated with sensory or motor findings on
the opposite side of the body (the latter due to the
crossing of longitudinal tracts below the level of the
lesion). The major brainstem syndromes are best
understood through discussion of the clinical findings
resulting from infarcts in the distribution of specific
vessels serving brainstem territories. This entry
provides an overview of some of these syndromes.
A brief summary of the vascular supply to each
brainstem region precedes the discussion of the
clinical syndromes.
VASCULAR SUPPLY OF THE MEDULLA
The brainstem’s large regional arteries have three
types of branches: the paramedian arteries, which
penetrate the ventral brainstem surface and supply
midline structures; the short circumferential arteries,
which traverse laterally on the brainstem and
penetrate its ventrolateral and lateral surfaces; and
the long circumferential arteries, which course
around the brainstem and supply its posterior
structures and cerebellum. The blood supply to the
medulla may be subdivided into two groups: the
paramedian bulbar branches and the lateral bulbar
branches.

CLINICAL APPLICATIONS
A peripheral (i.e., conductive or cochlear) hearing
loss typically causes a delay or absence of wave I and
subsequent components (Fig. 2B); thus, BAEPs can
also detect peripheral auditory dysfunction. When
the stimulus intensity is decreased, the BAEPs show
progressive latency and amplitude changes and
eventually disappear, permitting measurement of a
threshold. Such BAEP audiometry permits hearing
assessment in subjects in whom conventional audio-
metry is not feasible. Frequency-limited stimuli and
masking noise can be used to confer some frequency
specificity on the threshold measurements.
BAEPs are also highly sensitive for the detection of
eighth nerve and brainstem tumors (Figs. 2C and 2D)
as well as demyelinating disease affecting the infra-
tentorial auditory pathways (Figs. 2E and 2F). Abnor-
mal neural conductions within the eighth nerves or the
brainstem auditory pathways typically cause prolon-
gation of the interpeak intervals or loss of BAEPs
generated rostral to the area of abnormality (Figs. 2C–
2E) and/or an abnormally small IV–V:I amplitude
ratio (Fig. 2F). The ascending auditory pathways
rostral to the cochlear nuclei are bilateral; each ear
activates auditory pathways on both sides of the
brainstem. However, the BAEPs appear to predomi-
nantly reflect activity in the ipsilateral ascending
pathways. Unilateral brainstem lesions that produce
unilateral BAEP abnormalities involving either the I–
III or the III–V interpeak interval usually do so upon
stimulation of the ear ipsilateral to the lesion.
BAEPs are highly resistant to anesthetic effects and
are useful for monitoring the ears, eighth nerves, and
brainstem auditory pathways during posterior fossa
surgery. Cerebellar retraction can stretch the eighth
nerve and cause hearing loss even when surgery does
not directly affect the auditory pathways, and BAEP
monitoring has been shown to lead to improved
hearing outcomes during operations such as poster-
ior fossa microvascular decompression.
—Alan D. Legatt
See also–Auditory System, Central; Auditory
System, Peripheral; Event-Related Potentials
(ERPs); Evoked Potentials (EPs); Hearing Loss;
Somatosensory Evoked Potentials; Visual
Evoked Potentials
Further Reading
American Electroencephalographic Society (1994). Guideline nine:
Guidelines on evoked potentials. J. Clin. Neurophysiol. 11,
40–73.
BRAINSTEM SYNDROMES 455
Chiappa, K. H. (1997). Evoked Potentials in Clinical Medicine,
3rd ed. Lippincott-Raven, Philadelphia.
Jewett, D. L., and Williston, J. S. (1971). Auditory-evoked far
fields averaged from the scalp of humans. Brain 94, 681–696.
Legatt, A. D. (1999). Brainstem auditory evoked potentials:
Methodology, interpretation, and clinical application. In
Electrodiagnosis in Clinical Neurology (M. J. Aminoff, Ed.),
4th ed., pp. 451–484. Churchill Livingstone, New York.
Legatt, A. D., Arezzo, J. C., and Vaughan, H. G., Jr (1988). The
anatomical and physiological bases of brainstem auditory
evoked potentials. Neurol. Clin. 6, 681–704.
Brainstem Syndromes
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRAINSTEM contains both long tracts of the
nervous system, which travel in a rostrocaudal plane,
and cranial nerve nuclei and fascicles, which
originate at distinct levels in the brainstem. Lesions
affecting the brainstem can thus be exquisitely
localized based on the findings of the neurological
history and examination. Often, lesions of the
brainstem cause ‘‘crossed’’ syndromes in which signs
of damage to cranial nerve nuclei or fascicles on one
side are associated with sensory or motor findings on
the opposite side of the body (the latter due to the
crossing of longitudinal tracts below the level of the
lesion). The major brainstem syndromes are best
understood through discussion of the clinical findings
resulting from infarcts in the distribution of specific
vessels serving brainstem territories. This entry
provides an overview of some of these syndromes.
A brief summary of the vascular supply to each
brainstem region precedes the discussion of the
clinical syndromes.
VASCULAR SUPPLY OF THE MEDULLA
The brainstem’s large regional arteries have three
types of branches: the paramedian arteries, which
penetrate the ventral brainstem surface and supply
midline structures; the short circumferential arteries,
which traverse laterally on the brainstem and
penetrate its ventrolateral and lateral surfaces; and
the long circumferential arteries, which course
around the brainstem and supply its posterior
structures and cerebellum. The blood supply to the
medulla may be subdivided into two groups: the
paramedian bulbar branches and the lateral bulbar
branches.
456 BRAINSTEM SYNDROMES
Paramedian Bulbar Branches
The paramedian portion of the medulla (the hypo-
glossal nucleus and emergent nerve fibers, the medial
longitudinal fasciculus, the medial lemniscus, the
pyramids, and the medial part of the inferior olivary
nucleus) is supplied by the vertebral artery. At lower
medullary levels, the anterior spinal artery also
contributes to the paramedian zone.
Lateral Bulbar Branches
The lateral portion of the medulla is supplied by the
intracranial vertebral artery (fourth segment) or the
posterior inferior cerebellar artery. Occasionally, the
basilar artery or the anterior inferior cerebellar artery
also contributes.
MEDULLARY SYNDROMES
Medial Medullary Syndrome (Dejerine’s
Anterior Bulbar Syndrome)
This syndrome results from occlusion of the anterior
spinal artery or its parent vertebral artery. The
anterior spinal artery supplies the ipsilateral pyra-
mid, medial lemniscus, and hypoglossal nerve and
nucleus. Its occlusion thus results in the following
signs:
* Ipsilateral paresis, atrophy, and fibrillation of the
tongue (due to cranial nerve XII affection). The
protruded tongue deviates toward the lesion (away
from the hemiplegia).
* Contralateral hemiplegia (due to involvement of
the pyramid) with sparing of the face.
*
Contralateral loss of position and vibratory
sensation (due to involvement of the medial lemnis-
cus). Because the more dorsolateral spinothalamic
tract is unaffected, pain and temperature sensation
are spared.
The medial medullary syndrome may occur
bilaterally, resulting in quadriplegia (with facial
sparing), bilateral lower motor neuron lesions of
the tongue, and complete loss of position and
vibratory sensation affecting all four extremities.
Because the hypoglossal fibers run slightly laterally
to the medial lemniscus and pyramid, they are
occasionally spared in cases of anterior spinal artery
occlusion. Occasionally, only the pyramid is da-
maged, resulting in a pure motor hemiplegia that
spares the face.
Lateral Medullary (Wallenberg’s) Syndrome
This syndrome is most often secondary to intracra-
nial vertebral artery or posterior inferior cerebellar
artery occlusion. Spontaneous dissections of the
vertebral arteries are a common cause.
The characteristic clinical picture results from
damage to a wedge-shaped area of the lateral
medulla and inferior cerebellum and consists of
several signs:
* Ipsilateral facial hypalgesia and thermoanesthe-
sia (due to trigeminal spinal nucleus and tract
involvement). Ipsilateral facial pain is common.
* Contralateral trunk and extremity hypalgesia
and thermoanesthesia (due to damage to the spi-
nothalamic tract).
* Ipsilateral palatal, pharyngeal, and vocal cord
paralysis with dysphagia and dysarthria (due to
involvement of the nucleus ambiguus or its ipscicle).
* Ipsilateral Horner’s syndrome (due to affection
of the descending sympathetic fibers) resulting in
ipsilateral miosis, ptosis, and facial anhydrosis.
* Vertigo, nausea, and vomiting (due to involve-
ment of the vestibular nuclei).
* Ipsilateral cerebellar signs and symptoms (due to
involvement of the inferior cerebellar peduncle and
cerebellum).
* Occasionally, hiccups (due perhaps to involve-
ment of the medullary respiratory centers) and
diplopia (perhaps secondary to involvement of the
lower pons).
The motor system (pyramids), tongue movements,
and vibration and position sense are typically spared
with lateral medullary lesions because the corre-
sponding anatomical structures are located in the
medial medulla.
Rarely, a combined syndrome (medial and lateral
medullary syndromes) may occur (hemimedullary
syndrome), usually due to occlusion of the intracra-
nial vertebral artery.
Lateral Pontomedullary Syndrome
This syndrome may result from occlusion of an
aberrant arterial branch arising from the upper
vertebral artery and running superiorly and laterally
to the region of exit of cranial nerves VII and VIII
from the pons. It may also occur with pontine
hemorrhage. The clinical findings are those seen in
the lateral medullary syndrome plus several pontine
findings, including ipsilateral facial weakness (due to

involvement of cranial nerve VII) and ipsilateral
tinnitus and, occasionally, hearing disturbance (due
to involvement of cranial nerve VIII).
Medullary Hemorrhage
Primary medullary hemorrhage is extremely uncom-
mon and presents with a characteristic syndrome of
sudden onset of headache and vertigo with neurolo-
gical signs that correspond to various combinations
of medial and lateral medullary involvement. The
most frequent symptoms at onset include vertigo,
sensory symptoms, and dysphagia. Presenting signs
include palatal weakness, nystagmus, hypoglossal
palsy, cerebellar ataxia, and limb weakness.
VASCULAR SUPPLY OF THE PONS
The blood supply to the pons derives from three
groups. First, paramedian vessels (four to six) arise
from the basilar artery and penetrate perpendicularly
into the pontine parenchyma. They supply the medial
basal pons, including the pontine nuclei, the corti-
cospinal fibers, and the medial lemniscus. Second,
short circumferential arteries also arise from the
basilar artery and enter the brachium pontis. These
vessels supply the ventrolateral basis pontis. Third
are the long circumferential arteries, which include
the following: the anterior inferior cerebellar artery,
which most often arises from the basilar artery and
supplies the lateral tegmentum of the lower two-
thirds of the pons and the ventrolateral cerebellum;
the internal auditory artery, which arises from the
anterior inferior cerebellar artery (occasionally from
the basilar artery) and supplies the auditory and
facial cranial nerves; and the superior cerebellar
artery, which arises from the basilar artery near its
bifurcation, supplies the dorsolateral pons and
brachium pontis, the dorsal reticular formation,
and the periaqueductal region (occasionally, the
ventrolateral pontine tegmentum is also supplied by
this vessel).
PONTINE SYNDROMES
Ventral Pontine Syndromes
Millard–Gubler Syndrome: A unilateral lesion of
the ventrocaudal pons may involve the basis pontis
and the fascicles of cranial nerves VI and VII. This
involvement results in contralateral hemiplegia (spar-
ing the face) due to pyramidal tract involvement,
ipsilateral lateral rectus paresis (cranial nerve VI)
BRAINSTEM SYNDROMES 457
with diplopia that is accentuated when the patient
‘‘looks toward’’ the lesion, and ipsilateral peripheral
facial paresis (cranial nerve VII).
Raymond Syndrome: A unilateral lesion of the
ventral medial pons, which affects the ipsilateral
abducens nerve fascicles and the corticospinal tract
but spares cranial nerve VII, may cause this rare
syndrome (also called alternating abducens hemi-
plegia). This syndrome consists of ipsilateral lateral
rectus paresis (cranial nerve VI) and contralateral
hemiplegia, sparing the face, due to pyramidal tract
involvement.
Pure Motor Hemiparesis: Lesions (especially la-
cunar infarction) involving the corticospinal tracts in
the basis pontis may produce a pure motor hemi-
plegia with or without facial involvement. A
combination of dysarthria and a history of previous
transient gait abnormality or vertigo favor a pontine
lesion as a cause of pure motor hemiparesis rather
than a more common internal capsular lesion.
Dysarthria–Clumsy Hand Syndrome: A lesion in
the basis pontis (especially a lacunar infarction) at
the junction of the upper one-third and lower two-
thirds of the pons may result in the dysarthria–
clumsy hand syndrome. In this syndrome, facial
weakness and severe dysarthria and dysphagia occur
together with clumsiness and paresis of the hand.
Hyper-reflexia and a Babinski sign may occur on
the same side as the arm paresis, but sensation is
spared.
Ataxic Hemiparesis: A lesion (usually a lacunar
infarction) in the basis pontis at the junction of the
upper one-third and the lower two-thirds of the pons
may result in the ataxic hemiparesis (homolateral
ataxia and crural paresis) syndrome. In this syn-
drome, hemiparesis, which is more severe in the
lower extremity, is associated with ipsilateral hemi-
ataxia and occasionally dysarthria, nystagmus, and
paresthesias. The lesion is in the contralateral pons.
The ataxia is unilateral, probably because transverse
fibers originating from the contralateral pontine
nuclei (and projecting to the contralateral cerebel-
lum) are spared.
Locked-in Syndrome: Bilateral ventral pontine
lesions (infarction, tumor, hemorrhage, trauma, or
central pontine myelinolysis) may result in the
locked-in syndrome (deefferented state). This syn-
drome consists of the following signs: quadriplegia
due to bilateral corticospinal tract involvement in the
458 BRAINSTEM SYNDROMES
basis pontis; aphonia due to involvement of the
corticobulbar fibers innervating the lower cranial
nerve nuclei; and, occasionally, impairment of
horizontal eye movements due to bilateral involve-
ment of the fascicles of cranial nerve VI.
Because the reticular formation is not injured, the
patient is fully awake. The supranuclear ocular
motor pathways lie dorsally and are therefore
spared; thus, vertical eye movements and blinking
are intact (the patient may actually convey his or her
wishes in Morse code). Deefferentation may also
occur with purely peripheral lesions (e.g., polio,
polyneuritis, and myasthenia gravis).
Dorsal Pontine Syndromes
Foville Syndrome: This syndrome is due to lesions
involving the dorsal pontine tegmentum in the caudal
third of the pons. It consists of contralateral
hemiplegia (with facial sparing) due to interruption
of the corticospinal tract, ipsilateral peripheral-type
facial palsy due to involvement of the nucleus or
fascicle of cranial nerve VII or both, and an inability
to move the eyes conjugately to the ipsilateral side
(gaze is ‘‘away from’’ the lesion) due to involvement
of the paramedian pontine reticular formation or
abducens nucleus or both.
Raymond–Cestan Syndrome: This syndrome is
seen with rostral lesions of the dorsal pons. It
includes cerebellar signs (ataxia) with a coarse
‘‘rubral’’ tremor due to involvement of the cerebel-
lum and contralateral reduction of all sensory
modalities (face and extremities) due to involvement
of the medial lemniscus and the spinothalamic tract.
With ventral extension, there may be contralateral
hemiparesis (due to corticospinal tract involvement)
or paralysis of conjugate gaze toward the side of the
lesion (due to involvement of the paramedian
pontine reticular formation).
Paramedian Pontine Syndromes: Several clinical
syndromes of paramedian pontine infarction have
been described:
* Unilateral mediobasal infarcts: These patients
present with severe faciobrachiocrural hemiparesis,
dysarthria, and homolateral or bilateral ataxia.
* Unilateral mediolateral basal infarcts: Most
patients show slight hemiparesis with ataxia and
dysarthria, ataxic hemiparesis, or dysarthria–clumsy
hand syndrome.
* Unilateral mediocentral or mediotegmental in-
farcts: Presentations include clumsy hand–dysarthria
syndrome, ataxic hemiparesis with prominent sen-
sory or eye movement disorders, and hemiparesis
with contralateral facial or abducens palsy.
*
Bilateral centrobasal infarcts: These patients
have pseudobulbar palsy and bilateral sensorimotor
disturbances.
The most common etiology for paramedian
pontine infarcts is small vessel disease; vertebrobasi-
lar large vessel disease and cardiac embolism are less
common causes.
Lateral Pontine Syndromes
Marie–Foix Syndrome: This syndrome is seen
with lateral pontine lesions, especially those affecting
the brachium pontis. It consists of ipsilateral
cerebellar ataxia due to involvement of cerebellar
connections, contralateral hemiparesis due to invol-
vement of the corticospinal tract, and variable
contralateral hemihypesthesia for pain and tempera-
ture due to involvement of the spinothalamic tract.
Pontine Hemorrhage: Pontine hemorrhage usually
arises from paramedian arterioles and often begins
in the basis pontis. Signs and symptoms of pontine
hematoma depend on size, location, and the pre-
sence or absence of ventricular rupture or hydro-
cephalus. ‘‘Partial’’ pontine hematoma syndromes are
increasingly recognized. Massive (classic) pontine
hemorrhages cause coma, decerebrate rigidity, quad-
riparesis, hyperthermia, absent horizontal eye move-
ments, and miotic but reactive pupils. Ocular
bobbing may be present. An acute locked-in syn-
drome may occur, but often these lesions symme-
trically dissect the pons, destroying the more dorsal
structures.
Primary pontine hemorrhages have been classified
into three clinical types:
* Classic type (60%): There is severe pontine
destruction with quadriparesis, coma, and death.
* Hemipontine syndrome (20%): The hematoma
involves both the basis pontis and the pontine
tegmentum unilaterally and manifests by hemi-
paresis, preserved consciousness, skew deviation,
unilateral absent corneal reflex, dysarthria, facial
nerve palsy, contralateral extremity and ipsilateral
facial sensory changes, and survival with functional
recovery.

* Dorsolateral tegmental syndrome (20%): This
syndrome manifests by gaze paresis or ipsilateral
abducens nerve palsy or both, skew deviation,
unilateral absent corneal reflex, unilateral facial
nerve palsy, contralateral extremity and ipsilateral
facial sensory loss, dysarthria, motor sparing, pre-
served consciousness, occasional gait or limb ataxia,
and survival with functional recovery.
VASCULAR SUPPLY OF THE
MESENCEPHALON
The mesencephalon’s vascular supply includes para-
median and circumferential vessels. The paramedian
vessels (the retromammillary trunk) arise from the
origins of the posterior cerebral arteries and include
the thalamoperforating arteries (supplying the thala-
mus) and the peduncular arteries (supplying the
medial peduncles and the midbrain tegmentum,
including the oculomotor nucleus, the red nucleus,
and the substantia nigra).
The circumferential (peripeduncular) arteries in-
clude the quadrigeminal arteries (arising from the
posterior cerebral arteries), which supply the superior
and inferior colliculi; the superior cerebellar arteries,
which send branches to the cerebral peduncles and
brachium conjunctivum before supplying the super-
ior cerebellum; the posterior choroidal arteries,
which supply the cerebral peduncles, the lateral
superior colliculi, the thalamus, and the choroid
plexus of the third ventricle; the anterior choroidal
arteries (from the internal carotids or middle cerebral
arteries), which in some cases help supply the
cerebral peduncles as well as supramesencephalic
structures; and the posterior cerebral arteries, which
also give rise to some mesencephalic branches.
MESENCEPHALIC SYNDROMES
Ventral Cranial Nerve III Fascicular
Syndrome (Weber’s Syndrome)
A lesion affecting the cerebral peduncle, especially
the medial peduncle, may damage pyramidal fibers
and the fascicle of cranial nerve III. This results in
Weber’s syndrome, which consists of contralateral
hemiplegia (including the lower face) due to corti-
cospinal and corticobulbar tract involvement and
ipsilateral oculomotor paresis, including parasympa-
thetic cranial nerve III paresis (i.e., dilated pupil).
This syndrome may be seen with intrinsic or extrinsic
brainstem lesions. When supranuclear fibers for
BRAINSTEM SYNDROMES 459
horizontal gaze are interrupted in the medial
peduncle, a supranuclear-type conjugate gaze palsy
to the opposite side may occur (the midbrain
syndrome of Foville).
Dorsal Cranial Nerve III Fascicular Syndrome
(Benedikt’s Syndrome)
A lesion affecting the mesencephalic tegmentum may
affect the red nucleus, the brachium conjunctivum,
and the fascicle of cranial nerve III. More ventral
tegmental lesions result in Benedikt’s syndrome,
which consists of ipsilateral oculomotor paresis,
usually with a dilated pupil; and contralateral
involuntary movements, including intention tremor,
hemichorea, or hemiathetosis, due to destruction of
the red nucleus. Similar clinical manifestations are
noted with more dorsal midbrain tegmental lesions
that injure the dorsal red nucleus and brachium
conjunctivum (Claude’s syndrome) but with promi-
nent cerebellar signs and no hemichorea on athetosis.
Dorsal Mesencephalic Syndromes
Dorsal rostral mesencephalic lesions produce mainly
neuroophthalmological abnormalities. The dorsal
mesencephalic syndrome (also known as the Sylvian
aqueduct syndrome, the Koeber–Salus–Elschnig syn-
drome, or Parinaud’s syndrome) is most often seen
with hydrocephalus or tumors of the pineal region.
This syndrome includes all or some of the following
signs:
* Paralysis of conjugate upward gaze (occasionally
downward gaze).
* Pupillary abnormalities (pupils are usually large
with light-near dissociation).
* Convergence–retraction nystagmus on upward
gaze (especially elicited by inducing upward saccades
by a down-moving optokinetic target).
*
Pathological lid retraction (Collier’s sign).
* Lid lag.
* During horizontal refixations, the abducting eye
may move more slowly than the adducting eye
(pseudoabducens palsy), perhaps reflecting excess
convergence tone.
Mesencephalic Hemorrhage
Hemorrhage within the mesencephalon often pre-
sents with headache and vomiting followed by loss of
consciousness. Unequal pupils, which are unreactive
to light but retain the near reflex, are common, as is
impairment of conjugate upward gaze. Partial dorsal
mesencephalic hemorrhages may cause a dorsal
460 BRAIN TRAUMA, CONTRECOUP
mesencephalic (Parinaud’s) syndrome (with rostral
tectal plate bleed), a vertical gaze palsy, skew
deviation, bilateral or unilateral Horner’s syndrome,
as well as bilateral trochlear nerve palsies.
Top of the Basilar Syndrome
Occlusive vascular disease of the rostral basilar artery,
usually embolic, frequently results in the top of the
basilar syndrome due to infarction of the midbrain,
thalamus, and portions of the temporal and occipital
lobes. This syndrome variably includes disorders of
eye movements, such as unilateral or bilateral
paralysis of upward or downward gaze, disordered
convergence, pseudoabducens palsy, convergence–
retraction nystagmus, ocular abduction abnormal-
ities, elevation and retraction of the upper eyelids
(Collier’s sign), skew deviation, and lightning-like eye
oscillations; pupillary abnormalities—small and re-
active, large or midposition and fixed, corectopia, and
occasionally oval pupils; behavioral abnormalities,
such as somnolence, peduncular hallucinosis, memory
difficulties, and agitated delirium; visual defects, such
as hemianopia, cortical blindness, and Balint’s syn-
drome; and motor and sensory deficits.
—Paul W. Brazis
See also–Locked-In Syndrome
Further Reading
Bassetti, C., Bogousslavsky, J., Barth, A., et al. (1996). Isolated
infarcts of the pons. Neurology 46, 165–175.
Bassetti, C., Bogousslavsky, J., Mattle, H., et al. (1997). Medial
medullary stroke: Report of seven patients and review of the
literature. Neurology 48, 882–890.
Bertholon, P., Michel, D., Convers, P., et al. (1996). Isolated body
lateropulsion caused by a lesion of the cerebellar peduncles. J.
Neurol. Neurosurg. Psychiatry 60, 356–357.
Brazis, P. W., Masdeu, J. C., and Biller, J. (1996). Localization in
Clinical Neurology, 3rd ed. Little, Brown, Boston.
Brochier, T., Ceccaldi, M., Milandre, L., et al. (1999). Dorsolateral
infarction of the lower medulla: Clinical–MRI study. Neurology
52, 190–193.
Kataoka, S., Hori, A., Shirakawa, T., et al. (1997). Paramedian
pontine infarction. Neurological/topographical correlation.
Stroke 28, 809–815.
Kim, J. S., and Choi-Kwon, S. (1999). Sensory sequelae of
medullary infarction. Differences between lateral and medial
medullary syndrome. Stroke 30, 2697–2703.
Kim, J. S., Kim, H. G., and Chung, C. S. (1995). Medial medullary
syndrome. Report of 18 patients and a review of the literature.
Stroke 26, 1548.
Kim, J. S., Lee, J. H., Im, J. H., et al. (1995). Syndromes of pontine
base infarction. A clinical–radiological correlation study. Stroke
26, 950.
Kim, J. S., Lee, J. H., and Lee, M. C. (1997). Patterns of sensory
dysfunction in lateral medullary infarction. Clinical–MRI
correlation. Neurology 49, 1557–1563.
Kim, J. S., Lee, J. H., and Choi, C. G. (1998). Patterns of lateral
medullary infarction. Vascular lesion–magnetic resonance
imaging correlation of 34 cases. Stroke 29, 645–652.
Tatu, L., Moulin, T., Bogoisslavsky, J., et al. (1996). Arterial
territories of human brain: Brainstem and cerebellum. Neurol-
ogy 47, 1125–1135.
Terao, S., Izumi, M., Takatsu, S., et al. (1998). Serial magnetic
resonance imaging shows separate medial and lateral medullary
infarctions resulting in the hemimedullary syndrome. J. Neurol.
Neurosurg. Psychiatry 65, 134–135.
Vaudens, P., and Bogousslavsky, J. (1998). Face–arm–trunk–leg
sensory loss limited to the contralateral side in lateral medullary
infarction: A new variant. J. Neurol. Neurosurg. Psychiatry 65,
255–257.
Vuilleumier, P., Bogousslavsky, J., and Regli, F. (1995). Infarction
of the lower brainstem. Clinical, aetiological, and MRI–
topographical correlation. Brain 118, 1013.
Brain Trauma, Contrecoup
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE WORD CONTRECOUP is French, meaning ‘‘coun-
ter blow,’’ and refers to a traumatic brain injury
contralateral to the site of impact. These injuries
result when the force of an impact moves the
intracranial contents away from the blow. The
intracranial contents (e.g., brain) are then stopped
by the skull opposite the site of the impact.
Contrecoup injuries often occur at the floors of the
frontal and temporal fossae, which have many bony
protuberances. The resulting traumatic injury can
include contusions and subarachnoid hemorrhage.
Surgical evacuation of hematomas may be required if
significant mass effect or increased intracranial
pressure result.
—Wendy Elder and Robert F. Spetzler
See also–Brain Injury, Traumatic:
Epidemiological Issues; Brain Trauma, Overview;
Head Trauma, Overview
Brain Trauma, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN INJURY is the major cause of death and
disability among trauma patients worldwide. Trau-
matic brain injury particularly affects younger
patients and imposes an enormous socioeconomic

Breath-Holding Spells
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BREATH-HOLDING SPELLS (BHSs) are the most com-
mon nonepileptic paroxysmal event of early child-
hood. Because the infant stops breathing, usually
becomes cyanotic, and loses consciousness, BHSs are
also one of the most frightening paroxysmal events a
parent or other person can witness. The historical
literature uses numerous terms for BHSs, including
cyanotic or pallid infantile syncope, reflex anoxic
seizures, nonepileptic vagal attacks, white reflex
syncope, and anoxic convulsions. The term BHS
incorrectly implies that an infant voluntarily holds
his or her breath during inspiration. In reality, these
events are an involuntary reflex occurring at the end
of expiration.
CLINICAL DESCRIPTION
There is a stereotyped clinical sequence in BHSs.
Something upsets, frightens, angers, or frustrates the
infant, and he or she begins to cry. After a variable
period, sometimes only a whimper or two and other
times a prolonged period of crying, the infant
become noiseless, the mouth is open in expiration,
and the face and limbs change color, usually cyanotic
but occasionally pale. Most episodes end immedi-
ately after this abrupt silent pause when the infant
takes a deep, usually loud inspiration and returns to
normal activity. In a simple BHS, the child does not
lose consciousness.
Severe BHSs continue after the expiratory pause.
In rapid sequence, the cyanosis or pallor gets worse
and the child becomes dazed, loses consciousness,
becomes hypotonic, and falls. Muscle tone suddenly
increases, and the child becomes opisthotonic.
Occasionally, the infant has myoclonic jerks and/or
urinary incontinence. At this point, breathing re-
starts, usually with a loud inspiratory gasp. During
the next few minutes, the child gradually returns to
normal consciousness. BHSs rarely trigger anoxic
seizures or status epilepticus.
Differential Diagnosis
BHSs are easily recognized and rarely confused with
other neurological problems; however, several differ-
ent disorders need to be considered in any child with
BHSs. Epileptic seizures are at the top of this but
usually are not provoked by crying, and during
BREATH-HOLDING SPELLS 473
seizures changes in muscle tone and posture usually
precede color changes. In addition, many children
with epileptic seizures have epileptiform discharges
on their electroencephalogram, whereas most chil-
dren with BHSs do not. Most children with ortho-
static syncope do not cry, are aware of the event, and
protect themselves when falling. Most apneic spells
occur during sleep and are easily distinguished from
BHSs that only occur during wakefulness. Chiari
malformations and other abnormalities of the
pontomedullary portion of the brainstem can usually
be excluded with a careful history and examination.
Gastroesophageal reflux and cardiac abnormalities,
especially long QT syndrome, need to be included in
the differential diagnosis and are easily eliminated
with appropriate diagnostic studies.
EPIDEMIOLOGY
Simple BHS are extremely common—they may occur
in more than 25% of children—and usually are not
reported to physicians. Severe BHSs are much less
frequent but still occur in up to 4.6% of healthy
infants.
The age of onset for BHSs is typically between 6
and 18 months. However, there are reports of onset
as early as the first weeks of life. Most clinicians
agree that onset after 24 months is unusual. A
positive family history can be found in as many as
25% of affected children; 80% are on the maternal
side, but the inheritance is thought to be autosomal
dominant with variable penetration.
In a prospective study of 95 children with BHSs,
DiMario found males and females equally involved.
Median onset was 6–12 months; the youngest patient
presented within hours of birth and the oldest at 30
months. Others have reported the initial BHS as late
as 42 months. The median frequency of BHSs was
weekly, but 30% of children had daily events,
frequently several per day. In this study, 51% of the
children had cyanotic BHSs, 28% had pallid spells,
and 21% had both pallid and cyanotic events.
Similar ratios were reported in other large studies.
Thirty-four percent of the children had an immediate
family member with BHSs. Fifteen children had
anoxic seizures. A few were treated with antiepileptic
medications, but seizures did not improve.
NATURAL HISTORY
Most children have onset before 1 year, peak BHS
frequency in the second year, a slow tapering during
474 BREATH-HOLDING SPELLS
the third and fourth years, and termination by 4
years. A few children will persist beyond 4 years, but
there has been no reported BHSs beyond 8 years.
LONG-TERM OUTCOME
As noted previously, most BHSs stop by 4 years. No
serious long-term neurological sequelae have been
reported, even in children with very frequent severe
BHSs or prolonged postanoxic seizures. Approxi-
mately 17% of children with BHSs develop syncope
in late childhood or adolescence. Up to 4.8% of
children with BHSs develop seizures, but many of
these are simple febrile seizures and there has not
been any reported increased incidence of epilepsy in
these children. A few children have died during
BHSs, presumably secondary to aspiration and
possibly complicated by incorrect resuscitation.
PATHOPHYSIOLOGY
The exact etiology of BHSs is unknown, but most
studies point to differences between cyanotic and
pallid events. Abnormalities in peripheral or central
chemosensors, peripheral respiratory mechanosen-
sors, or brainstem respiratory pathways have not
been demostrated. In cyanotic spells there appears to
be spasm of the glottis and respiratory muscles and
no movement of the diaphragm. Arterial oxygen
saturation falls below 20 mmHg within 20 sec.
Pulmonary or cardiac shunting during BHSs have
not been convincingly demonstrated, and it is not
known why arterial oxygen saturation decreases so
rapidly. Increased thoracic pressure causes cardiac
output to decrease, and consciousness is lost within
30 sec. When consciousness is lost, the glottis opens,
respiratory muscles relax, breathing resumes, oxygen
content increases, and cardiac output returns to
normal.
Autonomic dysfunction may cause pallid BHSs.
Ocular compression causes at least 2 sec of asystole
in the majority of infants with pallid spells, but it
does not cause asystole in children without BHSs and
in few children with cyanotic BHSs. DiMario et al.
demonstrated significant differences in the peripheral
autonomic nervous system between children with
and without pallid BHSs. A subsequent study
demonstrated significant differences in heart rate
control in children with pallid BHSs and speculated
that they had a defect in central parasympathetic
control.
Iron deficiency may have a role in BHSs. Mocan
et al. followed 91 children with BHSs. Sixty-three of
the patients had iron deficiency anemia and were
treated with iron; 28 did not have anemia, were not
treated, and were used as controls. Eighty-four
percent had complete or partial resolution with
treatment, but only 21% of the children without
anemia improved (po0:02). This study has not been
duplicated, and most series have not found signifi-
cant anemia in children with BHSs. Because iron is
needed for catecholamine metabolism and neuro-
transmitter function, some authors have speculated
that iron deficiency may have central effects that
predispose infants to BHSs.
EVALUATION
Every child with severe BHSs should have a complete
medical history and physical examination. A char-
acteristic description of the child’s BHSs coupled
with a normal neurological and developmental
examination is usually sufficient to rule out serious
neurological or medical causes, and neuroimaging or
extensive diagnostic testing are rarely indicated.
Every child should have a CBC to rule out iron
deficiency anemia and an electrocardiogram to rule
out long QT syndrome. Children with anoxic
seizures should have an electroencephalogram to
rule out possible epilepsy.
TREATMENT
Although frightening to watch, BHSs are benign and
do not require treatment. Clinicians need to counsel
parents and provide reassurance that the spells will
not harm their baby. The infant should be placed on
his or her side. Caretakers should not pick the child
up because this might prolong cerebral anoxia, they
should not attempt cardiopulmonary resuscitation
because this is unnecessary and may cause aspiration
or other problems, and they should not allow the
BHSs to alter child rearing or disciplining because
this may lead to later behavioral problems. When
present, iron deficiency and other types of anemia
should be treated. Brief myoclonic jerks or convul-
sions do not require treatment and do not respond to
antiepileptic medications. Children with prolonged
convulsions are usually treated with anticonvulsants,
but there are no convincing data that this practice
prevents or shortens future events. The rare infant
with prolonged convulsive activity can be treated as
necessary with rectal diazepam. Babies with frequent

or severe pallid BHSs and asystole with ocular
compression can be treated successfully with oral
atropine. Transdermal scopalamine, theophylline,
and cardiac pacemakers have been used successfully
in highly selected individuals but are rarely necessary
or indicated.
—Donald P. Younkin and Matthew T. Hendell
See also–Myoclonus; Respiration; Sudden Infant
Death Syndrome (SIDS); Syncope
Further Reading
DiMario, F. J. (1992). Breath-holding spells in childhood. Am. J.
Dis. Child. 146, 125–131.
DiMario, F. J. (2001). Prospective study of children with cyanotic
and pallid breath-holding spells. Pediatrics 107, 265–269.
DiMario, F. J., Chee, C. M., and Berman, P. B. (1990). Pallid
breath-holding spells: Evaluation of the autonomic nervous
system. Clin. Pediatr. 29, 17–24.
Kuhle, S., Tiefenthaler, M., Seidl, R., et al. (2000). Prolonged
generalized epileptic seizures triggered by breath-holding spells.
Pediatr. Neurol. 23, 271–273.
Mocan, H., Yildiran, A., Orhan, F., et al. (1999). Breath holding
spells in 91 children and response to treatment with iron. Arch.
Dis. Child. 81, 261–262.
Breathing
see Respiration
Broca, Pierre-Paul
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
PIERRE-PAUL BROCA (1824–1880) was one of the
great neurologists of the 19th century, and today he
is widely known for his many contributions to the
BROCA, PIERRE-PAUL 475
field. To Broca goes the credit for firmly establishing
the importance of the left posterior–inferior frontal
lobe in the production of speech, and his name is
attached to this area of the brain and to the aphasia
syndrome that results when it is damaged. He was
also the first to describe the limbic system, recogniz-
ing its significance by reference to its place in the
evolutionary development of Homo sapiens.
Broca was born in the small French town of Sainte-
Foy-la-Grande. His initial training was in medicine at
the University of Paris, and his interests were in
pathology and surgery as well as neurology. He even-
tually rose to the rank of professor of surgery. Early
in his career he turned to anthropology, his other
major career interest, and he was able to maintain an
active presence in both fields. Neurology and anthro-
pology served to complement each other in Broca’s
expansive mind. In anthropology, for example, he
was the first to describe Cro-Magnon man, and he
developed instruments for measuring skulls so as to
compare the cranial capacities of various species. He
was sympathetic to Charles Darwin’s theory of
evolution by natural selection, and Darwin’s collea-
gue T. H. Huxley was a strong admirer. Broca’s
founding of the Paris Society of Anthropology in
1859—the same year as the publication of Darwin’s
The Origin of Species—signified his opposition to the
established clerical orthodoxy of his day, and he
advocated a materialistic view of mental phenomena
that naturally led to the search for the localization of
brain function. Thus, his efforts in neurology and
anthropology were inextricably linked.
In 1861, Broca made his most important contribu-
tion to neurology and the neurosciences. Before the
Society of Anthropology, Broca presented the case of
an epileptic man who lost all ability to speak except
the single word ‘‘tan.’’ Naming this syndrome
‘‘aphemia,’’ he then reported the autopsy findings
of damage to the posterior part of the third frontal
convolution in the left hemisphere and concluded
that this part of the frontal lobe was indispensable
for speech production. Six months later, Broca
presented a similar case, again with damage to this
part of the left frontal lobe. Despite criticisms that
other areas of the brain were involved in his cases,
and that some cases with similar language disorder
did not have frontal lobe lesions, Broca’s observa-
tions came to be accepted because the weight of
subsequent evidence adequately supported his
claims. Today, Broca’s area in the left frontal lobe
is widely recognized as a critical component of the
language region, and Broca’s aphasia is the syndrome

or severe pallid BHSs and asystole with ocular
compression can be treated successfully with oral
atropine. Transdermal scopalamine, theophylline,
and cardiac pacemakers have been used successfully
in highly selected individuals but are rarely necessary
or indicated.
—Donald P. Younkin and Matthew T. Hendell
See also–Myoclonus; Respiration; Sudden Infant
Death Syndrome (SIDS); Syncope
Further Reading
DiMario, F. J. (1992). Breath-holding spells in childhood. Am. J.
Dis. Child. 146, 125–131.
DiMario, F. J. (2001). Prospective study of children with cyanotic
and pallid breath-holding spells. Pediatrics 107, 265–269.
DiMario, F. J., Chee, C. M., and Berman, P. B. (1990). Pallid
breath-holding spells: Evaluation of the autonomic nervous
system. Clin. Pediatr. 29, 17–24.
Kuhle, S., Tiefenthaler, M., Seidl, R., et al. (2000). Prolonged
generalized epileptic seizures triggered by breath-holding spells.
Pediatr. Neurol. 23, 271–273.
Mocan, H., Yildiran, A., Orhan, F., et al. (1999). Breath holding
spells in 91 children and response to treatment with iron. Arch.
Dis. Child. 81, 261–262.
Breathing
see Respiration
Broca, Pierre-Paul
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
PIERRE-PAUL BROCA (1824–1880) was one of the
great neurologists of the 19th century, and today he
is widely known for his many contributions to the
BROCA, PIERRE-PAUL 475
field. To Broca goes the credit for firmly establishing
the importance of the left posterior–inferior frontal
lobe in the production of speech, and his name is
attached to this area of the brain and to the aphasia
syndrome that results when it is damaged. He was
also the first to describe the limbic system, recogniz-
ing its significance by reference to its place in the
evolutionary development of Homo sapiens.
Broca was born in the small French town of Sainte-
Foy-la-Grande. His initial training was in medicine at
the University of Paris, and his interests were in
pathology and surgery as well as neurology. He even-
tually rose to the rank of professor of surgery. Early
in his career he turned to anthropology, his other
major career interest, and he was able to maintain an
active presence in both fields. Neurology and anthro-
pology served to complement each other in Broca’s
expansive mind. In anthropology, for example, he
was the first to describe Cro-Magnon man, and he
developed instruments for measuring skulls so as to
compare the cranial capacities of various species. He
was sympathetic to Charles Darwin’s theory of
evolution by natural selection, and Darwin’s collea-
gue T. H. Huxley was a strong admirer. Broca’s
founding of the Paris Society of Anthropology in
1859—the same year as the publication of Darwin’s
The Origin of Species—signified his opposition to the
established clerical orthodoxy of his day, and he
advocated a materialistic view of mental phenomena
that naturally led to the search for the localization of
brain function. Thus, his efforts in neurology and
anthropology were inextricably linked.
In 1861, Broca made his most important contribu-
tion to neurology and the neurosciences. Before the
Society of Anthropology, Broca presented the case of
an epileptic man who lost all ability to speak except
the single word ‘‘tan.’’ Naming this syndrome
‘‘aphemia,’’ he then reported the autopsy findings
of damage to the posterior part of the third frontal
convolution in the left hemisphere and concluded
that this part of the frontal lobe was indispensable
for speech production. Six months later, Broca
presented a similar case, again with damage to this
part of the left frontal lobe. Despite criticisms that
other areas of the brain were involved in his cases,
and that some cases with similar language disorder
did not have frontal lobe lesions, Broca’s observa-
tions came to be accepted because the weight of
subsequent evidence adequately supported his
claims. Today, Broca’s area in the left frontal lobe
is widely recognized as a critical component of the
language region, and Broca’s aphasia is the syndrome
476 BROCA, PIERRE-PAUL
Figure 1
Drawing of the brain showing Broca’s and Wernicke’s areas.
of nonfluent aphasia routinely associated with
damage to this area (Fig. 1).
Broca’s other major neuroscientific contribution
was his description of the limbic system. In this
neuroanatomical study, he also drew on his knowl-
edge of anthropology. In 1878, he was able to
identify a group of structures in the inner wall of the
cerebral hemispheres that was much more developed
in lower mammals than in humans. He correctly
observed that the limbic system, so named because it
occupied the border region (limbus is the Latin word
for border) around the diencephalon, was primarily
involved in the sense of smell and that higher
animals, including humans, depend less on this sense
than do those lower on the evolutionary scale.
Subsequently, it was determined that the limbic
system in humans is mainly devoted to emotion
and memory, a conclusion made possible by Broca’s
initial observation.
Today, Broca is recognized as one of the most
important neurologists who pioneered the under-
standing of brain–behavior relationships. His vigor-
ous advocacy of the concept of cerebral localization,
particularly of the capacity for articulate speech,
served to advance the notion that mental functions
could be represented in specific regions of the brain.
The significance of this accomplishment should not
be underestimated because in Broca’s day strong
resistance to the idea came both from the Church,
which opposed any attempt to explain mental
phenomena in material terms, and from scientists
who still recalled with disdain the legacy of
phrenology, the discredited pseudoscience of localiz-
ing behavioral traits by palpating bumps and ridges
on the skull. Broca’s persistence in advancing the idea
of cerebral localization led to much additional work
in his era and beyond. In 1874, for example, the
German neurologist Carl Wernicke described pa-
tients who lost the capacity to understand language
because of lesions in the left superior temporal lobe
and thus defined the other best known aphasia type
that is called Wernicke’s aphasia (Fig. 1). In the years
following these discoveries, a wealth of brain–
behavior relationships have been similarly eluci-
dated, and today the sophisticated neuroimaging
instruments are confirming many of these observa-
tions. Broca played a crucial role in laying the
foundation for these kinds of studies and demon-
strated the value of carefully analyzing single cases in
the effort to understand the organization of behavior
in the brain. Notwithstanding the dramatic technical
developments of the current era, the method of single
case study still proves very useful.
Broca’s academic output included approximately
500 scientific papers and a monograph on cerebral
aneurysms. His was a truly encyclopedic mind,
and he is one of the few intellectuals who achieved
major prominence in more than one field. A
committed humanist, he was also active and influen-
tial in many political issues of his day. Although
many of his views were highly controversial, he was
honored near the end of his life with election as a
lifetime member of the Senate of the French Republic.
In the history of neurology and the study of behavior
in general, developments stemming from his work
confirm that Broca’s achievements merit a high
position.
—Christopher Mark Filley
See also–Aphasia; Behavior, Neural Basis of;
Broca’s Area; Frontal Lobes; Limbic System;
Localization; Speech Disorders, Overview;
Wernicke’s Area (see Index entry Biography for
complete list of biographical entries)
Further Reading
Corsi, P. (Ed.) (1991). The Enchanted Loom. Chapters in the
History of Neuroscience. Oxford Univ. Press, New York.
Filley, C. M. (2001). Neurobehavioral Anatomy, 2nd Edition.
Univ. Press of Colorado, Boulder.
McHenry, L. C. (1969). Garrison’s History of Neurology. Thomas,
Springfield, IL.
Mesulam, M.-M. (2000). Principles of Behavioral and Cognitive
Neurology. Oxford Univ. Press, Oxford.
Schiller, F. (1979). Paul Broca, Founder of French Anthropology,
Explorer of the Brain. Univ. of California Press, Berkeley.

Broca’s Aphasia
see Aphasia
Broca’s Area
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BROCA’S AREA is considered one of the critical
anatomical sites within the human brain that has
been associated with language-related functions.
A classic model of language based on lesion localiza-
tion studies from acquired language disorders, or
aphasia, has demonstrated that language is strongly
lateralized (i.e., represented predominantly in one
cerebral hemisphere) and localized to critical anato-
mical sites. In most individuals, the critical language
areas are located within the left cerebral hemisphere
in anterior or frontal regions (Broca’s area) and in
posterior or temporal–parietal regions (Wernicke’s
area) that are interconnected by white matter path-
ways so information flows from posterior to anterior
regions. The anterior or frontal language areas then
‘‘map’’ onto the premotor and primary motor regions
to activate motor systems and produce speech. The
classic Broca’s area is located in the third frontal
convolution of the inferior frontal gyrus and is com-
posed of two adjacent anatomical areas: the more
rostral pars triangularis (Brodmann’s area 45) and the
immediately caudal pars opercularis (Brodmann’s
area 44). Following a brief historical review, the
anatomy and function of Broca’s area is discussed.
HISTORICAL REVIEW
In 1861, Paul Broca examined a patient who had lost
the ability to speak except for the word ‘‘tan,’’ which
he repeated over and over. This patient, who became
known as Tan, also had a dense right-sided weakness
(i.e., hemiparesis). An extensive left hemispheric
lesion involving most of the middle cerebral artery
territory was found postmortem, but Broca identified
a discrete region within the inferior frontal gyrus,
including the pars triangularis and pars opercularis,
as the ‘‘epicenter’’ of this lesion and responsible for
Tan’s expressive language disturbance. Broca found
that this same area was lesioned in a subsequent
series of eight right-handed patients who had dis-
turbed verbal output and a dense right hemiparesis.
BROCA’S AREA 477
Consequently, the region that he identified within the
third frontal convolution of the inferior frontal gyrus
has become known as Broca’s area, and the acquired
language disturbance has become known as Broca’s
aphasia.
Broca also made the important observation that a
language disturbance followed a lesion to the left
cerebral hemisphere, rather than the right, and set
the stage for the model of hemispheric specialization
of language. Although there is evidence that left-
sided lesions restricted to Broca’s area are probably
associated with only a transient loss of speech,
lesions of the right third frontal convolution rarely
produce any speech deficits. Over time, studies of
localized lesions in traumatic brain injury and stroke
and cortical stimulation and recent in vivo neuroi-
maging studies have provided support for the role of
the left inferior frontal lobe in speech production.
Patients who present with the acute onset of the
syndrome of Broca’s aphasia usually have a large left
frontal lesion that includes Broca’s area but extends
beyond the anatomical boundaries to adjacent
dorsolateral frontal and subcortical regions.
BROCA’S APHASIA
The clinical syndrome of Broca’s or motor/expressive
aphasia is characterized by nonfluent spontaneous
speech output and impaired naming and repetition,
with relative preservation of auditory comprehension.
In patients with Broca’s aphasia, verbal output is often
agrammatic because grammatical or filler words (e.g.,
‘‘is’’ and ‘‘the’’) and word endings (e.g., -‘‘ing’’ and
-‘‘es’’) are often omitted, whereas the content words
(e.g., nouns) are preserved, resulting in sparse, tele-
graphic speech output. As such, phrase length is
reduced and output is limited to grammatically simple
utterances. Speech output is often dysarthric and
effortful due to difficulty planning, initiating, and
sequencing articulatory movements, resulting in slur-
red, imprecise articulation. Similar motor planning
problems may be seen in the patient’s gestures because
limb apraxia is not uncommon. Motor speech deficits,
associated with right-sided hemiparesis, are not
uncommon and may further interfere with intellig-
ibility. Inflection and intonation are also affected so
that the patient’s speech is often monotone and lack-
ing the variations that characterize normal prosody.
Word retrieval or naming disturbances associated
with Broca’s aphasia are characterized by more
difficulty retrieving verbs compared to nouns. Para-
phasic errors, where phonemes are incorrectly added,
478 BROCA’S AREA
substituted, or omitted in spoken words or semanti-
cally related words are substituted, may be present.
Although auditory comprehension is relatively pre-
served, deficits are typically seen as the length and
complexity of the stimuli increase. Significant compre-
hension deficits may be present despite the fact that the
patient can follow one- and two-step commands,
which are often used during bedside screenings. State-
ments provided in the passive voice, where word order
provides limited information, are particularly difficult
to comprehend (i.e., ‘‘The boy was helped by the girl’’).
Similarly, individuals with a Broca’s aphasia have
difficulty understanding complex grammatical struc-
tures, termed asyntactic auditory comprehension defi-
cits. Impairments in reading and writing reflect the
deficits observed in oral language production and
comprehension; their written output is often tele-
graphic and they have relatively more difficulty using
grammatical words and verbs and less difficulty with
concrete nouns.
Many patients with acute onset of Broca’s aphasia
eventually recover to milder forms of aphasia,
including transcortical motor and anomic aphasias.
In cases in which a global aphasia is present initially
but the lesion spares posterior temporal regions and
subcortical white matter, the aphasia may evolve into
a chronic Broca’s aphasia, as seen in patients who
recover auditory comprehension and verbal abilities.
Studies of infarctions that selectively affect Broca’s
area have shown that patients develop a relatively
mild impairment of speech execution, or apraxia of
speech, that may resolve over time, which is in
keeping with Broca’s original conception of the role of
this region in articulation skills. There is evidence that
the neural mechanisms of recovery of speech produc-
tion skills may relate to the homologous frontal region
on the right. These observations suggest that although
the left inferior frontal lobe appears to be important
in speech production, other areas can be recruited to
participate, albeit in a more limited capacity, to either
compensate or substitute for this area.
NEURAL NETWORKS AND ANATOMICAL
REGIONS MEDIATING SPEECH AND
LANGUAGE FUNCTIONS
Current cognitive neuroscience models of language
argue against a precise anatomical location that has a
one-to-one structure–function correspondence. These
models contend that specific cognitive processes are
mediated by a widely distributed ‘‘network’’ of
cortical regions that are interconnected and function
together to mediate a specific cognitive process.
Grossly, the network that mediates speech–language
function is often divided along the horizontal axis of
the Sylvian fissure, with the central sulcus, or
Rolandic fissure, approximately determining the
anterior–posterior division. The anterior or pre-
Rolandic cortex plays a more prominent role in
expressing oral language, whereas the posterior, post-
Rolandic territory is more important for the percep-
tion and comprehension of spoken language. Anato-
mical regions important in speech–language functions
include portions of the superior, middle, and inferior
temporal gyri, the inferior parietal lobule, frontal lobe
areas including the inferior frontal gyrus, and motor
cortical areas. Despite the fact that multiple and
widely distributed anatomical regions contribute to
speech–language functions, the most critical areas are
localized within perisylvian cortical areas (i.e., Broca’s
and Wernicke’s areas) that are interconnected by
interhemispheric white matter commissures. Lan-
guage functions are highly lateralized, with the left
cerebral hemisphere playing a dominant role in most
linguistically intact right-handed and left-handed
adults, although left-handers are not as strongly
lateralized to the left. Thus, the left hemisphere is
considered dominant for speech–language functions.
ANATOMY OF BROCA’S AREA
Anatomically, Broca’s area is located in the third
frontal convolution of the inferior frontal gyrus
(Fig. 1). This region includes the pars triangularis
and pars opercularis. The inferior frontal gyrus is
divided into these constituent parts by the anterior
ascending rami of the Sylvian fissure. When viewed
from the lateral surface of the cerebral hemisphere,
the pars triangularis often has the shape of an
inverted triangle, hence the name pars triangularis.
The pars triangularis is bounded superiorly by the
inferior frontal sulcus, which forms the base of the
inverted triangle, and inferiorly by the anterior rami
of the Sylvian fissure. The anterior extent of the pars
triangularis is determined by the most anterior point
of the anterior horizontal ramus, whereas the
anterior ascending ramus determines its posterior
boundary. The intersection of the anterior horizontal
ramus and the anterior ascending ramus forms the
apex of the triangle. In the latter part of the 19th
century, Cunningham and Eberstaller described the
anatomy of this region in detail and noted that
the anterior rami, which constitute the inferior
boundary of the pars triangularis, may vary in their

Figure 1
The lateral surface of the human brain is depicted with Broca’s
area shown within the inferior frontal gyrus (IFG). The portion of
the IFG shown includes the pars triangularis and pars opercularis,
which are the anatomical subregions of Broca’s area.
morphology with characteristic configurations, in-
cluding (i) a single ramus, which is ‘‘I’’ or ‘‘J’’ shaped;
(ii) two rami emerging from a common stem, which
are ‘‘Y’’ shaped; and (iii) two widely separated rami,
which are ‘‘V’’ or ‘‘U’’ shaped. A single anterior
ramus may be seen on rare occasion, but it is more
common to see two distinct anterior rami.
The pars opercularis, which is often shaped like a
rectangle, is located immediately adjacent and caudal
to the pars triangularis. The anterior ascending ramus
simultaneously determines the posterior boundary of
the pars triangularis and the anterior boundary of the
pars opercularis, whereas the posterior boundary has
been variously defined as the precentral sulcus or the
subcentral sulcus. Pars triangularis and pars oper-
cularis also share superior–inferior boundaries. Like
the pars triangularis, the pars opercularis extends
inferiorly from the anterior rami of the Sylvian fissure
to the inferior frontal gyrus, superiorly. Thus, Broca’s
area extends along the inferior frontal gyrus and
encompasses the more anterior pars triangularis and
the more posterior pars opercularis, separated by the
anterior ascending ramus.
ANATOMICAL ASYMMETRIES OF
BROCA’S AREA
Early lesion studies suggested that language func-
tions were lateralized to the left hemisphere. How-
ever, it was not until the 1960s that anatomical
studies revealed structural asymmetries of language-
related cortex, which probably reflect some aspects
BROCA’S AREA 479
of hemispherical specialization for language func-
tions. Specifically, some language-related structures
were found to be larger in the left hemisphere
compared to right hemisphere homologs. This
leftward (left larger than right) structural asymmetry
was believed to reflect the leftward functional
lateralization or asymmetry of language. One of the
first documented cortical asymmetries was that of the
planum temporale, which lies deep within the Sylvian
fissure, on the horizontal plane of the temporal lobe,
and constitutes part of the area known as Wernicke’s
area. Initial postmortem studies found that the
planum temporale was larger on the left side
compared to the homologous area on the right. This
leftward structural asymmetry was believed to reflect
the functional asymmetry documented a century
earlier. Anatomical asymmetries of the frontal
operculum have been more difficult to document in
comparison to asymmetries of posterior cortical
language areas, even though functional asymmetry
is more marked anteriorly than posteriorly. One of
the earliest postmortem studies of the frontal
operculum in adult and infant brains failed to
identify any hemispherical asymmetry of the frontal
operculum; however, this study was limited to
measures of the surface area of the pars opercularis
and a posterior portion of the pars triangularis. As
such, the lack of asymmetry was believed to be an
artifact of the surface measuring technique. The
investigators speculated that an accurate measure of
the depths of the convolutions would likely reveal a
leftward asymmetry of this region because the
pattern of gyrification of the third frontal convolu-
tion was more elaborate in the left hemisphere. True
to this prediction, subsequent investigators measured
the depths of the convolutions and found a leftward
structural asymmetry (left larger than right) in some
portions of Broca’s area, consistent with the func-
tional asymmetry pattern suggested by lesion studies.
With the advent of volume acquisition magnetic
resonance imaging (MRI) scans in the 1990s,
investigators have been able to view brain regions
in vivo that were previously inaccessible on post-
mortem specimens and were not clearly visible on
conventional computed tomography or MRI scans.
Measures of language laterality and handedness
could be obtained in the same individuals who had
received volumetric MRI scans, allowing direct
structure–function correlations. The first evidence
of a leftward asymmetry of anterior language regions
was revealed in a group of healthy patients. A
measure of the intrasulcal surface area of the pars
480 BRODMANN, KORBINIAN

triangularis, a portion of Broca’s area, revealed a
leftward asymmetry in 7 of 8 right-handed subjects
and 3 of 8 left-handed subjects. Two subjects had
symmetrical structures, whereas 4 of the 8 left-
handed subjects showed a rightward asymmetry of
the pars triangularis. In another study, the pars
triangularis was measured on volumetric MRI scans
of patients with epilepsy who had undergone Wada
testing for language localization. Nine of the 10
patients with language lateralized to the left had a
leftward asymmetry of the pars triangularis. The 1
patient with language lateralized to the right hemi-
sphere had a significant rightward asymmetry of the
pars triangularis. These data suggest that anatomical
asymmetries of the pars triangularis, a portion of
Broca’s area, may be linked in part to some aspects of
language lateralization.
Although the pars opercularis is part of the classic
Broca’s area, it probably differs from the pars
triangularis both structurally and functionally. Cy-
toarchitectonic and functional imaging studies have
demonstrated that the pars triangularis is composed
of higher order heteromodal association cortex more
suited to complex cross-modal associations typical of
linguistic functions, whereas the pars opercularis is
composed of motor association cortex more suited to
articulatory and motor speech functions. Recent
functional neuroimaging studies have shown that
the anatomical subregions of Broca’s area may be
functionally distinct. Specifically, the pars triangularis
may function more critically in lexical retrieval (i.e.,
lexical–semantic functions), whereas the pars oper-
cularis may selectively subserve articulatory motor
speech functions (i.e., motor speech functions). There
anterior linguistic region (pars triangularis) and a
posterior motor speech region (pars opercularis).
Whether gross anatomical asymmetries of the pars
opercularis are more directly related to hand pre-
ference requires further functional correlation.
—Anne L. Foundas, Anastasia M. Raymer,
and Angela M. Bollich
See also–Anomia; Aphasia; Brain Anatomy;
Broca, Pierre-Paul; Language Disorders,
Overview; Language, Overview; Wernicke’s
Area (see Index entry Biography for complete
list of biographical entries)
Further Reading
Foundas, A. L., Leonard, C. M., Gilmore, R., et al. (1996). Pars
triangularis asymmetry and language dominance. Proc. Natl.
Acad. Sci. USA 93, 719–722.
Foundas, A. L., Eure, K. F., Luevano, L. F., et al. (1998). MRI
asymmetries of Broca’s area: The pars triangularis and pars
opercularis. Brain Language 64, 282–296.
Leonard, C. M. (1998). Language and the prefrontal cortex. In
Development of the Prefrontal Cortex: Evolution, Neurobiol-
ogy, and Behavior (N. A. Krasnegor, L. Reid, and P. E.
Goldman-Rakic, Eds.), pp. 141–166. Brookes, Baltimore.
Levine, D. N., and Sweet, E. (1983). Localization of lesions in
Broca’s motor aphasia. In Localization in Neuropsychology (A.
Kertesz, Ed.), pp. 185–208. Academic Press, New York.
Mohr, J. P., Pessin, M. S., Finkelstein, S., et al. (1978). Broca’s
aphasia: Pathologic and clinical aspects. Neurology 28,
311–324.
Brodmann, Korbinian
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

is also functional–anatomical evidence that these two

regions may subserve different functions. A study of
the morphology of the frontal operculum was
conducted to determine whether measurable asym-
metries of the pars opercularis exist and whether the
direction of these asymmetries differs in right- and
left-handers. There was a significant leftward asym-
metry of the pars triangularis in both right- and left-
handers, although the magnitude of the asymmetry
was reduced in the left-handers. In contrast, there was
a leftward asymmetry of the pars opercularis in the
right-handers and a rightward asymmetry in the left-
handers. Furthermore, there was a positive correla-
tion between pars opercularis asymmetries and hand
preference derived from a handedness inventory.
These data must be interpreted with caution due to KORBINIAN BRODMANN (1868–1918) was a German
the small sample size, but these findings support the neuroanatomist who is remembered today for devis-
notion that Broca’s area may fractionate into an ing a system whereby the cerebral cortex is divided
480 BRODMANN, KORBINIAN

triangularis, a portion of Broca’s area, revealed a
leftward asymmetry in 7 of 8 right-handed subjects
and 3 of 8 left-handed subjects. Two subjects had
symmetrical structures, whereas 4 of the 8 left-
handed subjects showed a rightward asymmetry of
the pars triangularis. In another study, the pars
triangularis was measured on volumetric MRI scans
of patients with epilepsy who had undergone Wada
testing for language localization. Nine of the 10
patients with language lateralized to the left had a
leftward asymmetry of the pars triangularis. The 1
patient with language lateralized to the right hemi-
sphere had a significant rightward asymmetry of the
pars triangularis. These data suggest that anatomical
asymmetries of the pars triangularis, a portion of
Broca’s area, may be linked in part to some aspects of
language lateralization.
Although the pars opercularis is part of the classic
Broca’s area, it probably differs from the pars
triangularis both structurally and functionally. Cy-
toarchitectonic and functional imaging studies have
demonstrated that the pars triangularis is composed
of higher order heteromodal association cortex more
suited to complex cross-modal associations typical of
linguistic functions, whereas the pars opercularis is
composed of motor association cortex more suited to
articulatory and motor speech functions. Recent
functional neuroimaging studies have shown that
the anatomical subregions of Broca’s area may be
functionally distinct. Specifically, the pars triangularis
may function more critically in lexical retrieval (i.e.,
lexical–semantic functions), whereas the pars oper-
cularis may selectively subserve articulatory motor
speech functions (i.e., motor speech functions). There
anterior linguistic region (pars triangularis) and a
posterior motor speech region (pars opercularis).
Whether gross anatomical asymmetries of the pars
opercularis are more directly related to hand pre-
ference requires further functional correlation.
—Anne L. Foundas, Anastasia M. Raymer,
and Angela M. Bollich
See also–Anomia; Aphasia; Brain Anatomy;
Broca, Pierre-Paul; Language Disorders,
Overview; Language, Overview; Wernicke’s
Area (see Index entry Biography for complete
list of biographical entries)
Further Reading
Foundas, A. L., Leonard, C. M., Gilmore, R., et al. (1996). Pars
triangularis asymmetry and language dominance. Proc. Natl.
Acad. Sci. USA 93, 719–722.
Foundas, A. L., Eure, K. F., Luevano, L. F., et al. (1998). MRI
asymmetries of Broca’s area: The pars triangularis and pars
opercularis. Brain Language 64, 282–296.
Leonard, C. M. (1998). Language and the prefrontal cortex. In
Development of the Prefrontal Cortex: Evolution, Neurobiol-
ogy, and Behavior (N. A. Krasnegor, L. Reid, and P. E.
Goldman-Rakic, Eds.), pp. 141–166. Brookes, Baltimore.
Levine, D. N., and Sweet, E. (1983). Localization of lesions in
Broca’s motor aphasia. In Localization in Neuropsychology (A.
Kertesz, Ed.), pp. 185–208. Academic Press, New York.
Mohr, J. P., Pessin, M. S., Finkelstein, S., et al. (1978). Broca’s
aphasia: Pathologic and clinical aspects. Neurology 28,
311–324.
Brodmann, Korbinian
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

is also functional–anatomical evidence that these two

regions may subserve different functions. A study of
the morphology of the frontal operculum was
conducted to determine whether measurable asym-
metries of the pars opercularis exist and whether the
direction of these asymmetries differs in right- and
left-handers. There was a significant leftward asym-
metry of the pars triangularis in both right- and left-
handers, although the magnitude of the asymmetry
was reduced in the left-handers. In contrast, there was
a leftward asymmetry of the pars opercularis in the
right-handers and a rightward asymmetry in the left-
handers. Furthermore, there was a positive correla-
tion between pars opercularis asymmetries and hand
preference derived from a handedness inventory.
These data must be interpreted with caution due to KORBINIAN BRODMANN (1868–1918) was a German
the small sample size, but these findings support the neuroanatomist who is remembered today for devis-
notion that Broca’s area may fractionate into an ing a system whereby the cerebral cortex is divided
 BRODMANN, KORBINIAN 481

into discrete areas based on distinct microscopic famous (Fig. 1). In this and subsequent publications
features. Despite many criticisms of his scheme, that slightly modified the depiction, he defined
Brodmann remains one of the most familiar neuro- approximately 50 areas of the cortex that had
anatomists because of the widespread acceptance of different architectonic features.
his system in the continuing research effort to Brodmann’s scheme was not the only attempt to
understand cortical structure and function. parcellate the cerebral cortex. Many other neuro-
Brodmann was born in Liggersdorf, Hohenzollern, anatomists offered similar systems, which could
and initially studied to become a general practitioner. include up to 200 different cortical zones. These
Within a year of practicing in Munich, however, he attempts, especially that of Brodmann, generated
contracted diphtheria and was obliged to recuperate strong opposition from many neuroscientists in the
in a sanatorium in northern Bavaria. While con- early 20th century. Some critics questioned whether
valescing, he met neuroanatomist Oscar Vogt, who discrete cortical areas could be reliably identified. It
encouraged him to pursue the study of neurology and was noted, for example, that different areas may
psychiatry, and in 1898 he received his medical blend imperceptibly into others without a distinct
degree at Leipzig. In the years 1900 and 1901, he border, and that individual brains vary in the degree
worked with Alois Alzheimer in Frankfurt-am-Main, to which certain areas can be found. Furthermore,
who was prominent in his time and is so currently, because specific Brodmann areas typically had no
and it was here that Brodmann developed his career known functional specialization at that time, the
interest in neuroanatomy. In 1901, he went to existence of subtle cytoarchitectonic differences was
Neurobiologisches Institute in Berlin to work with
Vogt, where he remained until 1910. Academic
opposition to his work led to economic uncertainty
for Brodmann in Berlin, and he spent the last 8 years
of his life in positions in Tubingen, Halle, and
Munich attempting to continue his earlier work.
Despite greater acceptance among his colleagues and
further professional advancement, the outbreak of
World War I in 1914 seriously interfered with his
research. He died in 1918 at the age of 50.
The major contributions made by Brodmann came
while he was in Berlin between 1901 and 1910. His
work focused on cytoarchitectonics, which is the
study of the arrangement of neurons in the brain.
This kind of work is done by the meticulous
observation of brain regions that have been prepared
for microscopic examination by careful sectioning
and staining of brain tissue obtained postmortem.
Because of the imposing complexity of the brain’s
anatomy, such a system is crucial if researchers are to
have a means of reliably identifying different brain
regions. In particular, Brodmann was interested in
cortical cytoarchitectonics, or the arrangement of
neurons in the cerebral cortex, the outermost layer of
the brain where it was assumed that the highest
human functions are organized.
In a series of papers published between 1903 and
1908, Brodmann presented his findings on the details
of cortical structure in humans and many other
species, concluding that the basic layering of the
cortex in all these species was the same. In 1909, he
published a major monograph in which appeared the Figure 1
human cortical map for which he would become The cortical map of Brodmann.
482 BRODMANN’S AREAS
further called into question. Others thought that
Brodmann had engaged in nothing more than a form
of phrenology, the discredited pseudoscience of the
previous century that claimed to link personality
traits with brain areas associated with bumps and
ridges on the skull.
Despite these criticisms, Brodmann’s map has
endured for nearly a century, and it has become a
standard reference used by clinical and basic in-
vestigators interested in cortical structure and func-
tion. With the advent of improved neuroanatomical
and neuroimaging techniques in the latter part of the
20th century, the importance of Brodmann areas for
understanding the functions and connections of
cortical regions has become more clear. Today, the
use of Brodmann areas is commonplace in research
articles on localization of cortical function. This is
not to suggest that all his areas have well-established
roles, but that they have proved to be convenient
landmarks providing a common topographical or-
ientation for the modern study of brain function.
Human cognitive neuroscience currently empha-
sizes that cognitive functions are organized in
distributed neural networks that include multiple
cortical and subcortical regions and their connec-
tions. Thus, there can be no one-to-one relationship
between a discrete cortical region and a given
behavior. In this context, no one of Brodmann’s
areas can be considered to have a single and unique
function, and it is not surprising that his work
engendered controversy over the strict localization of
function implied by their identification. However,
Brodmann performed a vital service by producing the
most useful cortical map—one that continues to
contribute to the understanding of cortical localiza-
tion of function. Sophisticated neuroimaging techni-
ques are now building on the foundation Brodmann
provided, permitting a much greater understanding
of brain–behavior relationships. Brodmann’s initial
identification of cortical areas that participate in the
higher functions of humans ensures his place in the
history of neuroscience.
—Christopher Mark Filley
See also–Brain Anatomy; Brodmann’s Areas;
Cerebral Cortex: Architecture and Connections;
Memory, Working (see Index entry Biography
for complete list of biographical entries)
Further Reading
Brodmann, K. (1909). Vergleichende Lokalisationslehre der
Grosshirnrinde. Barth, Leipzig.
Haymaker, W. (1953). The Founders of Neurology. Thomas,
Springfield, IL.
Kemper, T. L. B., and Galaburda, A. M. (1984). Principles of
cytoarchitectonics. In Cerebral Cortex. Volume 1: Cellular
Components of the Cerebral Cortex (A. Peters and E. G. Jones,
Eds.). Plenum, New York.
Mesulam, M.-M. (2000). Principles of Behavioral and Cognitive
Neurology. Oxford Univ. Press, Oxford.
Pena-Casanova, J., and Bohm, P. (2000). A century beyond
Brodmann: New insights into cortical cytoarchitectonics and
function. Brain Lang. 71, 181–184.
Brodmann’s Areas
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AT APPROXIMATELY the turn of the 20th century, a
group of neuroanatomists, including Alfred Walter
Campbell (1868–1937), Grafton Elliot Smith (1871–
1937), Korbinian Brodmann (1868–1918), and
Cécile (1875–1962) and Oskar Vogt (1870–1950),
set out to study the microanatomy of the cerebral
cortex. They noticed that the size, shape, packing
density, and lamination of neurons in preparations
stained for cell bodies (e.g., with the Nissl technique;
cytoarchitecture) or the distribution pattern of
myelin sheaths in preparations stained for myelin
(e.g., with the Heidenhain–Woelcke technique; mye-
loarchitecture) are not uniform across the cerebral
cortex. Instead, there are marked regional variations.
This allowed the delineation of cortical regions or
areas, characterized by a uniform cyto- or mye-
loarchitectonic pattern, and the definition of borders
between areas where the architectonic pattern
changes (Fig. 1). According to the elementary biolo-
gical principle, what differs in structure should also
differ in function (and vice versa), the question that
immediately arose was: What is the functional
meaning of these areas? The first investigators to
provide an answer to this question were Cécile and
Oskar Vogt, who also studied the cortex of nonhu-
man primates. The brains of animals (in contrast to
human beings) offer the advantage of directly
correlating microstructure with function. Upon
completion of electrophysiological experiments the
brains can be sectioned, sections can be stained for
cell bodies or myelin sheaths, and stimulation and/or
recording sites can be directly compared with the
architectonic pattern. Indeed, it was found that
neurons with similar electrophysiological proper-
ties lie within the same area and, conversely, the
482 BRODMANN’S AREAS
further called into question. Others thought that
Brodmann had engaged in nothing more than a form
of phrenology, the discredited pseudoscience of the
previous century that claimed to link personality
traits with brain areas associated with bumps and
ridges on the skull.
Despite these criticisms, Brodmann’s map has
endured for nearly a century, and it has become a
standard reference used by clinical and basic in-
vestigators interested in cortical structure and func-
tion. With the advent of improved neuroanatomical
and neuroimaging techniques in the latter part of the
20th century, the importance of Brodmann areas for
understanding the functions and connections of
cortical regions has become more clear. Today, the
use of Brodmann areas is commonplace in research
articles on localization of cortical function. This is
not to suggest that all his areas have well-established
roles, but that they have proved to be convenient
landmarks providing a common topographical or-
ientation for the modern study of brain function.
Human cognitive neuroscience currently empha-
sizes that cognitive functions are organized in
distributed neural networks that include multiple
cortical and subcortical regions and their connec-
tions. Thus, there can be no one-to-one relationship
between a discrete cortical region and a given
behavior. In this context, no one of Brodmann’s
areas can be considered to have a single and unique
function, and it is not surprising that his work
engendered controversy over the strict localization of
function implied by their identification. However,
Brodmann performed a vital service by producing the
most useful cortical map—one that continues to
contribute to the understanding of cortical localiza-
tion of function. Sophisticated neuroimaging techni-
ques are now building on the foundation Brodmann
provided, permitting a much greater understanding
of brain–behavior relationships. Brodmann’s initial
identification of cortical areas that participate in the
higher functions of humans ensures his place in the
history of neuroscience.
—Christopher Mark Filley
See also–Brain Anatomy; Brodmann’s Areas;
Cerebral Cortex: Architecture and Connections;
Memory, Working (see Index entry Biography
for complete list of biographical entries)
Further Reading
Brodmann, K. (1909). Vergleichende Lokalisationslehre der
Grosshirnrinde. Barth, Leipzig.
Haymaker, W. (1953). The Founders of Neurology. Thomas,
Springfield, IL.
Kemper, T. L. B., and Galaburda, A. M. (1984). Principles of
cytoarchitectonics. In Cerebral Cortex. Volume 1: Cellular
Components of the Cerebral Cortex (A. Peters and E. G. Jones,
Eds.). Plenum, New York.
Mesulam, M.-M. (2000). Principles of Behavioral and Cognitive
Neurology. Oxford Univ. Press, Oxford.
Pena-Casanova, J., and Bohm, P. (2000). A century beyond
Brodmann: New insights into cortical cytoarchitectonics and
function. Brain Lang. 71, 181–184.
Brodmann’s Areas
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
AT APPROXIMATELY the turn of the 20th century, a
group of neuroanatomists, including Alfred Walter
Campbell (1868–1937), Grafton Elliot Smith (1871–
1937), Korbinian Brodmann (1868–1918), and
Cécile (1875–1962) and Oskar Vogt (1870–1950),
set out to study the microanatomy of the cerebral
cortex. They noticed that the size, shape, packing
density, and lamination of neurons in preparations
stained for cell bodies (e.g., with the Nissl technique;
cytoarchitecture) or the distribution pattern of
myelin sheaths in preparations stained for myelin
(e.g., with the Heidenhain–Woelcke technique; mye-
loarchitecture) are not uniform across the cerebral
cortex. Instead, there are marked regional variations.
This allowed the delineation of cortical regions or
areas, characterized by a uniform cyto- or mye-
loarchitectonic pattern, and the definition of borders
between areas where the architectonic pattern
changes (Fig. 1). According to the elementary biolo-
gical principle, what differs in structure should also
differ in function (and vice versa), the question that
immediately arose was: What is the functional
meaning of these areas? The first investigators to
provide an answer to this question were Cécile and
Oskar Vogt, who also studied the cortex of nonhu-
man primates. The brains of animals (in contrast to
human beings) offer the advantage of directly
correlating microstructure with function. Upon
completion of electrophysiological experiments the
brains can be sectioned, sections can be stained for
cell bodies or myelin sheaths, and stimulation and/or
recording sites can be directly compared with the
architectonic pattern. Indeed, it was found that
neurons with similar electrophysiological proper-
ties lie within the same area and, conversely, the
 BRODMANN’S AREAS 483

for example, area 4 (gigantopyramidal area), area 1

Figure 1
Cytoarchitectonic features of a border between two cortical areas,
namely Brodmann’s area 4 (gigantopyramidal area) and area 3a.
Brodmann’s area 3 (rostral postcentral area) was later subdivided
by the Vogts into a rostral (area 3a) and a caudal (area 3b) part.
Note low cell density, poor lamination, marked columnar
arrangement of the cells, and the absence of an inner granular layer
(i.e., agranular cortex) in area 4. Giant pyramidal or Betz cells are
missing in this photograph. Across the border from area 3a, cell
density increases, cortical layers stand out more clearly, and an
inner granular layer (stars) emerges (i.e., granular cortex). Scale
bar ¼ 1 mm (reproduced with permission from Geyer et al., 1999).
(intermediate postcentral area), or area 17 (striate
area)—are present in almost all species examined.
Other regions in the frontal, posterior parietal, or
temporal cortex increasingly differentiate and new
areas emerge as one ascends the evolutionary tree. In
the human cortex, Brodmann defined 11 ‘‘Haupt-
regionen’’ (regions; Table 1), each of which was
subdivided into a varying number of ‘‘Einzelfelder’’
(areas). In general, he numbered the areas in the
order in which they appeared when investigating
serial sections of smaller tissue blocks cut in
appropriate planes (e.g., horizontally in the case of
areas 1–7, obliquely in the case of areas 8–11, and
vertically in the case of areas 17–19). The areas were
numbered consecutively from 1 to 52. However,
there are several exceptions to the numerical
sequence: The Regio insularis was subdivided into

properties of neurons change across an architectonic

border. Thus, architectonic areas are also functional
entities. This triggered a ‘‘golden age’’ of cyto- and
myeloarchitectonic mapping at the beginning of the
20th century. Within two decades, maps of the cortex
of man and several other mammals were published.
The most famous parcellation of the human brain is
the map of Korbinian Brodmann. Starting in 1901,
he worked together with the Vogts in Berlin and
studied the cytoarchitecture of sections stained with
the Nissl technique. After 8 years of intensive work,
he published his data in a comprehensive monograph
(published in 1909) which contains the famous
map (Fig. 2).

BRODMANN’S MAP
A major goal of Brodmann was to elucidate the
evolutionary background of structural differentiation
in the cortex. Hence, in his 1909 monograph
(Treatise on Comparative Localization in the Cere-
bral Cortex) he published cytoarchitectonic maps of
Figure 2
the cortex of Homo sapiens (Fig. 2) and eight other Brodmann’s cytoarchitectonic map of the human cerebral cortex
mammals ranging from nonhuman primates to (top, lateral view; bottom, medial view), published in 1909.
insectivores. He found that some cortical areas— Symbols and numbers denote cortical areas (see Table 1).
484 BRODMANN’S AREAS
Table 1 SUMMARY OF THE 11 REGIONS AND 43 AREAS DESCRIBED BY BRODMANN IN 1909
Name of region Approximate location
Regio postcentralis Postcentral gyrus
Regio praecentralis Precentral gyrus
Regio frontalis Frontal lobe
Regio parietalis Parietal lobe
Regio occipitalis Occipital lobe
Regio temporalis Temporal lobe
Regio insularis Insula
Regio cingularis Cingulate gyrus
Regio retrosplenialis Retrosplenial part of cingulate gyrus
Regio hippocampica Parahippocampal gyrus
Regio olfactoria Olfactory tubercle
an anterior and a posterior region (without num-
bers), the Regio olfactoria was not subdivided
further, and there are two gaps in the sequence.
Areas 12 (frontopolar area), 13 (granular insular
area), 14–16 (agranular insular areas), 48 (retro-
subicular area), 49 (parasubicular area), 50 (tempor-
al area), and 51 (prepiriform area) were defined in
nonhuman primates and lower mammals but they
are missing in humans. This results in 43 numbered
areas in the human cortex.
Brodmann published a second map in 1914. It
differs from the map of 1909 only in some minor
details: areas 7 (superior parietal area) and 44
(opercular area) were subdivided into areas 7a and
7b and areas 44 and 44o, respectively. In addition,
areas 52 (parainsular area) and 12 (frontopolar area)
were added to the map. In the 1909 version, area 52
had been described in the text and its location had been
shown only in a small sketch showing the insula and
the supratemporal plane and area 12 had been defined
only in nonhuman primates and lower mammals.
Regions of the cortex missed by Brodmann in both
versions of his map include major parts of the
allocortex, such as the fascia dentata, cornu ammo-
nis, and subiculum. Only a presubicular area (27)
and two entorhinal areas (28 and 34) were defined.
In addition, the complex transition from the en-
torhinal allocortex to the temporal isocortex was
defined as only one region (perirhinal area 35).
THE VALUE OF BRODMANN’S MAP AS A
GUIDE TO FUNCTIONAL UNITS IN THE
HUMAN CEREBRAL CORTEX
Brodmann’s map has had a tremendous impact and is
still found in many neuroscience and neurology
Areas in the sequence
1–3, 43
4, 6
8–11, 44, 45, 47, 46
5, 7, 40, 39
17–19
36–38, 20–22, 52, 41, 42
Anterior region, posterior region
23, 31, 24, 32, 33, 25
26, 29, 30
27, 28, 34, 35
textbooks. However, from today’s perspective, ser-
ious problems arise when an investigator wants to
use the map as a structural guide to functional units
in the cerebral cortex.
First, more sensitive microstructural mapping
techniques that have been developed in recent years
(e.g., histochemical, immunohistochemical, and
autoradiographic approaches) have revealed func-
tionally relevant subregions within many of the areas
considered by Brodmann to be homogeneous. For
example, area 19 (preoccipital area) is actually a
mosaic of different regions belonging to the extra-
striate visual cortex. Likewise, area 6 (frontal
agranular area) contains several fields that together
make up the supplementary, presupplementary,
dorsolateral, and ventrolateral premotor cortex.
Second, Brodmann’s publications contain neither
verbal descriptions nor any pictorial material of each
area’s cytoarchitectonic features. Instead, he only
briefly comments on their topographical locations. In
addition, the map shows each area’s location and
extent only on the exposed cortical surface. The sulci
are not opened up and no information is available on
the precise areal topography within each sulcus.
Hence, it is very difficult to compare Brodmann’s
map with those of other authors and virtually
impossible to remap his areas in histological sections
stained for cell bodies.
Third, ‘‘classic’’ brain maps such as Brodmann’s
oeuvre were published in print format. This raises
problems when structural data from these maps are
to be matched with, e.g., functional imaging data
obtained from different brains. Classic maps are
schematic drawings that reflect the topographical
situation in one representative brain and do not
address the problem of interindividual macro- and

microanatomical variability. Furthermore, these
maps are ‘‘rigid,’’ i.e., they are not based on a spatial
reference system and cannot be adapted to individual
brains. Hence, multimodal integration of structural
and functional data is impossible.
On the other hand, state-of-the-art functional
imaging techniques, such as positron emission
tomography (PET) and functional magnetic reso-
nance imaging (fMRI), map the cerebral cortex with
increasing spatial resolution, but they can relate foci
of activation only to macroanatomical landmarks of
the cortex (i.e., gyri and sulci). Plenty of evidence in
animals, however, has shown that it is microstructure
(and not macroanatomy) that parallels function.
Unfortunately, most microstructurally defined inter-
areal borders in the human cortex do not match
macroanatomical landmarks and these borders are
topographically quite variable across different in-
dividuals. Hence, structural–functional correlations
based only on macroanatomy are questionable and
may account for at least some of the conflicting
results functional imaging studies have provided in
recent years (e.g., the debate regarding whether the
human primary sensorimotor cortex is activated
during imagined movements).
Recently published atlases (e.g., the reference
system of Talairach and Tournoux that uses Brod-
mann’s nomenclature) are of limited value as well
because their cortical maps are not based on genuine
microstructural data (the authors seem to have
transferred each area from Brodmann’s schematic
drawing to a corresponding position on the cortex of
their reference brain). In addition, Talairach and
Tournoux give only the approximate position of an
area (borders between areas are not indicated), and
they do not address the problem of interindividual
variability (only one brain is depicted in the atlas).
PROBABILISTIC MICROSTRUCTURAL–
FUNCTIONAL CORRELATION: A NEW
STRUCTURAL GUIDE TO FUNCTIONAL
UNITS IN THE CORTEX
Microstructure can be correlated with function in a
direct way in animals. In humans, for obvious ethical
reasons, functional in vivo and anatomical postmor-
tem studies cannot be performed in the same brain.
This precludes a direct correlation of microstructure
with function in humans. However, there are indirect
ways to achieve a match.
A recent development, namely computerized brain
atlases, offers the computational tools that are
BRODMANN’S AREAS 485
necessary to achieve this goal. On the one hand,
genuine microstructural data (e.g., cytoarchitectonic
analysis of whole brain sections stained for cell
bodies) are brought into the standard anatomical
format of a computerized atlas. By importing micro-
structural data from several brains (approximately 10
to keep the time-consuming and cumbersome proce-
dure of microstructural parcellation within reasonable
limits) one can assess the degree of interindividual
variability. On the other hand, functional imaging
data can be brought into the identical standard
anatomical format. Both data sets can then be
superimposed and correlated with each other on a
probabilistic basis. This approach, termed probabil-
istic microstructural–functional correlation, opens up
the interesting possibilities of (i) defining volumes of
interest (VOIs) of cortical areas that are not based on
macroanatomical landmarks but instead on cytoarch-
itectonic mapping of postmortem brains and of (ii)
determining in these VOIs changes in regional cere-
bral blood flow data obtained from PET or fMRI
experiments. In the human frontal cortex, for
example, this new approach has been successfully
used to probabilistically map the primary motor
cortex (Brodmann’s area 4) and two subregions within
it (areas 4a and 4p) and to correlate microstructural
VOIs of these regions with functional PET data.
CONCLUSIONS
Although of tremendous importance in the past,
Brodmann’s map is of little practical value today. The
recent detection of functionally relevant subregions
within many areas considered by Brodmann to be
homogeneous, no descriptions of each area’s cy-
toarchitectonic features, and the problems associated
with a classic map in print format greatly diminish its
practical value as a reliable and universal structural
guide to functional units in the human cerebral
cortex. A recent development, termed probabilistic
microstructural–functional correlation, overcomes
many of the shortcomings associated with Brod-
mann’s map and opens up new strategies to correlate
postmortem microstructural with in vivo functional
imaging data.
—Stefan Geyer
See also–Brain Mapping and Quantitative EEG;
Brodmann, Korbinian; Cerebral Cortex:
Architecture and Connections; Magnetic
Resonance Imaging (MRI); Memory, Working;
Positron Emission Tomography (PET)
486 BROWN-SÉQUARD, CHARLES EDOUARD
Further Reading
Amunts, K., Malikovic, A., Mohlberg, H., et al. (2000). Brodmann’s
areas 17 and 18 brought into stereotaxic space—Where and how
variable? Neuroimage 11, 66–84.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der
Grohirnrinde. Barth, Leipzig. (English translation: Garey, L.
J. (1999). Brodmann’s ‘‘Localisation in the Cerebral Cortex.’’
Imperial College Press, London).
Geyer, S., Ledberg, A., Schleicher, A., et al. (1996). Two different
areas within the primary motor cortex of man. Nature 382,
805–807.
Geyer, S., Schleicher, A., and Zilles, K. (1999). Areas 3a, 3b, and
1 of human primary somatosensory cortex: 1. Microstructural
organization and interindividual variability. Neuroimage 10,
63–83.
Ono, M., Kubik, S., and Abernathey, C. D. (1990). Atlas of the
Cerebral Sulci. Thieme, Stuttgart.
Rademacher, J., Caviness, V. S., Steinmetz, H., et al. (1993).
Topographical variation of the human primary cortices:
Implications for neuroimaging, brain mapping, and neurobiol-
ogy. Cereb. Cortex 3, 313–329.
Rajkowska, G., and Goldman-Rakic, P. S. (1995). Cytoarchitec-
tonic definition of prefrontal areas in the normal human cortex:
II. Variability in locations of areas 9 and 46 and relationship to
the Talairach coordinate system. Cereb. Cortex 5, 323–337.
Roland, P. E., and Zilles, K. (1994). Brain atlases—A new research
tool. Trends Neurosci. 17, 458–467.
Talairach, J., and Tournoux, P. (1988). Co-Planar Stereotaxic
Atlas of the Human Brain. 3-Dimensional Proportional System:
An Approach to Cerebral Imaging. Thieme, Stuttgart.
Vogt, C., and Vogt, O. (1919). Allgemeinere Ergebnisse unserer
Hirnforschung. J. Psychol. Neurol. 25, 279–461.
Brown-Séquard, Charles
Edouard
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
Portrait of Brown-Séquard from the archives of the former
Faculté de Médecine de Paris, currently the Bibliothèque
Inter-universitaire, Paris.
BROWN-SÉQUARD’S syndrome, a combination of
signs induced by unilateral spinal cord damage,
encompasses several fundamental pillars of clinical
neurology. Damage to only one side of the spinal
cord causes paralysis of all muscles innervated by
nerves below the level of injury on the same side of
the body and contralateral loss of pain sensation.
Although the syndrome in its purest form is only
rarely encountered in clinical neurological practice,
its description serves as an important crystallization
of spinal cord anatomy and physiology; hence,
Brown-Séquard’s syndrome is part of the working
vocabulary of medical students and physicians.
In 1846, at the age of 29 years, as a part of his
medical school graduation thesis, Brown-Séquard
(1817–1894) demonstrated the complex but rigor-
ously systematic anatomy of the spinal cord.
Through his studies on experimental animals, he
established that the crossing, or decussation, of the
sensory tract occurred within the spinal cord and not
within the brain or brainstem, as previously de-
scribed by Charles Bell and Longet (Fig. 1). In
subsequent studies from 1849 and 1850, he ex-
panded on his early observations in a series of
publications on pathological rather than normal
anatomy, summarized and synthesized in his Amer-
ican lectures. In his Experimental Researches Ap-
plied to Physiology and Pathology (1853), he
reported on his entire series of experiments on
unilateral spinal cord damage and remarked on the
previous literature: ‘‘There are but few cases on
record in which there was a less or a diminution of
sensibility on one side and of voluntary movement in
the other.’’ In his 1855 text, Physiology and
Pathology of the Spinal Cord, he emphasized the
clinical syndrome and the pathological basis of
unilateral spinal cord damage. He described the
effects of
an alteration occupying the entire thickness of a portion of the
lateral half of the spinal cord: The parts of the body situated
behind it on the same side are paralyzed of voluntary movement
and the corresponding parts on the other side are paralyzed of
sensibility.
Although his findings were pivotal, more than 10
years passed before Brown-Séquard’s conclusions
were generally accepted. Paul Broca headed a
commission sponsored by the Société de Biologie to
evaluate the experimental rigor of Brown-Séquard’s
work and found it of impeccable quality. Comment-
ing several years later on the significance of Brown-
Séquard’s contribution, the celebrated clinical neu-
rologist Jean-Martin Charcot called this work ‘‘one
of the clearest and most fruitful outcomes recently
486 BROWN-SÉQUARD, CHARLES EDOUARD
Further Reading
Amunts, K., Malikovic, A., Mohlberg, H., et al. (2000). Brodmann’s
areas 17 and 18 brought into stereotaxic space—Where and how
variable? Neuroimage 11, 66–84.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der
Grohirnrinde. Barth, Leipzig. (English translation: Garey, L.
J. (1999). Brodmann’s ‘‘Localisation in the Cerebral Cortex.’’
Imperial College Press, London).
Geyer, S., Ledberg, A., Schleicher, A., et al. (1996). Two different
areas within the primary motor cortex of man. Nature 382,
805–807.
Geyer, S., Schleicher, A., and Zilles, K. (1999). Areas 3a, 3b, and
1 of human primary somatosensory cortex: 1. Microstructural
organization and interindividual variability. Neuroimage 10,
63–83.
Ono, M., Kubik, S., and Abernathey, C. D. (1990). Atlas of the
Cerebral Sulci. Thieme, Stuttgart.
Rademacher, J., Caviness, V. S., Steinmetz, H., et al. (1993).
Topographical variation of the human primary cortices:
Implications for neuroimaging, brain mapping, and neurobiol-
ogy. Cereb. Cortex 3, 313–329.
Rajkowska, G., and Goldman-Rakic, P. S. (1995). Cytoarchitec-
tonic definition of prefrontal areas in the normal human cortex:
II. Variability in locations of areas 9 and 46 and relationship to
the Talairach coordinate system. Cereb. Cortex 5, 323–337.
Roland, P. E., and Zilles, K. (1994). Brain atlases—A new research
tool. Trends Neurosci. 17, 458–467.
Talairach, J., and Tournoux, P. (1988). Co-Planar Stereotaxic
Atlas of the Human Brain. 3-Dimensional Proportional System:
An Approach to Cerebral Imaging. Thieme, Stuttgart.
Vogt, C., and Vogt, O. (1919). Allgemeinere Ergebnisse unserer
Hirnforschung. J. Psychol. Neurol. 25, 279–461.
Brown-Séquard, Charles
Edouard
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
Portrait of Brown-Séquard from the archives of the former
Faculté de Médecine de Paris, currently the Bibliothèque
Inter-universitaire, Paris.
BROWN-SÉQUARD’S syndrome, a combination of
signs induced by unilateral spinal cord damage,
encompasses several fundamental pillars of clinical
neurology. Damage to only one side of the spinal
cord causes paralysis of all muscles innervated by
nerves below the level of injury on the same side of
the body and contralateral loss of pain sensation.
Although the syndrome in its purest form is only
rarely encountered in clinical neurological practice,
its description serves as an important crystallization
of spinal cord anatomy and physiology; hence,
Brown-Séquard’s syndrome is part of the working
vocabulary of medical students and physicians.
In 1846, at the age of 29 years, as a part of his
medical school graduation thesis, Brown-Séquard
(1817–1894) demonstrated the complex but rigor-
ously systematic anatomy of the spinal cord.
Through his studies on experimental animals, he
established that the crossing, or decussation, of the
sensory tract occurred within the spinal cord and not
within the brain or brainstem, as previously de-
scribed by Charles Bell and Longet (Fig. 1). In
subsequent studies from 1849 and 1850, he ex-
panded on his early observations in a series of
publications on pathological rather than normal
anatomy, summarized and synthesized in his Amer-
ican lectures. In his Experimental Researches Ap-
plied to Physiology and Pathology (1853), he
reported on his entire series of experiments on
unilateral spinal cord damage and remarked on the
previous literature: ‘‘There are but few cases on
record in which there was a less or a diminution of
sensibility on one side and of voluntary movement in
the other.’’ In his 1855 text, Physiology and
Pathology of the Spinal Cord, he emphasized the
clinical syndrome and the pathological basis of
unilateral spinal cord damage. He described the
effects of
an alteration occupying the entire thickness of a portion of the
lateral half of the spinal cord: The parts of the body situated
behind it on the same side are paralyzed of voluntary movement
and the corresponding parts on the other side are paralyzed of
sensibility.
Although his findings were pivotal, more than 10
years passed before Brown-Séquard’s conclusions
were generally accepted. Paul Broca headed a
commission sponsored by the Société de Biologie to
evaluate the experimental rigor of Brown-Séquard’s
work and found it of impeccable quality. Comment-
ing several years later on the significance of Brown-
Séquard’s contribution, the celebrated clinical neu-
rologist Jean-Martin Charcot called this work ‘‘one
of the clearest and most fruitful outcomes recently

Figure 1
Two plates, Fig. 21 and Fig. 22, from Brown-Séquard’s Lectures of
the Physiology and Pathology of the Central Nervous System
(Collins, Philadelphia, 1860). (Left) Figure 21 shows the different
locations for crossing of the motor fibers and sensory fibers for
pain sensation as understood by Brown-Séquard. 1, The nervous
system above the medulla, where descending motor fibers (dark
dashes) have not yet crossed and ascending pain fibers (light
dashes) have already crossed. Unilateral lesions at this level would
be associated with contralateral weakness and contralateral loss of
pain sensation; 2, the level of the pyramidal motor tract
decussation; 3, the spinal cord below the motor decussation—at
this point, the celebrated Brown-Séquard’s syndrome of crossed
motor and sensory abnormalities (ipsilateral weakness but
contralateral pain sensation loss) occurs in a unilateral lesion.
Figure 22 focuses specifically on the motor tracts and identifies the
predominant crossed pathway (L, lateral pyramidal tract) in
contrast to the more minor anterior pyramidal tract (A) that
remains uncrossed.
provided by experimental physiology, and this
contribution is due in its entirety to the work of my
friend, Professor Brown-Séquard.’’
The description of spinal cord organization and
the clinical condition that follows its unilateral
damage are Brown-Séquard’s most important con-
tributions. However, Brown-Séquard also studied
numerous other neurological and medical topics. His
personal life and career were punctuated with an
erratic rhythm of high, even feverish, productivity
and lapses of disorganization and silence leaving
several aspects of his work incomplete or poorly
BROWN-SÉQUARD, CHARLES EDOUARD 487
founded. As a physiologist and laboratory scientist,
in an era in which the French scientific school of
neurology was dominated by anatomy and clinical
medicine, Brown-Séquard was in many ways a
visionary of the subsequent generations for which
physiology and laboratory research would become
the primary research arenas.
Brown-Séquard was born in Port Louis on the
Mauritius Islands to a French mother, Henriette
Séquard, and her husband, American merchant
marine captain C. E. Brown. Young Charles Edouard
was raised exclusively by his mother and never knew
his father, who was lost at sea. In 1838, mother and
son moved to Paris, and after a failed attempt to
enter the world of letters, Brown-Séquard enrolled in
medical school. He passed the competition to
become an extern, but in 1841, before the much
more rigorous internship examination, his mother
died. In despair, Brown-Séquard left Paris and
abandoned his studies to return to his birthplace.
This behavioral pattern of geographical moves
during periods of stress would mark much of this
peripatetic man’s career. He returned to Paris 2 years
later to complete his studies, and in 1846 defended
his graduation thesis on spinal cord anatomy and
physiology. Unlike many graduation theses that were
only modestly original and usually based heavily on
the work of students’ academic sponsors, this study
was based on novel experiments using various
laboratory animals. It showed Brown-Séquard’s
breadth of documentation as well as his originality
and confidence to defend hypotheses that were
contrary to established concepts. Despite this im-
portant graduation document, Brown-Séquard’s ab-
sence from Paris had precluded his becoming an
intern, a very crucial step in the development of an
academic career in French medicine. Without this
credential, he was effectively blocked from a
hospital-based academic career as a physician in
France. In addition, although raised as a Frenchman,
he was actually a British subject because the
Mauritius Islands came under British control as part
of an 1814 peace arrangement. Living within these
realities and the government changes within France
at the time, Brown-Séquard developed a career
outside of the hospital and based himself instead in
the experimental laboratories. In the 1850s, however,
he again began a series of moves in which short and
often abruptly interrupted stays would find him in
the United States, Great Britain, France, and the
Mauritius Islands during the next several years.
These moves were associated with an equally erratic
488 BROWN-SÉQUARD, CHARLES EDOUARD
record of work, sometimes including high produc-
tivity, well-received lectures, and continued scientific
research, and, in contrast, sometimes including
inactivity and periods of ambivalence or indolence.
In the United States, he became well-known in
scientific circles, especially in New York, Boston,
and Philadelphia, publishing two important mono-
graphs on his research in English—Experimental
Researches Applied to Physiology and Pathology
(1853) and Physiology and Pathology of the Spinal
Cord (1855). In England, where he was recognized as
a physician, his clinical work predominated over
laboratory studies, and he became one of the
founding physicians at London’s National Hospital,
Queen Square. During this period, he published
Physiology and Pathology of the Central Nervous
System (1860). Harvard Medical School offered him
the first American professorship in neurological
science when it established the post of professor of
physiology and pathology of the nervous system
(1864). However, letters between the dean and
Brown-Séquard clearly demonstrate the grandiosity,
wavering indecision, and mental instability that
doomed Brown-Séquard’s Boston career. They cap-
ture his fluctuations between periods of lassitude and
inability to work and exhilaration and feverish
energy, all highly suggestive of manic–depressive or
bipolar illness. After finally organizing himself to
begin lecturing at Harvard, Brown-Séquard began
his inaugural course, but he could not complete it
and ultimately resigned to begin traveling again. The
scientist’s complexity is revealed by his remarkable
success during periods of productivity because he
continued to publish and perform research wherever
he settled, establishing a reputation as an interna-
tionally renowned clinician and receiving honors
including the editorship of several scientific journals.
The year 1878 was a pivotal one in Brown-
Séquard’s career because Claude Bernard, the cele-
brated French physiologist, died, leaving vacant the
most coveted scientific post in France, the chaired
professorship at the Collège de France. Brown-
Séquard was selected as his successor. His peripatetic
career ended here, and Brown-Séquard never left this
post. He installed his laboratory in the facilities
developed by his predecessor, taking on Bernard’s
former assistant Arsène d’Arsonval, who became his
close collaborator and confidant. In close succession,
Brown-Séquard received other national and interna-
tional honors, including the post of chevalier in the
French Legion of Honor, election to the highest
scientific body in France, the Académie des Sciences,
and an honorary doctoral degree from the University
of Cambridge.
Despite these accolades, Brown-Séquard had aged,
and for his 1881 lecture series his assistant gave the
winter course, a pattern that would expand to his full
retirement from formal course work in 1888. One
particular area of research in which they closely
collaborated concerned testicular extracts and their
medicinal properties. These studies included experi-
ments in which Brown-Séquard tested testicular
extracts from dogs and guinea pigs as a regeneration
tonic to enhance the physical and intellectual life of
aging persons. He became his own best research
subject, taking the extract himself and publicizing to
his colleagues the merits of success. At a scientific
meeting in 1889, he presented his data and added
I was 72 years old last April 11. Today I am completely changed
and have regained all the strength I had several years ago, and
maybe even added to it. Intellectual work became easier for me.
I can also say that other capabilities that had not been lost, but
had diminished, are notably enhanced.
As objective evidence of his claims, Brown-
Séquard showed readings from a dynamometer, an
apparatus widely used at the time to measure muscle
strength in neurological practice. He also showed
records on the new enhanced force of his urinary
stream. With this topic, as with almost every aspect
of Brown-Séquard’s work except his spinal cord
studies, he found himself in the midst of scientific
controversy. On the one hand, cries of autosugges-
tion swarmed from his critics, but at the same time,
requests of an ever-increasing demand from practi-
tioners, including academic luminaries for a brief
time, depleted his stores of available extracts. For
several years, organotherapy became widespread and
the medical world transiently witnessed the intro-
duction of a broad array of pancreatic, liver, brain,
and other extracts for therapeutic use. Although
scientific enthusiasm for organotherapy did not
last, Brown-Séquard’s concepts and experiments
place him as a pioneer in the field of hormonal
therapy.
Several other areas besides spinal cord physiology
and organotherapy occupied his attention during
these years and included studies of the autonomic
nervous system and especially the neural control of
vasomotor function. He strongly opposed the con-
cept of cerebral localization, a major topic of
international debate during the last quarter of the
19th century. The debate focused on whether
individual brain regions were associated with specific

functions or whether the brain was organized in
more loosely arranged networks that defied a link
between a lesion in one area and a predictable
clinical syndrome. Against Charcot’s clear and
articulate arguments based exclusively on human
autopsy material, Brown-Séquard attempted to draw
on his laboratory evidence from numerous animal
experiments. He failed in this effort, but stubbornly
held to his tenants despite a very large body of
human work from Charcot, Hughlings Jackson, and
Broca as well as experimental studies from Fritsch
and Hitzich and Ferrier. Likewise, his work on
epilepsy was misguided when he claimed that
convulsions occurred when the spinal cord or sciatic
nerve were sectioned. The source of these errors has
been variously ascribed to misinterpretation of
primitive spinal cord reflexes or to lice infestation
within the animal colonies of his laboratory.
The totality of Brown-Séquard’s scientific work
numbers almost 600 publications, with books and
scientific articles published in English and French.
Erratic in their scientific content and intermittent in
their production, these documents cover a large array
of topics but are unified in their emphasis on
laboratory research and physiology. In these do-
mains, he was known as a highly skilled and
respected experimentalist, bubbling with ideas but
often guided more by intuition than intellectual rigor.
His contrast with Charcot places him as an
important transitional figure of the late 19th century
in neurological history. Whereas Charcot embodied
the established neurological method of research
based on anatomy rather than physiology, clinical
rather than experimental work, and hospital-based
rather than laboratory-based science, these ap-
proaches had largely been expanded as far as they
could by the end of the century. The next generation
would rely increasingly on physiological studies
conducted on experimental animals within a labora-
tory setting and performed on humans only after
extensive research was completed in this basic
science arena. Brown-Séquard embodied the transi-
tion out of the hospital and into the medical
laboratory, a scientific approach that would dom-
inate research in the subsequent decades. As the
seminal figure of this transition, Brown-Séquard
played a pivotal role in guiding neurological science
toward this next evolutionary step that was essential
for the development of major new discoveries in
neurophysiology, neurotoxicity, and neuropharma-
cology.
—Michel Bonduelle and Christopher G. Goetz
BROWN-SÉQUARD’S SYNDROME 489
See also–Brown-Séquard’s Syndrome; Paralysis;
Spinal Cord Anatomy (see Index entry Biography
for complete list of biographical entries)
Further Reading
Aminoff, M. J. (1993). Brown-Séquard. A Visionary of Science.
Raven Press, New York.
Delhoume, L. (1939). De Claude Bernard à d’Arsonval. Baillière,
Paris.
Koelher, P. J. (1989). Het Localisatieconcept in de Neurologie van
Brown-Séquard. Rodopi, Amsterdam.
Olmstead, J. M. D. (1953). Charles Edouard Brown-Séquard: A
Nineteenth Century Neurologist and Endocrinologist. Johns
Hopkins Univ. Press, Baltimore.
Role, A. (1977). La vie Étrange d’un Grand Savant, le Professeur
Brown-Séquard. Plon, Paris.
Rouget, F. A. (1930). Brown-Séquard et son œuvre. General
Printing & Stationery, Port-Louis, Île Maurice.
Tyler, H. R., and Tyler, K. L. (1984). Charles Edouard Brown-
Séquard: Professor of physiology and pathology of the nervous
system at Harvard Medical School. Neurology 34, 1231–1236.
Brown-Séquard’s Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BROWN-SÉQUARD’S SYNDROME is named after
Charles Edouard Brown-Séquard (1817–1894), and
it arises from disorders affecting one side of the
spinal cord. The major clinical features are consistent
with the anatomy of the major sensory and motor
pathways in the cord. Thus, the corticospinal tract
and dorsal column both contain uncrossed fibers so
that their involvement results in an ipsilateral upper
motor neuron deficit and ipsilateral loss of proprio-
ception caudal to the lesion. The spinothalamic tract
contains axons that have entered the spinal cord on
one side and then crossed to the opposite side over
one or two segments. A lesion on one side of the cord
therefore leads to contralateral loss of pain and
thermal sensation beginning one or two segments
caudally. Tactile sensation is not affected because it is
represented bilaterally in the cord.
Brown-Séquard’s work on the afferent pathways in
the spinal cord formed part of his doctoral thesis in
1846. At the time, it was believed that all sensation
traveled to the brain in the posterior columns.
Brown-Séquard refuted this view by showing that
complete posterior column lesions preserved sensa-
tion and led instead to hyperesthesia. In other
experiments, he hemisected the spinal cord and
found that animals developed ipsilateral paralysis

functions or whether the brain was organized in
more loosely arranged networks that defied a link
between a lesion in one area and a predictable
clinical syndrome. Against Charcot’s clear and
articulate arguments based exclusively on human
autopsy material, Brown-Séquard attempted to draw
on his laboratory evidence from numerous animal
experiments. He failed in this effort, but stubbornly
held to his tenants despite a very large body of
human work from Charcot, Hughlings Jackson, and
Broca as well as experimental studies from Fritsch
and Hitzich and Ferrier. Likewise, his work on
epilepsy was misguided when he claimed that
convulsions occurred when the spinal cord or sciatic
nerve were sectioned. The source of these errors has
been variously ascribed to misinterpretation of
primitive spinal cord reflexes or to lice infestation
within the animal colonies of his laboratory.
The totality of Brown-Séquard’s scientific work
numbers almost 600 publications, with books and
scientific articles published in English and French.
Erratic in their scientific content and intermittent in
their production, these documents cover a large array
of topics but are unified in their emphasis on
laboratory research and physiology. In these do-
mains, he was known as a highly skilled and
respected experimentalist, bubbling with ideas but
often guided more by intuition than intellectual rigor.
His contrast with Charcot places him as an
important transitional figure of the late 19th century
in neurological history. Whereas Charcot embodied
the established neurological method of research
based on anatomy rather than physiology, clinical
rather than experimental work, and hospital-based
rather than laboratory-based science, these ap-
proaches had largely been expanded as far as they
could by the end of the century. The next generation
would rely increasingly on physiological studies
conducted on experimental animals within a labora-
tory setting and performed on humans only after
extensive research was completed in this basic
science arena. Brown-Séquard embodied the transi-
tion out of the hospital and into the medical
laboratory, a scientific approach that would dom-
inate research in the subsequent decades. As the
seminal figure of this transition, Brown-Séquard
played a pivotal role in guiding neurological science
toward this next evolutionary step that was essential
for the development of major new discoveries in
neurophysiology, neurotoxicity, and neuropharma-
cology.
—Michel Bonduelle and Christopher G. Goetz
BROWN-SÉQUARD’S SYNDROME 489
See also–Brown-Séquard’s Syndrome; Paralysis;
Spinal Cord Anatomy (see Index entry Biography
for complete list of biographical entries)
Further Reading
Aminoff, M. J. (1993). Brown-Séquard. A Visionary of Science.
Raven Press, New York.
Delhoume, L. (1939). De Claude Bernard à d’Arsonval. Baillière,
Paris.
Koelher, P. J. (1989). Het Localisatieconcept in de Neurologie van
Brown-Séquard. Rodopi, Amsterdam.
Olmstead, J. M. D. (1953). Charles Edouard Brown-Séquard: A
Nineteenth Century Neurologist and Endocrinologist. Johns
Hopkins Univ. Press, Baltimore.
Role, A. (1977). La vie Étrange d’un Grand Savant, le Professeur
Brown-Séquard. Plon, Paris.
Rouget, F. A. (1930). Brown-Séquard et son œuvre. General
Printing & Stationery, Port-Louis, Île Maurice.
Tyler, H. R., and Tyler, K. L. (1984). Charles Edouard Brown-
Séquard: Professor of physiology and pathology of the nervous
system at Harvard Medical School. Neurology 34, 1231–1236.
Brown-Séquard’s Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BROWN-SÉQUARD’S SYNDROME is named after
Charles Edouard Brown-Séquard (1817–1894), and
it arises from disorders affecting one side of the
spinal cord. The major clinical features are consistent
with the anatomy of the major sensory and motor
pathways in the cord. Thus, the corticospinal tract
and dorsal column both contain uncrossed fibers so
that their involvement results in an ipsilateral upper
motor neuron deficit and ipsilateral loss of proprio-
ception caudal to the lesion. The spinothalamic tract
contains axons that have entered the spinal cord on
one side and then crossed to the opposite side over
one or two segments. A lesion on one side of the cord
therefore leads to contralateral loss of pain and
thermal sensation beginning one or two segments
caudally. Tactile sensation is not affected because it is
represented bilaterally in the cord.
Brown-Séquard’s work on the afferent pathways in
the spinal cord formed part of his doctoral thesis in
1846. At the time, it was believed that all sensation
traveled to the brain in the posterior columns.
Brown-Séquard refuted this view by showing that
complete posterior column lesions preserved sensa-
tion and led instead to hyperesthesia. In other
experiments, he hemisected the spinal cord and
found that animals developed ipsilateral paralysis
490 BRUDZINSKI’S SIGN
and hyperesthesia below the lesion, combined with
contralateral loss of pain sensation. The ipsilateral
hyperesthesia that forms part of the complete
syndrome is generally neglected, partly because its
origins are poorly understood and partly because it is
believed to occur only transiently.
Any disease that is capable of affecting the spinal
cord focally can give rise to the syndrome. It is
encountered most commonly with compressive le-
sions (intrinsic or extrinsic spinal cord tumors or
spinal spondylosis) and with multiple sclerosis.
However, a number of additional causes have been
documented, including trauma (open or closed
injuries, including those due to chiropractic manip-
ulation and sporting accidents), epidural hematomas
and intradural arteriovenous fistulas, vertebral artery
dissection, inflammatory and infectious diseases (in-
cluding systemic lupus erythematosus, postimmuniza-
tion myelitis, radiation myelopathy, and lyme
disease), decompression sickness, and following
cardiac bypass. However, it is unusual for pathologi-
cal processes to produce a precise hemisection of the
cord, so the complete syndrome is rarely encountered.
Brown-Séquard’s syndrome may therefore be
regarded as a classic neurological presentation that
exemplifies the anatomical organization of the
sensory and motor pathways in the spinal cord.
—Raju Kapoor
See also–Brown-Séquard, Charles-Eduoard;
Spinal Cord Diseases
Further Reading
Aminoff, M. J. (1996). Historical perspective: Brown-Séquard and
his work on the spinal cord. Spine 2, 133–140.
Brown-Séquard, C. E. (1860). Course of Lectures on the
Physiology and Pathology of the Central Nervous System.
Collins, Philadelphia.
Brudzinski’s Sign
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRUDZINSKI’S SIGN, named after Jozef Brudzinski
(1874–1917), a Polish physician, is an indication of
meningeal infection or inflammation. In 1909,
Brudzinski described five different meningeal signs
in children, recognizing that some could be pre-
sent while others may be absent. Brudzinski took
his clinical observations of these signs into the
laboratory, where he experimented with animals to
determine their reliability. Today, the nape-of-the-
neck sign—Brudzinski’s sign—is his best known sign.
The nape-of-the-neck sign was reported by Brud-
zinski to be present in 96% of his patients with
meningitis, whereas Kernig’s sign was present in
only 57%.
The classic Brudzinski’s nape-of-the-neck sign is
elicited with the patient supine. Flexion of the neck
produces hip and knee flexion. This protective reflex
is to prevent stretching of the inflamed and irritated
nerve roots caused by purulent exudate or hemor-
rhage in the subarachnoid space due to meningitis.
Other signs of meningitis described by Brudzinski
include a leg sign, in which passive flexion of the
patient’s leg or hip causes the contralateral leg to
begin to flex. Brudzinski’s reciprocal contralateral
sign is positive when the leg that exhibited the active
flexion begins to extend spontaneously in a reflex
motion resembling a small kick. Brudzinski’s cheek
sign is elicited by pressure on both cheeks below the
bones causing a rapid reflex raising of both upper
extremities with simultaneous flexion of the elbow
joints. Another of Brudzinski’s signs, the symphysis
sign, occurs when pressure is applied over the
symphysis. This causes contraction of the lower
extremities. The arm sign may occur as part of the
nape-of-the-neck sign when the arms flex as well as
the hips and knees. The cheek and symphysis signs
noted by Brudzinski occurred in children with
tuberculosis meningitis. Brudzinski believed all these
signs should be tested since even the infamous stiff
neck of meningitis might not appear while other
signs may be present.
—Nancy Pippen Eckerman
See also–Bacterial Meningitis; Fungal Meningitis
Further Reading
Dodge, P. R., and Swartz, M. N. (1965). Bacterial meningitis—A
review of selected aspects: General clinical features, special
problems and unusual meningeal reaction, mimicking bacterial
meningitis. N. Engl. J. Med. 272, 725–731.
Roos, K. L. (1996). Clinical presentation of bacterial meningitis. In
Meningitis: 100 Maxims in Neurology (K. L. Roos, Ed.), pp.
20–35. Arnold, London.
Bulimia Nervosa
see Eating Disorders
490 BRUDZINSKI’S SIGN
and hyperesthesia below the lesion, combined with
contralateral loss of pain sensation. The ipsilateral
hyperesthesia that forms part of the complete
syndrome is generally neglected, partly because its
origins are poorly understood and partly because it is
believed to occur only transiently.
Any disease that is capable of affecting the spinal
cord focally can give rise to the syndrome. It is
encountered most commonly with compressive le-
sions (intrinsic or extrinsic spinal cord tumors or
spinal spondylosis) and with multiple sclerosis.
However, a number of additional causes have been
documented, including trauma (open or closed
injuries, including those due to chiropractic manip-
ulation and sporting accidents), epidural hematomas
and intradural arteriovenous fistulas, vertebral artery
dissection, inflammatory and infectious diseases (in-
cluding systemic lupus erythematosus, postimmuniza-
tion myelitis, radiation myelopathy, and lyme
disease), decompression sickness, and following
cardiac bypass. However, it is unusual for pathologi-
cal processes to produce a precise hemisection of the
cord, so the complete syndrome is rarely encountered.
Brown-Séquard’s syndrome may therefore be
regarded as a classic neurological presentation that
exemplifies the anatomical organization of the
sensory and motor pathways in the spinal cord.
—Raju Kapoor
See also–Brown-Séquard, Charles-Eduoard;
Spinal Cord Diseases
Further Reading
Aminoff, M. J. (1996). Historical perspective: Brown-Séquard and
his work on the spinal cord. Spine 2, 133–140.
Brown-Séquard, C. E. (1860). Course of Lectures on the
Physiology and Pathology of the Central Nervous System.
Collins, Philadelphia.
Brudzinski’s Sign
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRUDZINSKI’S SIGN, named after Jozef Brudzinski
(1874–1917), a Polish physician, is an indication of
meningeal infection or inflammation. In 1909,
Brudzinski described five different meningeal signs
in children, recognizing that some could be pre-
sent while others may be absent. Brudzinski took
his clinical observations of these signs into the
laboratory, where he experimented with animals to
determine their reliability. Today, the nape-of-the-
neck sign—Brudzinski’s sign—is his best known sign.
The nape-of-the-neck sign was reported by Brud-
zinski to be present in 96% of his patients with
meningitis, whereas Kernig’s sign was present in
only 57%.
The classic Brudzinski’s nape-of-the-neck sign is
elicited with the patient supine. Flexion of the neck
produces hip and knee flexion. This protective reflex
is to prevent stretching of the inflamed and irritated
nerve roots caused by purulent exudate or hemor-
rhage in the subarachnoid space due to meningitis.
Other signs of meningitis described by Brudzinski
include a leg sign, in which passive flexion of the
patient’s leg or hip causes the contralateral leg to
begin to flex. Brudzinski’s reciprocal contralateral
sign is positive when the leg that exhibited the active
flexion begins to extend spontaneously in a reflex
motion resembling a small kick. Brudzinski’s cheek
sign is elicited by pressure on both cheeks below the
bones causing a rapid reflex raising of both upper
extremities with simultaneous flexion of the elbow
joints. Another of Brudzinski’s signs, the symphysis
sign, occurs when pressure is applied over the
symphysis. This causes contraction of the lower
extremities. The arm sign may occur as part of the
nape-of-the-neck sign when the arms flex as well as
the hips and knees. The cheek and symphysis signs
noted by Brudzinski occurred in children with
tuberculosis meningitis. Brudzinski believed all these
signs should be tested since even the infamous stiff
neck of meningitis might not appear while other
signs may be present.
—Nancy Pippen Eckerman
See also–Bacterial Meningitis; Fungal Meningitis
Further Reading
Dodge, P. R., and Swartz, M. N. (1965). Bacterial meningitis—A
review of selected aspects: General clinical features, special
problems and unusual meningeal reaction, mimicking bacterial
meningitis. N. Engl. J. Med. 272, 725–731.
Roos, K. L. (1996). Clinical presentation of bacterial meningitis. In
Meningitis: 100 Maxims in Neurology (K. L. Roos, Ed.), pp.
20–35. Arnold, London.
Bulimia Nervosa
see Eating Disorders

Burn Encephalopathy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BURN ENCEPHALOPATHY is the acute onset of a
reduction in conscious level, often accompanied by
confusion, seizures, and sometimes neurological
signs. More than 2.5 million Americans have medical
attention annually for burns; at least 5% develop an
encephalopathy. Most burns are thermal due to flash
or flame. Thermal burns primarily involve the skin
but can cause, usually indirectly, a multitude of
systemic and central nervous system (CNS) effects.
The incidence of CNS complications of burns
increases with large surface area burns, a burn
infection with Pseudomonas aeruginosa and Candida
species, or bacterial endocarditis as a complication.
At least 30% of hospitalized patients develop
features of delirium. Of fatal burn cases, more than
half have CNS complications.
The onset of the neurological features from the
burn injury is variable; it may be weeks after the
injury, when the fever and metabolic derangements
have settled. Early encephalopathy and early seizures
often relate to anoxia or electrolyte disturbance; later
encephalopathy more commonly relates to septic
complications (including vascular lesions, multiorgan
failure, and CNS infection).
Delirium in burn patients may be characterized by
agitation, hallucinations, and coarse tremor. Patients
may deteriorate to coma. Late seizures, focal or
generalized, are more common in children than in
adults, where they may reflect vascular complica-
tions, hyponatremia, or hypoxia.
The mechanisms for burn encephalopathy are not
mutually exclusive. Most cases qualify as metabolic
encephalopathies, often secondary to multiorgan fail-
ure. Metabolic encephalopathies outnumber vascular
and infective mechanisms, even in fatal cases. Anoxic
encephalopathy, in contrast to most septic patients, is
common in autopsied burn patients. This can relate to
anoxic hypoxia, carbon monoxide poisoning, or
anoxic–ischemic mechanisms. Hyperplasia of proto-
plasmic astrocytes is common and often relates to
renal failure. Approximately 20% of fatal cases reveal
CNS infections. More than 75% of CNS infections
are due to Candida species, P. aeruginosa, or
Staphylococcus aureus. Microabscesses or septic
infarcts at autopsy are more common with Candida
and S. aureus bacteremia. Meningitis is caused most
commonly by P. aeruginosa. Patients with CNS
BURN ENCEPHALOPATHY 491
infections usually have had the systemic inflammatory
response syndrome and extensive, deep burns.
Cerebral infarcts occur in 18% of cases; some are
macroscopic. These relate to septic arterial occlu-
sions often from Candida or Aspergillus species.
Others are due to meningitis, infected emboli from
endocarditis, or to an arteritis without endocarditis
or meningitis, disseminated intravascular coagula-
tion (DIC), and septic shock. Septic infarcts always
occur after the first week. In one-third of patients,
such infarcts related to atherosclerosis, atrial fibrilla-
tion, or other causes found in the general population.
Cortical vein thrombosis occurred in 2 of 20 children
with burn encephalopathy.
Intracranial hemorrhages occur approximately
one-third as often as infarcts and usually relate to
DIC with thrombocytopenia. Blood cultures are
usually positive in patients who develop intracranial
hemorrhages.
Some patients develop severe cerebral edema with
resultant compromise of intracranial circulation. The
edema may relate to anoxia with early presentation
or to the later development of toxic encephalopathy.
Occasionally, central pontine myelinolysis occurs.
This is thought to be due to abrupt increases in serum
osmolality, whether from a hyponatremic value or an
increase to hypernatremic concentrations from pre-
viously normal osmolality.
Iatrogenic causes of coma include electrolyte
disturbances and drug side effects from administra-
tion of sedatives, analgesics, antibiotics, anticonvul-
sants, and other medications. The free fraction of the
serum concentration of drugs can change consider-
ably after burns. Since albumin is often decreased
with burns, the free fraction of drugs that are
normally bound to albumin (e.g., phenytoin) in-
creases. Those drugs that bind to the acute phase
reactant a1 acid glycoprotein, which increases with
burns and infection, show greater protein binding
and a lower percentage of free fraction. The net total
concentration measured needs to be reinterpreted,
even though drug handling by the body and the total
concentration of the drug do not change.
—G. Bryan Young
See also–Sepsis-Associated Encephalopathy;
Toxic Encephalopathy
Further Reading
Haynes, B. W., Jr., and Bright, R. (1967). Burn coma: A syndrome
associated with severe burn wound infection. J. Trauma 7, 464–
475.
492 BYPASS SURGERY
Mohnot, D., Snead, O. C., III, and Benton, J. W., Jr. (1981). Burn
encephalopathy in children. Ann. Neurol. 12, 42–47.
Bypass Surgery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRAIN, like every other organ in the body,
requires a regular and adequate blood supply to
function. The blood supplies oxygen, glucose, and
other nutrients and removes metabolic waste pro-
ducts. Four arteries (i.e., two internal carotid and
two vertebral arteries) carry blood to the brain. An
interruption or a decrease in this blood supply
(ischemia) can impair the function of the brain by
causing neuronal cell death (cerebral infarction/
stroke) in the affected areas. A bypass procedure is
a neurosurgical operation intended to provide or
improve blood flow to ischemic areas of the brain or
to areas that will lose their blood supply as a result of
treatment (e.g., removing certain tumors of the skull
base or aneurysms that involve arteries supplying the
brain).
There are three primary indications for a bypass
procedure. The first is cerebral ischemic disease
caused by an obstruction or occlusion of a supplying
artery. This indication is relatively rare, and the
decision to perform a bypass is made only after
extensive investigations have confirmed that de-
creased blood flow is adversely affecting brain
function or that the condition cannot be treated by
a simpler surgical procedure or other medical means.
Such patients suffer from atherosclerotic disease of
the arteries that supply the brain or have other
diseases (e.g., moyamoya) that reduce the blood
supply to the brain by causing arterial occlusion.
The second indication is tumors that encase the
arteries that supply the brain as these arteries enter
the base of the skull. To remove these tumors
completely, it is sometimes necessary to resect the
portion of the artery encased by tumor.
The third indication is the presence of certain
aneurysms (dilatations of the arterial wall) on an
artery that supplies the brain. Such aneurysms may
be very large or in a location that is difficult to reach
(i.e., cavernous sinus). These aneurysms may be
unamenable to surgical clipping and may need to be
trapped where the arterial lumen proximal and
distal to the aneurysm is occluded. Such trapping
may be performed surgically or with interventional
radiology techniques. If an aneurysm or skull base
tumor is the indication for the bypass, the lesion may
be treated during the same operation or during a
second procedure performed days or weeks later.
To ascertain the need for a bypass operation,
patients undergo computerized tomography (CT) or
magnetic resonance imaging to identify areas of
ischemia and other pathology. Xenon CT can help
identify areas of brain with an inadequate blood
supply. The anatomy of the arterial supply to the
brain is studied by cerebral angiography, a test in
which dye is injected into the blood vessels that
supply the brain to make them visible. At the same
time, a balloon occlusion test may be performed to
assess whether the patient can tolerate permanent
occlusion of the relevant artery without suffering
adverse consequences. A balloon is inflated in the
artery during angiography to occlude the lumen of
the artery. If the patient tolerates this temporary
arterial occlusion without exhibiting any symptoms,
a bypass may be unnecessary. If, however, the patient
becomes symptomatic, a bypass is mandatory.
Various bypass procedures can be performed
depending on the arteries involved. Depending on
the volume of blood that can flow through the
donor vessel and its size, the bypass will be
considered either low-flow or high-flow. A low-flow
bypass is needed to revascularize a distal vessel;
a high-flow bypass may be needed if a larger,
proximal artery is being occluded. Arteries that
supply the scalp (i.e., the superficial temporal artery
and occipital artery) can be used to redirect blood
to the brain and to provide low-flow bypasses. If a
high-flow bypass is required, a conduit (graft) is
placed to carry blood between the arteries of the
neck or base of the skull and the intracranial arteries.
The graft is usually taken from the saphenous vein in
the leg.
The operation requires a microscope because the
vessels involved are small. The vessels are sewn
together with fine synthetic suture material. During
the operation, there is a brief period during which the
blood supply to part of the brain is interrupted while
the vessels are joined (anastomosed). To prevent a
stroke during this period of ischemia, patients are
administered various agents that decrease the meta-
bolic activity of the brain, thereby providing
neuronal protection. This protection enables the
brain to tolerate the temporary ischemia. At the
end of the operation, blood flow through the bypass
is confirmed by intraoperative angiography or
Doppler ultrasonography.
492 BYPASS SURGERY
Mohnot, D., Snead, O. C., III, and Benton, J. W., Jr. (1981). Burn
encephalopathy in children. Ann. Neurol. 12, 42–47.
Bypass Surgery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE BRAIN, like every other organ in the body,
requires a regular and adequate blood supply to
function. The blood supplies oxygen, glucose, and
other nutrients and removes metabolic waste pro-
ducts. Four arteries (i.e., two internal carotid and
two vertebral arteries) carry blood to the brain. An
interruption or a decrease in this blood supply
(ischemia) can impair the function of the brain by
causing neuronal cell death (cerebral infarction/
stroke) in the affected areas. A bypass procedure is
a neurosurgical operation intended to provide or
improve blood flow to ischemic areas of the brain or
to areas that will lose their blood supply as a result of
treatment (e.g., removing certain tumors of the skull
base or aneurysms that involve arteries supplying the
brain).
There are three primary indications for a bypass
procedure. The first is cerebral ischemic disease
caused by an obstruction or occlusion of a supplying
artery. This indication is relatively rare, and the
decision to perform a bypass is made only after
extensive investigations have confirmed that de-
creased blood flow is adversely affecting brain
function or that the condition cannot be treated by
a simpler surgical procedure or other medical means.
Such patients suffer from atherosclerotic disease of
the arteries that supply the brain or have other
diseases (e.g., moyamoya) that reduce the blood
supply to the brain by causing arterial occlusion.
The second indication is tumors that encase the
arteries that supply the brain as these arteries enter
the base of the skull. To remove these tumors
completely, it is sometimes necessary to resect the
portion of the artery encased by tumor.
The third indication is the presence of certain
aneurysms (dilatations of the arterial wall) on an
artery that supplies the brain. Such aneurysms may
be very large or in a location that is difficult to reach
(i.e., cavernous sinus). These aneurysms may be
unamenable to surgical clipping and may need to be
trapped where the arterial lumen proximal and
distal to the aneurysm is occluded. Such trapping
may be performed surgically or with interventional
radiology techniques. If an aneurysm or skull base
tumor is the indication for the bypass, the lesion may
be treated during the same operation or during a
second procedure performed days or weeks later.
To ascertain the need for a bypass operation,
patients undergo computerized tomography (CT) or
magnetic resonance imaging to identify areas of
ischemia and other pathology. Xenon CT can help
identify areas of brain with an inadequate blood
supply. The anatomy of the arterial supply to the
brain is studied by cerebral angiography, a test in
which dye is injected into the blood vessels that
supply the brain to make them visible. At the same
time, a balloon occlusion test may be performed to
assess whether the patient can tolerate permanent
occlusion of the relevant artery without suffering
adverse consequences. A balloon is inflated in the
artery during angiography to occlude the lumen of
the artery. If the patient tolerates this temporary
arterial occlusion without exhibiting any symptoms,
a bypass may be unnecessary. If, however, the patient
becomes symptomatic, a bypass is mandatory.
Various bypass procedures can be performed
depending on the arteries involved. Depending on
the volume of blood that can flow through the
donor vessel and its size, the bypass will be
considered either low-flow or high-flow. A low-flow
bypass is needed to revascularize a distal vessel;
a high-flow bypass may be needed if a larger,
proximal artery is being occluded. Arteries that
supply the scalp (i.e., the superficial temporal artery
and occipital artery) can be used to redirect blood
to the brain and to provide low-flow bypasses. If a
high-flow bypass is required, a conduit (graft) is
placed to carry blood between the arteries of the
neck or base of the skull and the intracranial arteries.
The graft is usually taken from the saphenous vein in
the leg.
The operation requires a microscope because the
vessels involved are small. The vessels are sewn
together with fine synthetic suture material. During
the operation, there is a brief period during which the
blood supply to part of the brain is interrupted while
the vessels are joined (anastomosed). To prevent a
stroke during this period of ischemia, patients are
administered various agents that decrease the meta-
bolic activity of the brain, thereby providing
neuronal protection. This protection enables the
brain to tolerate the temporary ischemia. At the
end of the operation, blood flow through the bypass
is confirmed by intraoperative angiography or
Doppler ultrasonography.

Soon after surgery, a bypass graft can occlude and
cause a stroke. Late occlusions of bypass grafts,
however, are usually without consequence. The long-
term patency of bypass grafts has been reported to be
85–95% depending on the bypass. Bypasses con-
structed of arteries (i.e., superficial temporal artery
or occipital artery) have a higher patency rate than
bypasses constructed from veins.
—Atul Tyagi, Paul W. Detwiler, Randall W. Porter,
and Robert F. Spetzler
See also–Aneurysms, Surgery; Brain Tumors,
Clinical Manifestations and Treatment; Cerebral
Blood Flow, Measurement of
BYPASS SURGERY 493
Further Reading
Carter, L. P., Spetzler, R. F., and Hamilton, M. G. (Eds.) (1995).
Neurovascular Surgery. McGraw-Hill, New York.
Collice, M., Arena, O., and Fontana, R. A. (1986). Superficial
temporal artery to proximal middle cerebral artery anastomo-
sis: Clinical and angiographic long term results. Neurosurgery
19, 922–927.
Day, A. L., Rhoton, A. L., Jr., and Little, J. R. (1986). The
Extracranial–Intracranial Bypass Study. Surg. Neurol. 26, 222–
226.
Goldring, S., Zervas, N., and Langfitt, T. (1987). The Extra-
cranial–Intracranial Bypass Study. A report of the committee
appointed by the American Association of Neurological
Surgeons to examine the study. N. Engl. J. Med. 316, 817–820.
Little, J. R., Furlan, A. J., and Bryerton, B. (1983). Short
vein grafts of cerebral revascularization. J. Neurosurg. 59,
384–388.
CADASIL
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE LENGTHY APPELLATION ‘‘cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy’’ (CADASIL), coined in 1993,
highlights the hereditary nature of this disorder as
well as its hallmark pathological, clinical, and
radiological features. Initial reports of the condition
date back to 1955 when Van Bogaart described two
sisters with ‘‘subcortical encephalopathy of Binswan-
ger’s type.’’ In 1977, Sourander and Walinder
described a hereditary multi-infarct dementia with
recurrent stroke-like episodes related to a small
vessel arteriopathy. Identified first in Europe, CADA-
SIL has now been recognized in hundreds of families
throughout the world.
CLINICAL PRESENTATION
Migraine with aura is present in 40% of CADASIL
families and is often the first clinical manifestation.
As is true in the wider population of migraineurs,
auras are usually visual and sensory in nature. In
CADASIL, prolonged aura and transient hemiplegia,
confusion, fever, and coma have also been reported.
Ischemic stroke, which is the most frequently
described clinical manifestation of the disorder, is
often heralded by transient ischemic attacks begin-
ning at approximately the age of 50 years, in the
absence of traditional vascular risk factors. Particu-
larly at the onset of the disease, ischemic signs and
symptoms often suggest lacunar syndromes, being
purely motor or purely sensory in nature. Severe
mood disturbances have been described in approxi-
mately 20% of patients with CADASIL and often
include recurrent episodes of depression and mania.
Onset of bipolar disease after the age of 50 years
should raise the level of suspicion for CADASIL.
Psychiatric symptoms have been attributed to
ischemia within the frontal white matter and the
basal ganglia. Dementia is observed at a mean age of
60 years in persons with CADASIL. Although it
usually progresses in a stepwise fashion in conjunc-
tion with recurrent episodes of cerebral ischemia, in
a minority of cases dementia is an isolated phenom-
enon. Basal ganglia infarction with remote metabolic
effects may underlie the cognitive decline. Focal and
generalized seizures have been described in fewer
than 10% of patients with CADASIL. Myelopathy,
radiculopathy, optic neuropathy, and other cranial
neuropathies have not been associated with this
disorder and may help distinguish CADASIL from
other white matter diseases. The mean age of death
in CADASIL is 65 years after disease duration of
15–30 years.
PATHOLOGY
In CADASIL, small infarcts occur in the basal
ganglia, brainstem (especially pons), and white
matter, with cortical sparing. Light microscopy
shows thickening of the arterioles with luminal
narrowing. Perivascular smooth muscle cells are
often degenerated and replaced by collagen fibers.
On electron microscopy, granular osmiophilic mate-
rial of uncertain origin is seen in the vicinity of the
perivascular smooth muscle cells in the brain as well
495
496 CALCIUM
as in other organs, including skin, muscle, nerve,
kidneys, and heart. Skin and nerve biopsy may be
particularly helpful in confirming the diagnosis.
Cerebrospinal fluid may have elevated protein, but
oligoclonal bands are seldom identified.
NEUROIMAGING
Widespread increased signal intensities in the white
matter on T2-weighted magnetic resonance imaging
(MRI) are a hallmark of CADASIL and may be
present before the onset of symptoms. By the age of
40, data suggest that all persons with CADASIL will
have characteristic abnormalities on MRI. The
degree of signal abnormalities increases with advan-
cing age, but in general cortical and cerebellar
lesions are rare. Functional MRI studies in persons
with CADASIL suggest decreased cerebral blood
flow within the white matter in a topographical
distribution corresponding to T2 signal abnormal-
ities. Both parameters correlate with the degree of
clinical severity. Cerebral angiography is usually
normal.
GENETICS
In 1993, the gene for CADASIL was assigned to the
short arm of chromosome 19 based on genetic
linkage analysis performed in two large French
families. Three years later, the same group of
investigators reported several mutations of the
notch-3 gene on chromosome 19 in persons with
CADASIL. A genetic test that is able to detect 70%
of the causitive mutations is now commercially
available. Recently, there have been reports of
spontaneous mutations in this gene leading to de
novo cases of CADASIL. Study of the expression of
the protein encoded by the notch-3 gene and also of
the notch signaling pathway in vascular and brain
tissue may reveal the molecular mechanisms leading
to the development of CADASIL.
SUMMARY
CADASIL is characterized by recurrent subcortical
ischemic infarcts and vascular dementia. Diffuse
white matter abnormalities are secondary to
small vessel noninflammatory, nonamyloid, and
nonatherosclerotic arteriopathy. MRI studies are
helpful in the diagnosis of CADASIL because
prominent abnormalities on T2-weighted imaging
are present in virtually all adults after the fourth
decade of life who carry the genetic mutation
for CADASIL on chromosome 19. Genetic testing
is now available outside of the research setting
and is able to identify the majority of causitive
mutations. Electron microscopy of skin or nerve
biopsies may offer corroborating evidence of
CADASIL.
—Gretchen E. Tietjen
See also–Behavior, Neuropathology of; Bipolar
Disorders; Dementia; Migraine with Aura
Further Reading
Chabriat, H., Vahedi, K., Joutel, A., et al. (1997). Cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL). Neurologist 3, 137–145.
Chabriat, H., Pappata, S., Ostergaard, L., et al. (2000). Cerebral
hemodynamics in CADASIL before and after acetazolamide
challenge assessed with MRI bolus tracking. Stroke 31,
1904–1912.
Joutel, A., Corpechot, C., Ducros, A., et al. (1996). Notch 3
mutations in CADASIL, a hereditary adult-onset condition
causing stroke and dementia. Nature 383, 707–710.
Ruchoux, M. M., Chabriat, H., Bousser, M. G., et al.
(1994). Presence of ultrastructural arterial lesions in muscle
and skin vessels of patients with CADASIL. Stroke 25,
2291–2292.
Tournier-Lasserve, E., Joutel, A., Melki, J., et al. (1993). Cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy maps on chromosome 19q12. Nat.
Genet. 3, 256–259.
Calcium
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CALCIUM, the most abundant extracellular polyva-
lent ion, was discovered in 1808 by Humphry Davy.
In 1883, Sidney Ringer showed that calcium was
required for myocardial contractility, and Katz and
colleagues demonstrated in the 1950s and 1960s that
chemical neurotransmission at the neuromuscular
junction depended on calcium influx into nerve
terminals. We now know that calcium has important
intra- and extracellular functions in the nervous
system, in which it regulates neuonal excitability and
stimulus–response coupling.
EXTRACELLULAR CALCIUM
The importance of extracellular calcium for
neurological function is evident from the clinical
496 CALCIUM
as in other organs, including skin, muscle, nerve,
kidneys, and heart. Skin and nerve biopsy may be
particularly helpful in confirming the diagnosis.
Cerebrospinal fluid may have elevated protein, but
oligoclonal bands are seldom identified.
NEUROIMAGING
Widespread increased signal intensities in the white
matter on T2-weighted magnetic resonance imaging
(MRI) are a hallmark of CADASIL and may be
present before the onset of symptoms. By the age of
40, data suggest that all persons with CADASIL will
have characteristic abnormalities on MRI. The
degree of signal abnormalities increases with advan-
cing age, but in general cortical and cerebellar
lesions are rare. Functional MRI studies in persons
with CADASIL suggest decreased cerebral blood
flow within the white matter in a topographical
distribution corresponding to T2 signal abnormal-
ities. Both parameters correlate with the degree of
clinical severity. Cerebral angiography is usually
normal.
GENETICS
In 1993, the gene for CADASIL was assigned to the
short arm of chromosome 19 based on genetic
linkage analysis performed in two large French
families. Three years later, the same group of
investigators reported several mutations of the
notch-3 gene on chromosome 19 in persons with
CADASIL. A genetic test that is able to detect 70%
of the causitive mutations is now commercially
available. Recently, there have been reports of
spontaneous mutations in this gene leading to de
novo cases of CADASIL. Study of the expression of
the protein encoded by the notch-3 gene and also of
the notch signaling pathway in vascular and brain
tissue may reveal the molecular mechanisms leading
to the development of CADASIL.
SUMMARY
CADASIL is characterized by recurrent subcortical
ischemic infarcts and vascular dementia. Diffuse
white matter abnormalities are secondary to
small vessel noninflammatory, nonamyloid, and
nonatherosclerotic arteriopathy. MRI studies are
helpful in the diagnosis of CADASIL because
prominent abnormalities on T2-weighted imaging
are present in virtually all adults after the fourth
decade of life who carry the genetic mutation
for CADASIL on chromosome 19. Genetic testing
is now available outside of the research setting
and is able to identify the majority of causitive
mutations. Electron microscopy of skin or nerve
biopsies may offer corroborating evidence of
CADASIL.
—Gretchen E. Tietjen
See also–Behavior, Neuropathology of; Bipolar
Disorders; Dementia; Migraine with Aura
Further Reading
Chabriat, H., Vahedi, K., Joutel, A., et al. (1997). Cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL). Neurologist 3, 137–145.
Chabriat, H., Pappata, S., Ostergaard, L., et al. (2000). Cerebral
hemodynamics in CADASIL before and after acetazolamide
challenge assessed with MRI bolus tracking. Stroke 31,
1904–1912.
Joutel, A., Corpechot, C., Ducros, A., et al. (1996). Notch 3
mutations in CADASIL, a hereditary adult-onset condition
causing stroke and dementia. Nature 383, 707–710.
Ruchoux, M. M., Chabriat, H., Bousser, M. G., et al.
(1994). Presence of ultrastructural arterial lesions in muscle
and skin vessels of patients with CADASIL. Stroke 25,
2291–2292.
Tournier-Lasserve, E., Joutel, A., Melki, J., et al. (1993). Cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy maps on chromosome 19q12. Nat.
Genet. 3, 256–259.
Calcium
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CALCIUM, the most abundant extracellular polyva-
lent ion, was discovered in 1808 by Humphry Davy.
In 1883, Sidney Ringer showed that calcium was
required for myocardial contractility, and Katz and
colleagues demonstrated in the 1950s and 1960s that
chemical neurotransmission at the neuromuscular
junction depended on calcium influx into nerve
terminals. We now know that calcium has important
intra- and extracellular functions in the nervous
system, in which it regulates neuonal excitability and
stimulus–response coupling.
EXTRACELLULAR CALCIUM
The importance of extracellular calcium for
neurological function is evident from the clinical

syndromes that result from derangements in calcium
metabolism.
Hypercalcemia usually results from hyperparathyr-
oidism or cancer and produces neurological symp-
toms by increasing the depolarization threshold of
nerve and muscle, causing them to be underexcitable.
Neurological symptoms of hypercalcemia, which
tend to occur at serum calcium levels higher than
17 mg/dl (8.5 mEq/liter), include lethargy, weakness,
and headache. Encephalopathy, myopathic weakness,
and signs of focal cerebral disturbance may be seen.
Diagnosis depends on whether an elevated serum
calcium concentration is measured, which may be
associated with electrocardiogram abnormalities,
especially a shortened QT interval. Occult cancer
should be suspected and searched for. Acute medical
treatment involves intravenous fluids and diuretics to
promote rehydration and calciuresis. More definitive
treatment of an underlying neoplasm or surgery for
hyperparathyroidism should then be considered.
Hypocalcemia occurs in the setting of chronic
renal failure, hypoparathyroidism, vitamin D defi-
ciency, or pancreatitis. In contrast to hypercalcemia,
it causes increased neuronal excitability. Typical
symptoms include encephalopathy, which is some-
times associated with agitation or hallucinations,
seizures, and circumoral and acral paresthesia. The
principal neurological sign of hypocalcemia is tetany
or intermittent, involuntary tonic contraction of
skeletal muscle. This may be spontaneous (manifest
or overt tetany, as exemplified by carpal or pedal
spasm) or induced (latent tetany). Forms of latent
tetany include Chvostek’s sign (contraction of the
facial muscles elicited by percussion over the facial
nerve) and Trousseau’s sign (carpal spasm induced by
compression of the arm with a tourniquet). Labora-
tory findings in hypocalcemia include decreased
ionized serum calcium and a prolonged QT interval.
Treatment is with calcium replacement and, in some
cases, vitamin D.
Table 2 HEREDITARY CALCIUM CHANNELOPATHIES
Disorder Mutant subunit
Hypokalemic periodic paralysis (periodic paralysis 1) a1S
Malignant hyperthermia
MHS5 a1S
MHS3 a2d
Familial hemiplegic migraine a1A
Episodic ataxia, type 2 a1A
Spinocerebellar ataxia 6 a1A
CALCIUM 497
Table 1 CALCIUM CHANNEL SUBUNITS, SUBTYPES,
AND BLOCKERS
a1 Subunit Channel subtype Channel blockers
a1S,C,D, or F L Dihydropyridines
a1B N o-Conotoxins GVIA
a1G,H, or I T Mibefradil
a1A P/Q o-Agatoxin IVA
a1E R SNX-482
INTRACELLULAR CALCIUM
Calcium enters nerve and muscle cells from the
extracellular space, down an approximately 10,000-
fold concentration gradient, through porous mem-
brane proteins called ion channels. Once inside the
cell, calcium triggers a host of biochemical events
that culminate in critical physiological events such as
neurotransmitter release and muscle contraction.
The best characterized calcium channels are those
that open in response to membrane depolarization
and are therefore termed voltage-gated calcium
channels. These exist in a variety of forms, with
different protein subunit composition, electrophysio-
logical properties, and cellular localization. Voltage-
gated calcium channels consist of membrane-span-
ning, pore-forming a1 subunits and a series of
regulatory subunits with the designations a2d, b,
and g. Each of these subunits exists in a variety of
forms, and it is the specific type of a1 subunit present
that confers specific functional and pharmacological
properties on a channel. For example, neuronal
calcium channels involved in neurotransmitter release
are predominantly those with a1A or a1B subunits;
these are commonly referred to as P/Q-type and N-
type calcium channels, respectively. The a1 subunits
present and the drug sensitivity of the various calcium
channel subtypes are shown in Table 1.
Channel subtype Mutation
L Missense
L Missense
L Missense
P/Q Missense
P/Q Premature stop
P/Q CAG trinucleotide repeat expansion
498 CALLOSOTOMY
Disturbances in the function of voltage-gated
calcium channels have been implicated in clinical
disease. For example, an autoimmune disorder with
antibodies against P/Q-type calcium channels is
responsible for the defect in neuromuscular transmis-
sion seen in the Lambert–Eaton myasthenic syn-
drome. These patients have limb weakness,
depressed tendon reflexes, and ptosis, and repetitive
nerve stimulation yields a potentiated postetanic
contractile response of skeletal muscle. Autonomic
disturbances are also commonly present. Most
patients have underlying neoplasms or other auto-
immune diseases.
Several mutations in calcium channel subunits
have also been identified as the underlying defect in
neurological disorders in humans. These channelo-
pathies all show autosomal dominant inheritance.
They result from missense mutations associated with
single-nucleotide substitutions, frame-shift and
splice-site mutations leading to premature stops and
truncated proteins, and expanded trinucleotide re-
peats that code for polyglutamine tracts. Examples
are listed in Table 2. These include neuromuscular
disorders, such as hypokalemic periodic paralysis
and malignant hyperthermia, and cerebral disorders,
such as familial hemiplegic migraine, episodic ataxia,
and spinocerebellar ataxia.
—David A. Greenberg
See also–Ataxia; Channelopathies,
Clinical Manifestations; Malignant
Hyperthermia; Vitamin D; Women’s Health,
Neurology of
Further Reading
Greenberg, D. A. (1999). Neuromuscular disorders and calcium
channels. Muscle Nerve 22, 1341–1349.
Rose, M. R., and Griggs, R. C. (2001). Channelopathies of the
Nervous System. Butterworth Heinemann, Oxford.
Callosotomy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE GOAL of corpus callosotomy is to disrupt the
pathways used in the generalization or spread of
seizures. It is reserved for patients who experience
generalized seizures without a focus amenable to
resection and who experience seizures despite opti-
mal anticonvulsant medications. Patients with drop
attacks or the Lennox–Gestaut syndrome respond
most favorably.
In 1940, Van Wagenen and Herren first reported
sectioning the corpus callosum as a treatment for
epilepsy in 10 patients. Their rationale for the
technique was based on the observation that tumors
involving the corpus callosum were associated with
seizures. As more of the corpus callosum was
destroyed by tumor, however, the seizures diminished
or became focal. The procedure was seldom used
until the 1960s, when more extensive reports were
published.
The initial approach for the procedure was from
the right side; part or all of the callosum was
resected. In subsequent studies, two separate cranio-
tomies were used to section the anterior and poster-
ior portions of the callosum individually. Sectioning
other structures, including the massa intermedia,
anterior commissure, hippocampal commissure, and
unilateral fornix, was also described. Over time the
procedure has evolved, and sectioning of the corpus
callosum is now more refined.
The current technique can be performed with the
patient in the lateral decubitus or supine position.
The craniotomy usually extends across the sagittal
sinus. Using microsurgical technique, the interhemi-
spheric fissure is opened directly onto the corpus
callosum, separating the pericallosal arteries. The
corpus callosum can then be divided, typically along
the genu, with resection carried posteriorly to the
splenium.
The degree of resection among reports varies.
Some surgeons advocate the use of intraoperative
electroencephalography to document disruption of
bilateral synchrony once the extent of the resection
is sufficient. Postoperative signs such as mutism,
unilateral apraxia, and bilateral frontal lobe
reflexes are more severe after complete sectioning
compared to more limited resection. Therefore, some
surgeons have suggested a two-stage procedure
that begins with resection of the anterior callosum.
If seizures fail to improve, a second stage for
resection of the remainder of the callosum can be
considered.
The inconsistencies in the extent of sectioning and
the resection of other structures have made it difficult
to interpret results from this procedure. Some series
report a seizure-free rate as high as 11%, with 68%
of patients experiencing a 50–95% reduction in
seizures. Seizures are reduced less than 50% in 18%
498 CALLOSOTOMY
Disturbances in the function of voltage-gated
calcium channels have been implicated in clinical
disease. For example, an autoimmune disorder with
antibodies against P/Q-type calcium channels is
responsible for the defect in neuromuscular transmis-
sion seen in the Lambert–Eaton myasthenic syn-
drome. These patients have limb weakness,
depressed tendon reflexes, and ptosis, and repetitive
nerve stimulation yields a potentiated postetanic
contractile response of skeletal muscle. Autonomic
disturbances are also commonly present. Most
patients have underlying neoplasms or other auto-
immune diseases.
Several mutations in calcium channel subunits
have also been identified as the underlying defect in
neurological disorders in humans. These channelo-
pathies all show autosomal dominant inheritance.
They result from missense mutations associated with
single-nucleotide substitutions, frame-shift and
splice-site mutations leading to premature stops and
truncated proteins, and expanded trinucleotide re-
peats that code for polyglutamine tracts. Examples
are listed in Table 2. These include neuromuscular
disorders, such as hypokalemic periodic paralysis
and malignant hyperthermia, and cerebral disorders,
such as familial hemiplegic migraine, episodic ataxia,
and spinocerebellar ataxia.
—David A. Greenberg
See also–Ataxia; Channelopathies,
Clinical Manifestations; Malignant
Hyperthermia; Vitamin D; Women’s Health,
Neurology of
Further Reading
Greenberg, D. A. (1999). Neuromuscular disorders and calcium
channels. Muscle Nerve 22, 1341–1349.
Rose, M. R., and Griggs, R. C. (2001). Channelopathies of the
Nervous System. Butterworth Heinemann, Oxford.
Callosotomy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE GOAL of corpus callosotomy is to disrupt the
pathways used in the generalization or spread of
seizures. It is reserved for patients who experience
generalized seizures without a focus amenable to
resection and who experience seizures despite opti-
mal anticonvulsant medications. Patients with drop
attacks or the Lennox–Gestaut syndrome respond
most favorably.
In 1940, Van Wagenen and Herren first reported
sectioning the corpus callosum as a treatment for
epilepsy in 10 patients. Their rationale for the
technique was based on the observation that tumors
involving the corpus callosum were associated with
seizures. As more of the corpus callosum was
destroyed by tumor, however, the seizures diminished
or became focal. The procedure was seldom used
until the 1960s, when more extensive reports were
published.
The initial approach for the procedure was from
the right side; part or all of the callosum was
resected. In subsequent studies, two separate cranio-
tomies were used to section the anterior and poster-
ior portions of the callosum individually. Sectioning
other structures, including the massa intermedia,
anterior commissure, hippocampal commissure, and
unilateral fornix, was also described. Over time the
procedure has evolved, and sectioning of the corpus
callosum is now more refined.
The current technique can be performed with the
patient in the lateral decubitus or supine position.
The craniotomy usually extends across the sagittal
sinus. Using microsurgical technique, the interhemi-
spheric fissure is opened directly onto the corpus
callosum, separating the pericallosal arteries. The
corpus callosum can then be divided, typically along
the genu, with resection carried posteriorly to the
splenium.
The degree of resection among reports varies.
Some surgeons advocate the use of intraoperative
electroencephalography to document disruption of
bilateral synchrony once the extent of the resection
is sufficient. Postoperative signs such as mutism,
unilateral apraxia, and bilateral frontal lobe
reflexes are more severe after complete sectioning
compared to more limited resection. Therefore, some
surgeons have suggested a two-stage procedure
that begins with resection of the anterior callosum.
If seizures fail to improve, a second stage for
resection of the remainder of the callosum can be
considered.
The inconsistencies in the extent of sectioning and
the resection of other structures have made it difficult
to interpret results from this procedure. Some series
report a seizure-free rate as high as 11%, with 68%
of patients experiencing a 50–95% reduction in
seizures. Seizures are reduced less than 50% in 18%

of patients. Patients with drop attacks, atypical
absence, and myoclonic seizures have shown a better
response to the procedure than those with general-
ized tonic–clonic or tonic seizures. With contempo-
rary microsurgical technique, the mortality rate is
low, approximately 3%. As these percentages illus-
trate, the major disadvantage of the procedure is that
most patients only obtain partial control of their
seizures.
Complications specific to this surgical approach
include air embolism from entry into the sagittal
sinus and sagittal sinus bleeding. The most devastat-
ing complication is the disconnection syndrome,
which is more common with posterior callosotomy
than with anterior callosotomy. In left-hemisphere-
dominant patients, this syndrome consists of left-
sided tactile anomia, left-sided apraxia, pseudohe-
mianopsia, impaired complex figure copying with the
right hand, decreased spontaneity of speech, and
incontinence. The disconnection syndrome can occur
transiently in as many as 57% of patients but seldom
persists beyond 3–6 months.
Other neurological sequelae are rare. Neuropsy-
chological studies document difficulties associated
with the transfer of interhemispheric information,
but this problem seldom interferes with the patient’s
functional status. Occasionally, memory difficulties
have been reported.
Preliminary results using gamma knife stereotactic
radiosurgery to ablate the corpus callosum have also
been reported. Seizure activity improved, but the
number of cases is small and the collective follow-up
is still brief. In addition, the exact mechanism
by which the radiation interferes with callosal
functioning and the optimal dosage remain to be
determined.
Corpus callosotomy is a safe procedure in both
children and adults. It effectively palliates seizures in
most patients. The best results are obtained in
patients with drop attacks, myoclonic seizures, and
atypical seizures. The procedure can be beneficial in
those cases in which other, nonsurgical treatments
have failed to control seizures.
—Wendy Elder and Robert F. Spetzler
See also–Corpus Callosum; Epileptic Seizures
Further Reading
McInerney, J., Siegel, A. M., Nordgren, R. E., et al. (1999). Long-
term seizure outcome following corpus callosotomy in children.
Stereotact. Funct. Neurosurg. 73, 79–83.
CANAVAN DISEASE 499
Pendl, G., Eder, H. G., Schroettner, O., et al. (1999). Corpus
callosotomy with radiosurgery. Neurosurgery 45, 303–308.
Smith, J. R., Lee, M. R., Jenkins, P. D., et al. (1999). A 13-year
experience with epilepsy surgery. Stereotact. Funct. Neurosurg.
73, 98–103.
Sorenson, J. M., Wheless, J. W., Baumgartner, J. E., et al. (1997).
Corpus callosotomy for medically intractable seizures. Pediatr.
Neurosurg. 27, 260–267.
Wyler, A. R. (1993). Corpus callosotomy. In The Treatment of
Epilepsy: Principles and Practices (E. Wyllie, Ed.). Lea &
Febiger, Philadelphia.
Canavan Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CANAVAN DISEASE is a neurodegenerative disorder
characterized by severe progressive psychomotor
retardation, macrocephaly, and spongy degeneration
of the brain. The first neuropathological description
of the disease was presented by Myrtelle Canavan
(1931), but the clinical and inherited nature of the
disease was initially described by van Bogaert and
Bertrand (1949). During the past 10–15 years, it has
been shown that there is decreased aspartoacylase,
resulting in increased N-acetyl aspartic acid (NAA)
in the brain and urine of these patients.
CLINICAL PRESENTATION
The clinical presentation of patients with Canavan
disease is variable. Early descriptions of the disease
suggested three clinical variants including a con-
genital, infantile, and juvenile form, but it is more
probable that signs and symptoms of the disease
present in early infancy and manifest a variable rate
of disease progression in different patients. Infants
with Canavan disease usually present in the first 3 to
4 months of life with nonspecific problems, such as a
poor suck, poor visual tracking, increased head lag,
and hypotonia. However, these symptoms and signs
can be manifestations of various other age-related
neurodegenerative disorders in children. With time, a
delay in acquisition of milestones becomes apparent
as well as progressive macrocephaly and increased
feeding difficulties; in addition, seizures, although
not common, can be part of the clinical picture.
Ophthalmological findings include optic atrophy and
nystagmus. Hypotonia eventually evolves to hyper-
tonia, spasticity, and hyperreflexia. The prognosis for
this disorder is grim and although many earlier

of patients. Patients with drop attacks, atypical
absence, and myoclonic seizures have shown a better
response to the procedure than those with general-
ized tonic–clonic or tonic seizures. With contempo-
rary microsurgical technique, the mortality rate is
low, approximately 3%. As these percentages illus-
trate, the major disadvantage of the procedure is that
most patients only obtain partial control of their
seizures.
Complications specific to this surgical approach
include air embolism from entry into the sagittal
sinus and sagittal sinus bleeding. The most devastat-
ing complication is the disconnection syndrome,
which is more common with posterior callosotomy
than with anterior callosotomy. In left-hemisphere-
dominant patients, this syndrome consists of left-
sided tactile anomia, left-sided apraxia, pseudohe-
mianopsia, impaired complex figure copying with the
right hand, decreased spontaneity of speech, and
incontinence. The disconnection syndrome can occur
transiently in as many as 57% of patients but seldom
persists beyond 3–6 months.
Other neurological sequelae are rare. Neuropsy-
chological studies document difficulties associated
with the transfer of interhemispheric information,
but this problem seldom interferes with the patient’s
functional status. Occasionally, memory difficulties
have been reported.
Preliminary results using gamma knife stereotactic
radiosurgery to ablate the corpus callosum have also
been reported. Seizure activity improved, but the
number of cases is small and the collective follow-up
is still brief. In addition, the exact mechanism
by which the radiation interferes with callosal
functioning and the optimal dosage remain to be
determined.
Corpus callosotomy is a safe procedure in both
children and adults. It effectively palliates seizures in
most patients. The best results are obtained in
patients with drop attacks, myoclonic seizures, and
atypical seizures. The procedure can be beneficial in
those cases in which other, nonsurgical treatments
have failed to control seizures.
—Wendy Elder and Robert F. Spetzler
See also–Corpus Callosum; Epileptic Seizures
Further Reading
McInerney, J., Siegel, A. M., Nordgren, R. E., et al. (1999). Long-
term seizure outcome following corpus callosotomy in children.
Stereotact. Funct. Neurosurg. 73, 79–83.
CANAVAN DISEASE 499
Pendl, G., Eder, H. G., Schroettner, O., et al. (1999). Corpus
callosotomy with radiosurgery. Neurosurgery 45, 303–308.
Smith, J. R., Lee, M. R., Jenkins, P. D., et al. (1999). A 13-year
experience with epilepsy surgery. Stereotact. Funct. Neurosurg.
73, 98–103.
Sorenson, J. M., Wheless, J. W., Baumgartner, J. E., et al. (1997).
Corpus callosotomy for medically intractable seizures. Pediatr.
Neurosurg. 27, 260–267.
Wyler, A. R. (1993). Corpus callosotomy. In The Treatment of
Epilepsy: Principles and Practices (E. Wyllie, Ed.). Lea &
Febiger, Philadelphia.
Canavan Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CANAVAN DISEASE is a neurodegenerative disorder
characterized by severe progressive psychomotor
retardation, macrocephaly, and spongy degeneration
of the brain. The first neuropathological description
of the disease was presented by Myrtelle Canavan
(1931), but the clinical and inherited nature of the
disease was initially described by van Bogaert and
Bertrand (1949). During the past 10–15 years, it has
been shown that there is decreased aspartoacylase,
resulting in increased N-acetyl aspartic acid (NAA)
in the brain and urine of these patients.
CLINICAL PRESENTATION
The clinical presentation of patients with Canavan
disease is variable. Early descriptions of the disease
suggested three clinical variants including a con-
genital, infantile, and juvenile form, but it is more
probable that signs and symptoms of the disease
present in early infancy and manifest a variable rate
of disease progression in different patients. Infants
with Canavan disease usually present in the first 3 to
4 months of life with nonspecific problems, such as a
poor suck, poor visual tracking, increased head lag,
and hypotonia. However, these symptoms and signs
can be manifestations of various other age-related
neurodegenerative disorders in children. With time, a
delay in acquisition of milestones becomes apparent
as well as progressive macrocephaly and increased
feeding difficulties; in addition, seizures, although
not common, can be part of the clinical picture.
Ophthalmological findings include optic atrophy and
nystagmus. Hypotonia eventually evolves to hyper-
tonia, spasticity, and hyperreflexia. The prognosis for
this disorder is grim and although many earlier
500 CANAVAN DISEASE

reports stated survival past 1 to 2 years of life was

unlikely, there are recent reports of patients surviving
to the second and third decades of life. This may
relate to improved general supportive care or, indeed,
clinical heterogeneity of phenotypes.

NEUROIMAGING
Magnetic resonance imaging (MRI) shows diffuse,
symmetrical involvement of the cerebral white
matter, including the subcortical U fibers, which
appears to be involved early, progressing to ulti-
mately involve the periventricular white matter.
Abnormal signal can also be seen in the lentiform
nuclei. The white matter is hyperintense on T2
images suggesting a demyelinating process. MR
spectroscopy shows large N-acetyl aspartate peaks
in patients with this disorder and provides supportive
evidence for the diagnosis of the disease process
(Fig. 1).

NEUROPATHOLOGY
Histological examination of the brain shows spongy
degeneration of the white matter, swelling of the
astrocytes, and morphological changes of the mito-
chondria. There is vacuolar formation within the
deep layers of the cortex as well as the subcortical
white matter. Eventually, the progression of the
disease process includes cystic changes in the white
matter with atrophy of the gray matter. The exact
mechanism for brain injury is unclear, but NAA
accumulation in the white matter may act as an
osmolite causing increased water accumulation
within the brain.
DIAGNOSIS
Before the neurochemical abnormalities were identi-
fied in Canavan disease, the diagnosis was deter-
mined by brain biopsy that demonstrated spongiform
changes in the white matter of affected patients. The
association of N-acetyl aspartic aciduria in indivi-
duals with this disease was described by Matalon and
colleagues in 1988, and soon thereafter the deficiency
of the enzyme aspartoacylase was also identified. The
enzyme catalyzes the hydrolysis of NAA to aspartate
and acetate. The NAA level is substantially increased
in the brain of affected patients and is also found in
high concentration in the urine. The gene for
aspartoacylase was cloned in 1994.
Figure 1
T2-weighted MRI scan of a 4-year-old child with Canavan disease.
Note the abnormal signal involving the white matter, extending
peripherally to involve subcortical U fibers.
These findings have made the diagnosis of Canavan
disease much more specific and their determination is
noninvasive, including the measurement of NAA in
the urine, assay of the enzyme aspartoacylase from
cultured fibroblasts, and mutational analysis of DNA
from a blood sample. Prenatal testing is possible for
families for whom the mutation has been identified.
DNA mutational analysis can be performed on
placental cells; however, the determination of aspar-
toacylase activity from amniotic fluid is not helpful
since the levels are frequently normal (Table 1).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of patients with macro-
cephaly and developmental delay is broad and can
range from acquired macrocephaly, as in the case of
hydrocephalus, to infants with benign familial
macrocephaly. Some infants with large heads may
present with motor delay that can be related to
difficulty in raising a large head from a cot; moreover,
prolonged head lag and delayed motor milestones are
not uncommon in a variety of other disorders
affecting the nervous system. Neurodegenerative

Table 1 DIFFERENTIAL DIAGNOSIS OF MACROCEPHALY AND
DEVELOPMENTAL DELAY
Hydrocephalus
Hydranencephaly
Neurocutaneous disorders
Tuberous sclerosis
Neurofibromatosis
Hypomelanosis of Ito
Genetic disorders
Cerebral gigantism/Sotos syndrome
Benign familial macrocephaly
Metabolic disorders
Canavan disease
Alexander disease
GM2 gangliosidoses
Mucopolysaccharidoses
Glutaric aciduria type I
3-OH glutaric aciduria
disorders that are associated with macrocephaly
include those that primarily affect white matter,
namely, Canavan disease and Alexander disease.
Other storage disorders with associated macroce-
phaly include the mucopolysaccharidoses, GM2 gang-
liosidoses, and 3-OH glutaric aciduria. Children
considered to have a static encephalopathy who have
macrocephaly should be evaluated for a genetic or
neurometabolic disorder.
GENETICS
Canavan disease is inherited as an autosomal
recessive trait. The gene responsible for the disease
is located on the short arm of chromosome 17 and is
most prevalent in Ashkenazi Jews. In this population,
two mutations are responsible for more than 95% of
the disease in affected individuals—the Glu285Ala
missense mutation and the Tyr231X nonsense muta-
tion. DNA mutational analysis on this population
can detect almost all individuals affected with the
disease. In the non-Jewish population, the most
common mutation is the Ala305Glu mutation, which
was present in 60% of the 40 mutant chromosomes
tested by Kaul et al. This suggests that in the non-
Jewish population, mutations are more variable and
may not be identified on DNA mutational analysis of
a blood sample.
TREATMENT
There is no specific treatment or cure to halt this
progressive neurodegenerative disease. A recent trial
CAPILLARY TELANGIECTASIA 501
of gene therapy was performed but did not provide
positive results. Current treatment is directed at
careful general supportive care including physical,
occupational, and speech therapy. Attention must be
directed to nutritional status and aspiration risk.
Intellectual stimulation in an appropriate educa-
tional setting is also very important to stimulate
cognitive development. Despite this symptom-based
treatment, children usually succumb to this disease in
the first decade of life.
—Nancy E. Bass
See also–Alexander’s Disease; Bogaert, Ludo
van; Degenerative Disorders; Hydrocephalus;
Hypomelanosis of Ito; Neurofibromatosis;
Tuberous Sclerosis Complex (TSC)
Further Reading
Canavan, M. M. (1931). Schilder’s encephalitis periaxialis diffusa.
Report of a case in a child aged sixteen and a half months. Arch.
Neurol. Psychiatr. 25, 299–301.
Kaul, R., Gao, G. P., Balamurugan, K., et al. (1993). Cloning of the
human aspartoacylase cDNA and a common missense mutation
in Canavan disease. Nat. Genet. 5, 118–123.
Kaul, R., Gao, G. P., Balamurugan, K., et al. (1994). Canavan
disease: Mutations among Jewish patients. Am. J. Hum. Genet.
55, 34–41.
Matalon, R. K., Michaels, D., et al. (1988). Aspartoacylase
deficiency and N-acetylaspartic aciduria in patients with
Canavan disease. Am. J. Med. Genet. 29, 463–471.
Matalon, R. K., and Michals-Matalon, K. (1999). Prenatal
diagnosis of Canavan disease. Prenatal Diagn. 19, 670–699.
Matalon, R. M., and Michals-Matalon, K. (2000). Spongy
degeneration of the brain, Canavan disease: Biochemical and
molecular findings. Frontiers Biosci. 5, D307–D311.
Traeger, E. C., and Rapin, I. (1998). The clinical course of
Canavan disease. Pediatr. Neurol. 18, 207–212.
Van Bogaert, L., and Bertrand, I. (1949). Sur une idiote familiale
avec degenerescence spongieuse du neuraxe. Acta Neurol. Belg.
49, 572–587.
Capillary Telangiectasia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CAPILLARY TELANGIECTASES are vascular malforma-
tions that consist of a collection of dilated capillaries
with normal intervening brain parenchyma. They are
found throughout the central nervous system (CNS)
and are generally considered benign congenital
lesions. Typically, they are asymptomatic and of
clinical interest only for their occasional association
with other vascular malformations.

Table 1 DIFFERENTIAL DIAGNOSIS OF MACROCEPHALY AND
DEVELOPMENTAL DELAY
Hydrocephalus
Hydranencephaly
Neurocutaneous disorders
Tuberous sclerosis
Neurofibromatosis
Hypomelanosis of Ito
Genetic disorders
Cerebral gigantism/Sotos syndrome
Benign familial macrocephaly
Metabolic disorders
Canavan disease
Alexander disease
GM2 gangliosidoses
Mucopolysaccharidoses
Glutaric aciduria type I
3-OH glutaric aciduria
disorders that are associated with macrocephaly
include those that primarily affect white matter,
namely, Canavan disease and Alexander disease.
Other storage disorders with associated macroce-
phaly include the mucopolysaccharidoses, GM2 gang-
liosidoses, and 3-OH glutaric aciduria. Children
considered to have a static encephalopathy who have
macrocephaly should be evaluated for a genetic or
neurometabolic disorder.
GENETICS
Canavan disease is inherited as an autosomal
recessive trait. The gene responsible for the disease
is located on the short arm of chromosome 17 and is
most prevalent in Ashkenazi Jews. In this population,
two mutations are responsible for more than 95% of
the disease in affected individuals—the Glu285Ala
missense mutation and the Tyr231X nonsense muta-
tion. DNA mutational analysis on this population
can detect almost all individuals affected with the
disease. In the non-Jewish population, the most
common mutation is the Ala305Glu mutation, which
was present in 60% of the 40 mutant chromosomes
tested by Kaul et al. This suggests that in the non-
Jewish population, mutations are more variable and
may not be identified on DNA mutational analysis of
a blood sample.
TREATMENT
There is no specific treatment or cure to halt this
progressive neurodegenerative disease. A recent trial
CAPILLARY TELANGIECTASIA 501
of gene therapy was performed but did not provide
positive results. Current treatment is directed at
careful general supportive care including physical,
occupational, and speech therapy. Attention must be
directed to nutritional status and aspiration risk.
Intellectual stimulation in an appropriate educa-
tional setting is also very important to stimulate
cognitive development. Despite this symptom-based
treatment, children usually succumb to this disease in
the first decade of life.
—Nancy E. Bass
See also–Alexander’s Disease; Bogaert, Ludo
van; Degenerative Disorders; Hydrocephalus;
Hypomelanosis of Ito; Neurofibromatosis;
Tuberous Sclerosis Complex (TSC)
Further Reading
Canavan, M. M. (1931). Schilder’s encephalitis periaxialis diffusa.
Report of a case in a child aged sixteen and a half months. Arch.
Neurol. Psychiatr. 25, 299–301.
Kaul, R., Gao, G. P., Balamurugan, K., et al. (1993). Cloning of the
human aspartoacylase cDNA and a common missense mutation
in Canavan disease. Nat. Genet. 5, 118–123.
Kaul, R., Gao, G. P., Balamurugan, K., et al. (1994). Canavan
disease: Mutations among Jewish patients. Am. J. Hum. Genet.
55, 34–41.
Matalon, R. K., Michaels, D., et al. (1988). Aspartoacylase
deficiency and N-acetylaspartic aciduria in patients with
Canavan disease. Am. J. Med. Genet. 29, 463–471.
Matalon, R. K., and Michals-Matalon, K. (1999). Prenatal
diagnosis of Canavan disease. Prenatal Diagn. 19, 670–699.
Matalon, R. M., and Michals-Matalon, K. (2000). Spongy
degeneration of the brain, Canavan disease: Biochemical and
molecular findings. Frontiers Biosci. 5, D307–D311.
Traeger, E. C., and Rapin, I. (1998). The clinical course of
Canavan disease. Pediatr. Neurol. 18, 207–212.
Van Bogaert, L., and Bertrand, I. (1949). Sur une idiote familiale
avec degenerescence spongieuse du neuraxe. Acta Neurol. Belg.
49, 572–587.
Capillary Telangiectasia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CAPILLARY TELANGIECTASES are vascular malforma-
tions that consist of a collection of dilated capillaries
with normal intervening brain parenchyma. They are
found throughout the central nervous system (CNS)
and are generally considered benign congenital
lesions. Typically, they are asymptomatic and of
clinical interest only for their occasional association
with other vascular malformations.
502 CAPILLARY TELANGIECTASIA
Grossly, capillary telangiectases appear as a faint
pink blush on fresh sections of the brain. With
formalin fixation, the lesions appear dark brown
(Fig. 1). They tend to be small, measuring less than
1 cm in diameter.
Microscopically, capillary telangiectases appear as
a cluster of dilated, ectatic, thin-walled vessels
separated by normal tissue (Fig. 2). The veins into
which these capillary-like vessels drain may also be
enlarged; however, the feeding arterioles are always
normal. Histologically, the vessel walls appear
similar to normal capillaries, devoid of smooth
muscle or elastic fibers and lined with a single layer
of vascular endothelium. The vessels vary greatly in
size and often display areas of fusiform dilatation.
Occasional vessels may appear almost cavernous but
typically measure less than 30 mm in diameter. The
size of the vessels that compose the lesion is
abnormal, but their number is thought to be
relatively normal.
In postmortem studies, the reported prevalence of
capillary telangiectases ranges from 0.1 to 0.8%.
Capillary telangiectases are found throughout the
CNS but are most common in the pons. They are
believed to be congenital lesions that arise from an
early, localized failure in the normal involution of
Figure 1
Gross pathological specimen demonstrating a capillary
telangiectasis in the midbrain (arrowhead). The size of the small
punctate vascular channels varies. The dark discoloration is caused
by formalin fixation (original magnification  1).
Figure 2
Photomicrograph of a capillary telangiectasis revealing multiple
dilated capillary channels, separated by normal-appearing brain
parenchyma. A single layer of capillary endothelium lines the
vessel walls, which otherwise are normal except for their increased
size (hematoxylin–eosin stain, original magnification  100).
brain capillaries that occurs during the second month
of gestation.
Most capillary telangiectases are an incidental
finding at autopsy and have a benign clinical course;
however, clinically symptomatic lesions have occa-
sionally been reported, usually in association with
other cerebral vascular lesions. Combined lesions
with elements of both cavernous malformations and
capillary telangiectases are well documented. Histo-
logically, the features that differentiate these two
types of malformations include the presence of
normal intervening parenchyma and the size of the
vascular channels.
The occurrence of combined lesions and transi-
tional forms that are difficult to classify into either
category led several authors to propose that capillary
telangiectases may represent potential precursors of
cavernous malformations. However, this theory,
which was first proposed by Russell in 1931, has
not gained wide acceptance. In fact, Russell ulti-
mately rejected the idea. In the fifth edition of their
classic text (Pathology of Tumors of the Central
Nervous System), Russell and Rubenstein argued
that if capillary telangiectases were precursors of
cavernous malformations, they should be seen in
greater numbers than cavernous malformations and
be more common early in life.
Arteriovenous malformations (AVMs) and capil-
lary telangiectases can also be associated, but this is
uncommon, except in patients with hereditary
hemorrhagic telangiectases (HHT). HHT, also

known as Osler–Weber–Rendu disease, is an auto-
somally dominant disease characterized by the
development of capillary telangiectases in the skin,
gastrointestinal tract, nasal mucosa, and CNS. The
stereotypical lesions are absent at birth, developing
on a delayed basis during the second and third
decades of life. The delayed occurrence of pulmonary
and cerebral AVMs has been well documented in
patients with this disease.
Capillary telangiectases are benign congenital
lesions, occasionally found in association with other
vascular lesions of the CNS.
—Joseph M. Zabramski and Robert F. Spetzler
See also–Ataxia Telangiectasia; Arteriovenous
Malformations (AVM), Surgical Treatment of;
Cerebrovascular Malformations (Angiomas);
Osler-Weber-Rendu Syndrome
Further Reading
Awad, I. A., Robinson, J. R., Jr., Mohanty, S., et al. (1993). Mixed
vascular malformations of the brain: Clinical and pathogenetic
considerations. Neurosurgery 33, 179–188.
Chang, S. D., Steinberg, G. K., Rosario, M., et al. (1997). Mixed
arteriovenous malformation and capillary telangiectasia: A rare
subset of mixed vascular malformations. J. Neurosurg. 86,
699–703.
Golfinos, J., and Zabramski, J. M. (1996). The genetics of
intracranial vascular malformations. In The Molecular Basis
of Neurosurgical Disease. Vol. 8: Concepts in Neurosurgery (C.
Raffel and G. R. Harsh, Eds.), pp. 270–277. Williams &
Wilkins, Baltimore.
McCormick, W. F. (1984). Pathology of vascular malformations of
the brain. In Intracranial Arteriovenous Malformations (C. B.
Wilson and B. M. Stein, Eds.), pp. 44–63. Williams & Wilkins,
Baltimore.
Rengachary, S. S., and Kaylan-Raman, U. P. (1996). Telangiecta-
sias and venous angiomas. In Neurosurgery (R. H. Wilkins and
S. S. Rengachary, Eds.), pp. 2509–2514. McGraw-Hill, New
York.
Russell, D. S., and Rubenstein, L. J. (1989). Pathology of Tumors
of the Nervous System, 5th ed., pp. 727–736. Williams &
Wilkins, Baltimore.
Zabramski, J. M., Henn, J. S., and Coons, S. (1999). Pathology of
cerebral vascular malformations. Neurosurg. Clin. North Am.
10, 395–410.
Carbon Dioxide Narcosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARBON DIOXIDE (CO2) narcosis is associated with
an increase in cerebral blood flow, but there is no
CARBON DIOXIDE NARCOSIS 503
change in the cerebral metabolic consumption of
oxygen. Although there is no net change in adenosine
triphosphate, adenosine diphosphate, or energy
charge potential, at very high arterial oxygen
pressures (PaO2), there is a reduction of phospho-
creatine (PCr) in the brain. This decrease in PCr,
associated with an increase in the lactate:pyruvate
ratio, is likely due to intracellular acidosis from
increased carbonic acid’s effect on enzyme systems.
Additional metabolic changes include increased
glucose-6-phosphate and fructose-6-phosphate and
decreases in tricarboxylic acid (TCA) cycle and
amino acid pools. Carbohydrate depletion for the
TCA cycle is compensated for by increased amino
acid oxidation. This leads to increased intracellular
ammonia and hence glutamine concentration. These
changes occur acutely; there is likely greater intra-
cellular buffering of the effects of chronic respiratory
acidosis.
Since hypoxemia or sedating drugs are common
accompaniments of hypercarbia, it is difficult to
weigh their effects relative to those in producing the
obtundation. There is usually a background of
chronic pulmonary problems with acute decompen-
sation. Neuromuscular disorders may also lead to
ventilatory failure. The precipitant may be an
intercurrent illness or a sedative or narcotic drug
that suppresses the ventilatory drive. Early symptoms
of CO2 toxicity include diffuse headache, followed
by impairment of conscious level, impaired attention,
and coma. There may be considerable fluctuations in
the degree of obtundation. Brainstem reflexes are
spared, but pupils may be miotic. Exceptionally, with
the combination of hypoxemia and hypercarbia, an
early herniation syndrome may produce pupillary
nonreactivity, sometimes unilaterally. Coarse tremor,
asterixis, and multifocal myoclonus are very com-
mon. Paratonic rigidity and extensor plantar re-
sponses are also frequently found. Chronic
hypercarbia may be associated with papilledema
due to the increase in intracranial blood volume
because of arterial dilatation and increased brain
blood flow.
The principal investigation is the performance
of arterial or capillary blood gas determination.
This usually reveals hypercarbia, with PaCO2
usually higher than 70 mmHg and often higher
than 90 mmHg. Oxygenation of the arterial blood
is usually reduced because of hypoventilation.
Cerebrospinal fluid is under increased pressure
and the electroencephalogram shows diffuse
slowing.

known as Osler–Weber–Rendu disease, is an auto-
somally dominant disease characterized by the
development of capillary telangiectases in the skin,
gastrointestinal tract, nasal mucosa, and CNS. The
stereotypical lesions are absent at birth, developing
on a delayed basis during the second and third
decades of life. The delayed occurrence of pulmonary
and cerebral AVMs has been well documented in
patients with this disease.
Capillary telangiectases are benign congenital
lesions, occasionally found in association with other
vascular lesions of the CNS.
—Joseph M. Zabramski and Robert F. Spetzler
See also–Ataxia Telangiectasia; Arteriovenous
Malformations (AVM), Surgical Treatment of;
Cerebrovascular Malformations (Angiomas);
Osler-Weber-Rendu Syndrome
Further Reading
Awad, I. A., Robinson, J. R., Jr., Mohanty, S., et al. (1993). Mixed
vascular malformations of the brain: Clinical and pathogenetic
considerations. Neurosurgery 33, 179–188.
Chang, S. D., Steinberg, G. K., Rosario, M., et al. (1997). Mixed
arteriovenous malformation and capillary telangiectasia: A rare
subset of mixed vascular malformations. J. Neurosurg. 86,
699–703.
Golfinos, J., and Zabramski, J. M. (1996). The genetics of
intracranial vascular malformations. In The Molecular Basis
of Neurosurgical Disease. Vol. 8: Concepts in Neurosurgery (C.
Raffel and G. R. Harsh, Eds.), pp. 270–277. Williams &
Wilkins, Baltimore.
McCormick, W. F. (1984). Pathology of vascular malformations of
the brain. In Intracranial Arteriovenous Malformations (C. B.
Wilson and B. M. Stein, Eds.), pp. 44–63. Williams & Wilkins,
Baltimore.
Rengachary, S. S., and Kaylan-Raman, U. P. (1996). Telangiecta-
sias and venous angiomas. In Neurosurgery (R. H. Wilkins and
S. S. Rengachary, Eds.), pp. 2509–2514. McGraw-Hill, New
York.
Russell, D. S., and Rubenstein, L. J. (1989). Pathology of Tumors
of the Nervous System, 5th ed., pp. 727–736. Williams &
Wilkins, Baltimore.
Zabramski, J. M., Henn, J. S., and Coons, S. (1999). Pathology of
cerebral vascular malformations. Neurosurg. Clin. North Am.
10, 395–410.
Carbon Dioxide Narcosis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARBON DIOXIDE (CO2) narcosis is associated with
an increase in cerebral blood flow, but there is no
CARBON DIOXIDE NARCOSIS 503
change in the cerebral metabolic consumption of
oxygen. Although there is no net change in adenosine
triphosphate, adenosine diphosphate, or energy
charge potential, at very high arterial oxygen
pressures (PaO2), there is a reduction of phospho-
creatine (PCr) in the brain. This decrease in PCr,
associated with an increase in the lactate:pyruvate
ratio, is likely due to intracellular acidosis from
increased carbonic acid’s effect on enzyme systems.
Additional metabolic changes include increased
glucose-6-phosphate and fructose-6-phosphate and
decreases in tricarboxylic acid (TCA) cycle and
amino acid pools. Carbohydrate depletion for the
TCA cycle is compensated for by increased amino
acid oxidation. This leads to increased intracellular
ammonia and hence glutamine concentration. These
changes occur acutely; there is likely greater intra-
cellular buffering of the effects of chronic respiratory
acidosis.
Since hypoxemia or sedating drugs are common
accompaniments of hypercarbia, it is difficult to
weigh their effects relative to those in producing the
obtundation. There is usually a background of
chronic pulmonary problems with acute decompen-
sation. Neuromuscular disorders may also lead to
ventilatory failure. The precipitant may be an
intercurrent illness or a sedative or narcotic drug
that suppresses the ventilatory drive. Early symptoms
of CO2 toxicity include diffuse headache, followed
by impairment of conscious level, impaired attention,
and coma. There may be considerable fluctuations in
the degree of obtundation. Brainstem reflexes are
spared, but pupils may be miotic. Exceptionally, with
the combination of hypoxemia and hypercarbia, an
early herniation syndrome may produce pupillary
nonreactivity, sometimes unilaterally. Coarse tremor,
asterixis, and multifocal myoclonus are very com-
mon. Paratonic rigidity and extensor plantar re-
sponses are also frequently found. Chronic
hypercarbia may be associated with papilledema
due to the increase in intracranial blood volume
because of arterial dilatation and increased brain
blood flow.
The principal investigation is the performance
of arterial or capillary blood gas determination.
This usually reveals hypercarbia, with PaCO2
usually higher than 70 mmHg and often higher
than 90 mmHg. Oxygenation of the arterial blood
is usually reduced because of hypoventilation.
Cerebrospinal fluid is under increased pressure
and the electroencephalogram shows diffuse
slowing.
504 CARDIAC ARREST RESUSCITATION
The treatment of CO2 narcosis is forced ventilation
and correction of the underlying precipitant/cause.
—G. Bryan Young
See also–Cerebral Blood Flow, Measurement of;
Cerebral Metabolism and Blood Flow
Further Reading
Sieker, H. O., and Hickam, J. B. (1956). Carbon dioxide
intoxication: The clinical syndrome, its etiology and manage-
ment with particular reference to the use of mechanical
respirators. Medicine 35, 389–423.
Cardiac Arrest Resuscitation
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARDIAC ARREST is characterized by cessation of
effective mechanical contraction of the heart. This in
turn results in complete cessation of blood flow and
thus oxygen delivery to the brain as well as the rest of
the body. The act of cardiac arrest resuscitation
involves a combination of mechanical, electrical, and
pharmacological treatments that attempt to produce
return of spontaneous circulation (ROSC) along with
normal brain function.
EPIDEMIOLOGY
The epidemiology of cardiac arrest is complicated by
the fact that it is a symptom of numerous disease
states and it occurs at least once in every human.
Sudden unexpected death, defined as death within 24
hr of symptom onset in a previously functional
individual, accounts for up to one-third of all
nontraumatic deaths (with most occurring outside
the hospital). Of these, 75% are attributed to
cardiovascular disease, with the remaining 25%
caused by noncardiac causes. It can thus be estimated
that 670,000 of the 2 million nontraumatic deaths
each year in the United States occur suddenly; thus,
the incidence of sudden death is 0.26%. Of these,
500,000 could be attributed to cardiovascular
disease and the remaining 170,000 to noncardiac
causes such a severe respiratory diseases.
PATHOPHYSIOLOGY
The brain and heart are the organs most susceptible
to damage from the lack of oxygen delivery that
occurs during cardiac arrest. Irreversible ischemic
brain damage begins to occur after as few as 5 min
and restoration of prior neurological function
rarely occurs after durations of untreated cardiac
arrest of more than 10 min. After 10 min of complete
cessation of cerebral blood flow, approximately all
the brain’s immediate energy stores are exhausted
since the brain has very little capacity to sustain itself
with anaerobic metabolism (metabolism without
oxygen). In addition to the damage that occurs
during the period of global cessation of blood flow,
damage will also occur in the form of reperfusion
injury if ROSC occurs. The majority of these
deleterious molecular mechanisms occurring during
and after cardiac arrest are shared with other
types of brain insults, such as stroke or traumatic
brain injury. In general, the poor neurological
outcomes associated with survival from cardiac
arrest are puzzling since patients experiencing
stroke symptoms for up to 3 hr with large areas of
ischemic brain tissue may make near normal
recoveries. Why short periods of global brain
ischemia are less well tolerated than longer periods
of stroke is not entirely clear but may be due to the
involvement of brain areas called the hippocampus
(responsible for many aspects of memory and
learning), which are not commonly injured during
stroke. However, evidence suggests that in certain
conditions, restoration of previous neurological
function can occur after 20–60 min of cardiac arrest.
These circumstances include immediate
institution of chest compressions and certain
therapies after ROSC during the victim’s postresus-
citation care.
TREATMENT
Cardiac arrest resuscitation can be classified into
two stages: treatment to obtain ROSC and post-
resuscitation treatment. Treatment to obtain ROSC
is commonly termed cardiopulmonary resuscitation
(CPR). CPR is more than the act of providing chest
compressions and artificial ventilation. The Amer-
ican Heart Association has developed a sophisti-
cated set of guidelines that combine artificial
circulation and ventilation with administration of
electrical and pharmacological therapy. Electrical
therapy in the form of defibrillation is used to treat
certain heart rhythms that occur during cardiac
arrest (ventricular fibrillation and ventricular tachy-
cardia). Patients exhibiting either of these rhythms
as their initial rhythm and who are treated rapidly
504 CARDIAC ARREST RESUSCITATION
The treatment of CO2 narcosis is forced ventilation
and correction of the underlying precipitant/cause.
—G. Bryan Young
See also–Cerebral Blood Flow, Measurement of;
Cerebral Metabolism and Blood Flow
Further Reading
Sieker, H. O., and Hickam, J. B. (1956). Carbon dioxide
intoxication: The clinical syndrome, its etiology and manage-
ment with particular reference to the use of mechanical
respirators. Medicine 35, 389–423.
Cardiac Arrest Resuscitation
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARDIAC ARREST is characterized by cessation of
effective mechanical contraction of the heart. This in
turn results in complete cessation of blood flow and
thus oxygen delivery to the brain as well as the rest of
the body. The act of cardiac arrest resuscitation
involves a combination of mechanical, electrical, and
pharmacological treatments that attempt to produce
return of spontaneous circulation (ROSC) along with
normal brain function.
EPIDEMIOLOGY
The epidemiology of cardiac arrest is complicated by
the fact that it is a symptom of numerous disease
states and it occurs at least once in every human.
Sudden unexpected death, defined as death within 24
hr of symptom onset in a previously functional
individual, accounts for up to one-third of all
nontraumatic deaths (with most occurring outside
the hospital). Of these, 75% are attributed to
cardiovascular disease, with the remaining 25%
caused by noncardiac causes. It can thus be estimated
that 670,000 of the 2 million nontraumatic deaths
each year in the United States occur suddenly; thus,
the incidence of sudden death is 0.26%. Of these,
500,000 could be attributed to cardiovascular
disease and the remaining 170,000 to noncardiac
causes such a severe respiratory diseases.
PATHOPHYSIOLOGY
The brain and heart are the organs most susceptible
to damage from the lack of oxygen delivery that
occurs during cardiac arrest. Irreversible ischemic
brain damage begins to occur after as few as 5 min
and restoration of prior neurological function
rarely occurs after durations of untreated cardiac
arrest of more than 10 min. After 10 min of complete
cessation of cerebral blood flow, approximately all
the brain’s immediate energy stores are exhausted
since the brain has very little capacity to sustain itself
with anaerobic metabolism (metabolism without
oxygen). In addition to the damage that occurs
during the period of global cessation of blood flow,
damage will also occur in the form of reperfusion
injury if ROSC occurs. The majority of these
deleterious molecular mechanisms occurring during
and after cardiac arrest are shared with other
types of brain insults, such as stroke or traumatic
brain injury. In general, the poor neurological
outcomes associated with survival from cardiac
arrest are puzzling since patients experiencing
stroke symptoms for up to 3 hr with large areas of
ischemic brain tissue may make near normal
recoveries. Why short periods of global brain
ischemia are less well tolerated than longer periods
of stroke is not entirely clear but may be due to the
involvement of brain areas called the hippocampus
(responsible for many aspects of memory and
learning), which are not commonly injured during
stroke. However, evidence suggests that in certain
conditions, restoration of previous neurological
function can occur after 20–60 min of cardiac arrest.
These circumstances include immediate
institution of chest compressions and certain
therapies after ROSC during the victim’s postresus-
citation care.
TREATMENT
Cardiac arrest resuscitation can be classified into
two stages: treatment to obtain ROSC and post-
resuscitation treatment. Treatment to obtain ROSC
is commonly termed cardiopulmonary resuscitation
(CPR). CPR is more than the act of providing chest
compressions and artificial ventilation. The Amer-
ican Heart Association has developed a sophisti-
cated set of guidelines that combine artificial
circulation and ventilation with administration of
electrical and pharmacological therapy. Electrical
therapy in the form of defibrillation is used to treat
certain heart rhythms that occur during cardiac
arrest (ventricular fibrillation and ventricular tachy-
cardia). Patients exhibiting either of these rhythms
as their initial rhythm and who are treated rapidly

with defibrillation have the best chance of survival
and favorable neurological outcome. In general,
successful chances for ROSC are significantly
reduced each minute defibrillation is delayed.
Pharmacological therapy is aimed at elevating the
blood flow to the heart and brain by chest
compressions (using vasopressors such as epinephr-
ine and vasopressin) and making defibrillation of the
heart easier (using antiarrhythmics such as lidocaine
and amiodarone). This therapy also helps to prevent
rearrest after ROSC. As a general rule, achieving
ROSC after 30 min of full CPR is rarely successful.
Most patients at this time have a heart rhythm called
asystole, which is essentially electrical silence of
the heart.
If ROSC occurs, well-orchestrated efforts must
take place to prevent rearrest and ensure optimal
outcome. The underlying cause of the arrest must be
ascertained and reversed if possible. Of major
concern is whether the patient’s arrest was caused
by a myocardial infarction. If so, strategies to
recannulate the blocked coronary artery must be
instituted (chemical thrombolysis or mechanical
angioplasty). Although seemingly heart specific,
these therapies will aid in producing the best
neurological outcome possible by ensuring optimal
postresuscitation blood flow and oxygen delivery to
the brain, thus preventing deleterious secondary
ischemia. Unfortunately, no postresuscitation phar-
macological therapy aimed at combating the mole-
cular pathophysiology of cardiac arrest-induced
brain injury has proven successful in clinical trials
(oxygen free radical scavenging, excitatory amino
acid blockade, etc.). However, production of mild
hypothermia soon after arrest (reduction of core
body temperature from 37 to 341C for 24–48 hr) has
shown promise in improving neurological outcome,
but additional definitive studies are needed. Utiliza-
tion of certain growth factors such as insulin may
also eventually prove to be useful.
PROGNOSIS
Although more than 50% of resuscitated patients
die in the hospital, brain death accounts for only
1 or 2% of cases. Almost all resuscitated patients
are initially comatose. In patients who awaken
early after cardiac arrest, prognosis is dependent
primarily on cardiovascular function and any under-
lying disease. Good neurological outcomes in
patients comatose 24–72 hr after resuscitation ranges
CARDIAC ARREST RESUSCITATION 505
from 7 to 24%. Neurological complications of
cardiac arrest include seizures, postanoxic myoclo-
nus, amnestic syndrome, persistent or transient
vegetative states, cortical blindness, cognitive im-
pairment, cortical infarcts, secondary parkinsonism,
hypoxic ischemic leukoencephalopathy, spinal
stroke, and brain death. The decision to withdraw
life support in the absence of brain death or reliable
outcome predictors must be made on an individual
basis.
CONCLUSION
Without tremendous breakthroughs in the under-
standing of neurological injury and repair resulting
in production of new pharmacological salvaging
agents, significant improvements in neurological
outcome from cardiac arrest will be difficult to
attain. However, maximal efforts to shorten the
duration of cardiac arrest (point of arrest to ROSC)
can be effective. To this end, institution of bystander
CPR and use of automated external defibrillation
technology are proving beneficial. Both of these
strategies are currently gaining widespread accep-
tance.
—Kevin R. Ward and Robert Neumar
See also–Brain Death; Brain Trauma, Overview;
Cardiac Drugs; Cerebral Metabolism and Blood
Flow; Ischemic Cell Death, Mechanisms
Further Reading
American Heart Association (2000). Guidelines for cardiopul-
monary resuscitation and emergency cardiac care. Circulation
102, 1–147.
Bass, E. (1985). Cardiopulmonary arrest: Pathophysiology and
neurologic complications. Ann. Intern. Med. 103, 920–927.
Hossmann, V., and Hossman, K. A. (1973). Return of neurologic
functions after prolonged cardiac arrest. Brain Res. 60,
423–438.
Hypothermia after Cardiac Arrest Study Group (2002). Mild
therapeutic hypothermia to improve the neurologic outcome
after cardiac arrest. N. Engl. J. Med. 346, 549–556.
Neumar, R. W., and Ward, K. R., (2001). Adult resuscitation. In
Emergency Medicine: Concepts and Clinical Practice (J. Marx,
R. Hockberger, and R. Walls, Eds.), 5th ed., pp. 64–81. Mosby,
St. Louis
Steill, I. G., Wells, G. A., Field, B. J., et al. (1999). Improved out-
of-hospital cardiac arrest survival through the inexpensive
optimization of an existing defibrillation program: OPALS
study phase II. J. Am. Med. Assoc. 281, 1175–1181.
White, B. C., Grossman, L. I., O’Neil, B. J., et al. (1996). Global
brain ischemic and reperfusion. Ann. Emergency Med. 27,
588–594.
506 CARDIAC DRUGS
Cardiac Drugs
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARDIAC DISEASE is among the primary illnesses
affecting adults and children, and there are many
medications to treat heart disease. Several are
associated with neurotoxicity syndromes affecting
the central and peripheral nervous systems.
Digitalis is derived from the plant foxglove, and
when clinical digitalis toxicity develops, 40–50% of
patients show signs of central nervous system
problems. Neurological complications include nau-
sea, vomiting, visual disturbances, seizures, confu-
sion, delirium, mania, hallucinosis, and syncope. The
most frequent, and often the first, neurotoxic
reaction is nausea due to direct stimulation of the
chemoreceptor trigger zone located in the brainstem
area known as the medulla. Nausea associated with
digitalis toxicity is often accompanied by vomiting
and, when chronic, may lead to malnourishment and
cachexia. The incidence of digitalis-related visual
disturbances has been estimated at 40%. Clinically, it
presents with blurred vision, blind spots (scotomas),
double vision, defects of color vision, and blindness.
Seizures are most commonly seen in the pediatric
population, but among adults confusion, delirium,
and hallucinosis are more common and occur in as
many as 15% of patients with digitalis toxicity.
Although the mechanism for the symptoms is
unknown, they are usually not the result of altered
cardiac function. On the other hand, if digitalis
intoxication provokes irregular heart rhythms, poor
perfusion to the brain can occur and patients can
develop global attentional problems, confusion, and
lethargy as well as fainting spells.
Beta-blockers are drugs that block a subset of
receptor site proteins related to the neurochemical
norepinephrine. These drugs cause frequent neuro-
psychiatric symptoms, most notably depression and
impotence. Whereas most effects are thought to
relate to the chemistry of the norepinephrine system,
these drugs also affect a second neurochemical,
serotonin. Nonselective beta-blockers seem to cause
central nervous system-related side effects to a
greater extent than do b1-selective blockers. Lassi-
tude or insomnia and depression are the most
common reactions, although vivid dreams, night-
mares, hypnagogic hallucinations, and psychotic
behavior have been reported with high doses
(4500 mg/day of propranolol). Preexisting major
psychiatric illness and hyperthyroidism may predis-
pose to the previously mentioned symptoms.
Calcium-channel blockers, particularly flunarizine
and cinnarizine (available in Europe and elsewhere
outside the United States), have been associated with
a number of involuntary movement disorders,
including cramping contortions (dystonia); slowness,
rigidity tremor, and gait problems (parkinsonism);
and restlessness (akathisia). Theoretical explanations
for these events include the inhibition of calcium
influx into cells within the brain region of the
striatum and direct antagonistic properties of the
neurochemical system involving dopamine. In addi-
tion, the chemical structures of flunarizine and
cinnarizine, which are related to neuroleptics tran-
quilizer drugs, may explain the greater incidence of
such side effects with these agents compared to
calcium channel blockers currently available in the
United States. Suggested risk factors are advanced
age and a family history of tremors and/or Parkin-
son’s disease.
Angiotensin-converting enzyme (ACE) inhibitors
cause neurological problems with a similar frequency
to that of beta-blockers. The precise role of the ACE
in the central nervous system is not well defined.
Mild lethargy, sedation, and fatigue are the most
common complaints. Contrary to beta-blockers,
ACE inhibitors appear to have the lowest association
with depression and are therefore the drugs of choice
when depression is a risk. Approximately 2–4%
(depending on renal function and dose) of patients
on captopril develop diminution or loss of taste
perception. This sign is reversible and usually
resolves within 2 or 3 months, even with continued
drug administration.
Nitrates are primarily associated with headaches
through a chemical mechanism shared with nitric
oxide. Nitroglycerin produces a throbbing or
pulsating sensation in many patients and overt
pain in many others. Often, the headaches attenu-
ate or disappear with time, but 15–20% of patients
will not be able to tolerate long-acting nitrates
because of headache. Patients should be encour-
aged to use analgesics during the initial days or
weeks of nitrate therapy and should be educated as
to the nature of this problem and its probable
resolution with time. Nitroglycerin therapy can
cause dose-related increases in intracranial pres-
sure that can be associated with headaches and
visual problems, and the hypotensive effects of
nitroglycerin can result in dizziness, light-head-
edness, or even syncope.

Amiodarone is an agent that is used to treat
irregularities of heart rates, and this potent drug can
be toxic for almost every organ in the body, including
the central and peripheral nervous systems, especially
when taken at high doses for long periods of time.
The most common neurotoxic findings include
tremor, incoordination or ataxia, and proximal
muscle weakness with wasting. Tremor usually
appears early in the course of therapy and is maximal
when patients use their hands, so typical problems
include poor handwriting and eating. Rarely, the
tremor is associated with parkinsonian features of
slowness and stiffness. Other neurological manifesta-
tions include lightning-like body jerks, called myo-
clonus; wild, flinging movements of one side of the
body, called hemiballism; and involuntary jerking
movements of the extremities and orofacial area,
called dyskinesias.
Lidocaine is widely administered parenterally and
topically. It is oxidized to active and inactive
metabolites by hepatic enzymes in the cytochrome
P450 mixed oxidase system. Toxic effects of lido-
caine occur frequently and involve the cardiovascular
and central nervous systems. Although lidocaine-
associated central nervous system effects can be seen
with other local anesthetics, lidocaine is far more
common as the causative drug and this high
frequency relates to its rapid absorption across the
blood–brain barrier. The high frequency of toxicity is
probably due to a diffuse excitation of neuronal
systems. At concentrations o6 mg/ml, dizziness,
drowsiness, paresthesias, and visual disturbances
predominate; confusion, slurred speech, coma, con-
vulsions, cardiac arrhythmias, and respiratory arrest
are more often seen at concentrations 46 mg/ml. The
toxicity of lidocaine can be viewed as a self-
enhancing phenomenon: If not terminated immedi-
ately, a marked respiratory acidosis results, which
creates more of the active, ionized form of the drug.
Treatment focuses on adequate oxygenation and
support since the half-life of bolus lidocaine given
acutely is 6–8 min. Since repeated injections change
the kinetics of lidocaine and prolong its half-life to
approximately 90 min, more long-lasting effects can
be seen. Although most reports of adverse reactions
involve intravenous lidocaine, toxic signs have been
reported with topical or oral use.
Quinidine is present in the cinchona bark, along
with quinine and other alkaloids. Nervous system
manifestations are usually not significant, but with
overdosage or in susceptible individuals quinidine
causes an intoxication similar to that of quinine. The
CARDIOVASCULAR REGULATION 507
corresponding clinical syndrome, cinchonism, is
manifested as headache, nausea, vomiting, blurring
of vision, transient visual obscurations, and ringing
of the ears. The visual symptoms are short-lived but
can be confused with visual transient ischemic
attacks or the visual accompaniments of migraine.
More persistent quinidine amblyopia is the result of
direct damage to the retinal ganglion cells. Finally,
there have been two case reports of dementia
associated with chronic quinidine use that reversed
after drug discontinuation.
—Christopher G. Goetz and Katie Kompoliti
See also–Calcium; Cardiovascular Regulation;
Neurotoxicology, Overview
Further Reading
Dahlof, C., and Dimenas, E. (1990). Side effects of beta-blocker
treatments as related to the central nervous system. Am. J. Med.
Sci. 299, 236–244.
Garcia-Ruiz, P. J., Garcia de Yebenes, J., Jimenez-Jimenez, F. J., et
al. (1992). Parkinsonism associated with calcium channel
blockers: A prospective follow-up study. Clin. Neuropharma-
col. 15, 19–26.
Gengo, F. M., and Gabos, C. (1988). Central nervous system
considerations in the use of beta-blockers, angiotensin-convert-
ing enzyme inhibitors, and thiazide diuretics in managing
essential hypertension. Am. Heart J. 116, 305–310.
Goetz, C. G. (1985). Neurotoxins in Clinical Practice. Spectrum,
New York.
Kompoliti, K. (1998). Drug and iatrogenically-induced neurologi-
cal disorders. In Textbook of Clinical Neurology (C. G. Goetz,
Ed.), pp. 1123–1152. Saunders, Philadelphia.
Piltz, J. R., Wertenbaker, C., Lance, S. E., et al. (1993). Digoxin
toxicity. Recognizing the varied visual presentations. J. Clin.
Neuroophthalmol. 13, 275–280.
Cardiovascular Regulation
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
GRAVITATIONAL and physiological stresses require
precise hemodynamic adjustments to maintain sys-
temic arterial pressure and blood flow to vital
organs, particularly the brain. This is achieved
through activation of autonomic and neuroendocrine
reflexes, which produce rapid changes in sympathetic
and parasympathetic outflow and release several
hormones into the bloodstream. When autonomic
reflexes are impaired, blood pressure varies widely
and blood flow to organs, including the brain, may

Amiodarone is an agent that is used to treat
irregularities of heart rates, and this potent drug can
be toxic for almost every organ in the body, including
the central and peripheral nervous systems, especially
when taken at high doses for long periods of time.
The most common neurotoxic findings include
tremor, incoordination or ataxia, and proximal
muscle weakness with wasting. Tremor usually
appears early in the course of therapy and is maximal
when patients use their hands, so typical problems
include poor handwriting and eating. Rarely, the
tremor is associated with parkinsonian features of
slowness and stiffness. Other neurological manifesta-
tions include lightning-like body jerks, called myo-
clonus; wild, flinging movements of one side of the
body, called hemiballism; and involuntary jerking
movements of the extremities and orofacial area,
called dyskinesias.
Lidocaine is widely administered parenterally and
topically. It is oxidized to active and inactive
metabolites by hepatic enzymes in the cytochrome
P450 mixed oxidase system. Toxic effects of lido-
caine occur frequently and involve the cardiovascular
and central nervous systems. Although lidocaine-
associated central nervous system effects can be seen
with other local anesthetics, lidocaine is far more
common as the causative drug and this high
frequency relates to its rapid absorption across the
blood–brain barrier. The high frequency of toxicity is
probably due to a diffuse excitation of neuronal
systems. At concentrations o6 mg/ml, dizziness,
drowsiness, paresthesias, and visual disturbances
predominate; confusion, slurred speech, coma, con-
vulsions, cardiac arrhythmias, and respiratory arrest
are more often seen at concentrations 46 mg/ml. The
toxicity of lidocaine can be viewed as a self-
enhancing phenomenon: If not terminated immedi-
ately, a marked respiratory acidosis results, which
creates more of the active, ionized form of the drug.
Treatment focuses on adequate oxygenation and
support since the half-life of bolus lidocaine given
acutely is 6–8 min. Since repeated injections change
the kinetics of lidocaine and prolong its half-life to
approximately 90 min, more long-lasting effects can
be seen. Although most reports of adverse reactions
involve intravenous lidocaine, toxic signs have been
reported with topical or oral use.
Quinidine is present in the cinchona bark, along
with quinine and other alkaloids. Nervous system
manifestations are usually not significant, but with
overdosage or in susceptible individuals quinidine
causes an intoxication similar to that of quinine. The
CARDIOVASCULAR REGULATION 507
corresponding clinical syndrome, cinchonism, is
manifested as headache, nausea, vomiting, blurring
of vision, transient visual obscurations, and ringing
of the ears. The visual symptoms are short-lived but
can be confused with visual transient ischemic
attacks or the visual accompaniments of migraine.
More persistent quinidine amblyopia is the result of
direct damage to the retinal ganglion cells. Finally,
there have been two case reports of dementia
associated with chronic quinidine use that reversed
after drug discontinuation.
—Christopher G. Goetz and Katie Kompoliti
See also–Calcium; Cardiovascular Regulation;
Neurotoxicology, Overview
Further Reading
Dahlof, C., and Dimenas, E. (1990). Side effects of beta-blocker
treatments as related to the central nervous system. Am. J. Med.
Sci. 299, 236–244.
Garcia-Ruiz, P. J., Garcia de Yebenes, J., Jimenez-Jimenez, F. J., et
al. (1992). Parkinsonism associated with calcium channel
blockers: A prospective follow-up study. Clin. Neuropharma-
col. 15, 19–26.
Gengo, F. M., and Gabos, C. (1988). Central nervous system
considerations in the use of beta-blockers, angiotensin-convert-
ing enzyme inhibitors, and thiazide diuretics in managing
essential hypertension. Am. Heart J. 116, 305–310.
Goetz, C. G. (1985). Neurotoxins in Clinical Practice. Spectrum,
New York.
Kompoliti, K. (1998). Drug and iatrogenically-induced neurologi-
cal disorders. In Textbook of Clinical Neurology (C. G. Goetz,
Ed.), pp. 1123–1152. Saunders, Philadelphia.
Piltz, J. R., Wertenbaker, C., Lance, S. E., et al. (1993). Digoxin
toxicity. Recognizing the varied visual presentations. J. Clin.
Neuroophthalmol. 13, 275–280.
Cardiovascular Regulation
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
GRAVITATIONAL and physiological stresses require
precise hemodynamic adjustments to maintain sys-
temic arterial pressure and blood flow to vital
organs, particularly the brain. This is achieved
through activation of autonomic and neuroendocrine
reflexes, which produce rapid changes in sympathetic
and parasympathetic outflow and release several
hormones into the bloodstream. When autonomic
reflexes are impaired, blood pressure varies widely
and blood flow to organs, including the brain, may
508 CARDIOVASCULAR REGULATION
be compromised particularly during gravitational
stress of upright posture. The nervous control of the
circulation is achieved through central integration of
several inputs.
Information from receptors in the thorax reaches
the central nervous system (CNS), specifically the
nucleus tractus solitarius (NTS) in the medulla,
through the glossopharyngeal and vagus nerves that
have their cell bodies in the petrosal and nodose
ganglia, respectively. Vagal afferents carry informa-
tion from aortic, cardiac, pulmonary, and gastro-
intestinal receptors. Glossopharyngeal afferents carry
signals from baro- and chemoreceptors in the carotid
sinus. High-pressure baroreceptors in the aortic arch
and in the internal carotid arteries discharge syn-
chronously with the aortic pressure wave. Unencap-
sulated nerve endings in the vena cava and the atrium
regulate their discharge according to the magnitude
of venous return and circulating blood volume. Input
from chemoreceptors sensitive to changes in the
arterial levels of oxygen and carbon dioxide and
from receptors with either mechano- or chemosensi-
tive function located in the lungs, renal arteries, and
skeletal muscle also play a role in the reflex control
of the circulation and converge to the medulla in the
NTS. Neurons in the NTS provide excitatory inputs
to the caudal ventrolateral medulla, which in turn
inhibits the rostral ventrolateral medulla (RVLM),
where the pacemaker neurons that originate sympa-
thetic tone are believed to be located.
RVLM neurons project to preganglionic sympa-
thetic neurons in the intermediolateral column of the
spinal cord, which send fibers outside the CNS that
innervate blood vessels and the heart. Parasympa-
thetic activity is also modulated by the NTS through
projections to the nucleus ambiguus and the motor
nucleus of the vagus, where preganglionic parasym-
pathetic neurons that innervate the heart are located.
The NTS receives descending input from the
hypothalamus and the amygdala. Neurons in NTS
project rostrally to neurons in the supraoptic and
paraventricular nuclei of the hypothalamus that
control vasopressin release.
At normal blood pressure levels, baroreceptor
input tonically inhibits sympathetic outflow. When
blood pressure or circulating blood volume declines,
arterial and cardiopulmonary baroreceptors are
‘‘unloaded’’ and their discharge decreases, triggering
a rapid reflex increase in sympathetic outflow that
causes vasoconstriction (raising systemic vascular
resistance) and tachycardia (Fig. 1). As part of the
same reflex, parasympathetic activity decreases,
further increasing heart rate. Conversely, when blood
pressure increases, afferent baroreceptor discharge
increases and the opposite reflex changes occur.
In addition to these changes in vascular tone and
heart rate mediated by direct autonomic innervation,
other mechanisms that contribute to the acute and
chronic maintenance of blood pressure are also
influenced by the baroreflex. Increased sympathetic
renal nerve activity induces tubular sodium reab-
sorption directly and by stimulating the secretion of
renin from the juxtaglomerular apparatus. Renin and
converting enzyme convert circulating angiotensino-
gen into angiotensin II, which is a vasoconstrictor
and secretagogue of aldosterone from the adrenal
medulla. Aldosterone retains sodium in the kidney,
increasing extracellular fluid volume. In addition,
unloading of thoracic baroreceptors releases vaso-
pressin (AVP), also called antidiuretic hormone
(ADH), from the neurohypophysis into the systemic
circulation. Acting on specific receptors in vascular
smooth muscle cells, vasopressin produces vasocon-
striction and in the kidney it retains water and
expands extracellular fluid volume.
Two other circulating vasoactive peptides, atrial
natriuretic factor (ANF) and endothelin, are involved
in the regulation of blood pressure and extracellular
fluid volume and their secretion may also be
controlled, at least in part, by autonomic reflexes.
ANF is secreted from atrial myocytes when atrial
pressure increases. ANF produces natriuresis, relaxa-
tion of vascular smooth muscle, and inhibition of
renin and aldosterone secretions. When right atrial
pressure decreases, such as during the upright
posture, circulating levels of ANF quickly decline,
contributing to vasoconstriction and expansion of
extracellular fluid volume. Whether ANF is released
by the direct effect of pressure on the cardiocytes or
by a centrally mediated autonomic reflex is unclear.
We found that the response of circulating ANF to
changes in atrial pressure is preserved in patients
with baroreflex impairment, suggesting that a local
intracardiac reflex regulates the secretion of the
peptide. Endothelin, a powerful vasoconstrictor
synthesized by endothelial cells, has an important
role in the local control of the circulation. In
addition, endothelin is synthesized by neurons in
the paraventricular and supraoptic nuclei of the
hypothalamus and is coreleased with vasopressin
from the neurohypophysis into the bloodstream
when thoracic baroreceptors are unloaded. The
physiological function of the endothelin released
into plasma during baroreflex activation remains to

Figure 1
Autonomic and endocrine changes elicited by a decrease in blood pressure or blood volume. ANF, atrial natriuretic factor; AVP, arginine
vasopressin; CNS, central nervous system; ET, endothelin; NO, nitric oxide.
be defined, but it is likely that circulating endothelin
contributes to the vasoconstriction that maintains
blood pressure during the upright posture. Finally, it
is unknown whether autonomic reflexes regulate the
production of the potent vasodilator nitric oxide. In
summary, the baroreceptor reflex is a centrally
mediated polysynaptic reflex that modulates sympa-
thetic and parasympathetic outflow in response to
changes in blood pressure or blood volume. It
functions as a negative feedback mechanism that
buffers changes in blood pressure through rapid
changes of heart rate, cardiac output, and systemic
vascular resistance.
EXERCISE
The autonomic response to exercise involves both
central and peripheral mechanisms. The blood
pressure increase is partially related to the intensity
of the so-called central command (i.e., subjective
effort exerted), which probably affects the number of
motor units recruited. The peripheral mechanism
involves stimulation of small myelinated and un-
myelinated afferent fibers in skeletal muscle presum-
CARDIOVASCULAR REGULATION 509
ably by accumulation of metabolites in the
contracting muscle, which reflexly increase heart
rate and blood pressure (exercise pressor response).
The relative importance of the central and peripheral
mechanisms in the pressor response to exercise is
unclear. An interesting finding in patients with
muscle phosphorylase deficiency (McArdle’s disease),
who cannot develop lactic acidosis during ischemic
exercise, is that the normal increase in muscle
sympathetic activity evoked by exercise is absent.
—Horacio Kaufmann
See also–Autonomic Nervous System, Heart Rate
and; Cardiac Arrest Resuscitation; Cardiac Drugs;
Cerebral Blood Flow, Measurement of; Cerebral
Blood Vessels: Arteries; Cerebral Blood Vessels:
Veins and Venous Sinuses; Cerebral Metabolism
and Blood Flow; Stress, Neurological
Response to
Further Reading
Kaufmann, H., Oribe, E., and Oliver, J. A. (1991). Plasma
endothelin during upright tilt: Relevance for orthostatic
hypotension? Lancet 338, 1541–1545.
510 CARNITINE DEFICIENCY
Mancia, G., and Mark, A. L. (1983). Arterial baroreflexes in
humans. In Handbook of Physiology, Section 2: The Cardio-
vascular System, Vol. 3, Peripheral Circulation and Organ
Blood Flow, Part 2 (J. T. Shepherd and F. M. Abboud, Eds.), pp.
755–757. American Physiological Society, Bethesda, MD.
Palmer, R. M., Ashton, D. S., and Moncada, S. (1988). Vascular
endothelial cells synthesize nitric oxide from l-arginine. Nature
333, 664–666.
Pryor, S. L., Lewis, S. F., Haller, R. G., et al. (1990). Impairment of
sympathetic activation during static exercise in patients with
muscle phosphorylase deficiency (McArdle’s disease). J. Clin.
Invest. 85, 1444–1449.
Spyer, K. M. (1990). The central nervous organisation of reflex
circulatory control. In Central Regulation of Autonomic
Functions (A. D. Loewy and K. M. Spyer, Eds.), pp. 168–188.
Oxford Univ. Press, New York.
Carnitine Deficiency
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARNITINE (specifically l-carnitine or levocarnitine)
is a simple, ubiquitous molecule that acts primarily
to transport acyl groups into and out of the
mitochondrion. Thus, it plays a key role in energy
metabolism in health and disease. Abnormalities in
carnitine metabolism have been identified in a wide
variety of medical disorders, including cardiovascu-
lar, pulmonary, and kidney diseases and diabetes.
Neurological manifestations of carnitine deficiency
occur in patients with metabolic and mitochondrial
disorders, neuromuscular disorders, and epilepsy.
METABOLISM
Humans synthesize levocarnitine from dietary pre-
cursors, primarily from trimethyl lysine derived from
the breakdown of protein. Trimethyl lysine is first
hydroxylated and then cleaved to remove a terminal
glycine group. The resulting molecule, g-trimethyl
aminobutyraldehyde, is then converted to g-butyr-
obetaine, which is then hydroxylated to form
levocarnitine. g-Butyrobetaine is synthesized in many
tissues in the body, but hydroxylation to form
levocarnitine occurs only in kidney, liver, testis, and
brain. The activity of the enzyme involved in this
final step in the pathway is relatively low in newborn
infants but increases rapidly during early childhood.
l-Carnitine is also obtained from the diet. Princi-
pal dietary sources include red meat, milk products,
fish, and poultry. Human milk is particularly high in
carnitine. Carnitine is absorbed from the gut by an
active transport process. It is then actively trans-
ported from the blood into other tissues (e.g., heart
and skeletal muscle) against a concentration gradi-
ent. Of total body carnitine, 98% is in muscle and
the concentration of carnitine in muscle is 40–60
times that in blood.
Carnitine can be measured in the blood in both the
free form and the esterified form. Normally, esterified
or acylcarnitine accounts for 15–25% of total blood
carnitine, and acetylcarnitine accounts for most of
this esterified carnitine. Carnitine is excreted by the
kidney and actively reabsorbed in the proximal
tubule. Blood levels of carnitine are regulated by
the renal reabsorption of filtered carnitine.
Within the cell, carnitine functions primarily to
transport acyl groups into and out of the mitochon-
drion. Long-chain fatty acids are transported into the
mitochondrion, where they undergo oxidation to
generate ATP. Intramitochondrial acyl groups are
esterified with carnitine and then transported out of
the mitochondrion. This regenerates free levels of
coenzyme A within the mitochondrion, so carnitine
plays an important role in regulating coenzyme A
metabolism as well. Removal of potentially toxic
acyl groups from the mitochondrion is another
important function of carnitine. Toxic acyl groups
may be caused by inborn errors of metabolism or by
treatment with drugs such as valproic acid. These
acylcarnitine esters are transported out of the
mitochondrion and ultimately excreted by the
kidney.
CARNITINE DEFICIENCY
Carnitine levels can be deficient in blood, tissue
(usually muscle), or both. The normal blood levels in
humans are 50–60 mmol/liter for total carnitine and
40–50 mmol/liter for free carnitine. Carnitine blood
levels are readily available from many commercial
laboratories. A free carnitine level in the blood of
o20 mmol/liter is considered evidence of carnitine
deficiency. The acylcarnitine level is the difference
between the total and the free carnitine levels. A ratio
of acylcarnitine to free carnitine of more than 0.4 is
considered abnormal and represents carnitine insuf-
ficiency.
Primary Carnitine Deficiency
Primary systemic carnitine deficiency is caused by a
genetically determined, autosomal recessive abnorm-
ality in the active transport of carnitine. Hetero-
zygotes have low levels of transport activity but are
510 CARNITINE DEFICIENCY
Mancia, G., and Mark, A. L. (1983). Arterial baroreflexes in
humans. In Handbook of Physiology, Section 2: The Cardio-
vascular System, Vol. 3, Peripheral Circulation and Organ
Blood Flow, Part 2 (J. T. Shepherd and F. M. Abboud, Eds.), pp.
755–757. American Physiological Society, Bethesda, MD.
Palmer, R. M., Ashton, D. S., and Moncada, S. (1988). Vascular
endothelial cells synthesize nitric oxide from l-arginine. Nature
333, 664–666.
Pryor, S. L., Lewis, S. F., Haller, R. G., et al. (1990). Impairment of
sympathetic activation during static exercise in patients with
muscle phosphorylase deficiency (McArdle’s disease). J. Clin.
Invest. 85, 1444–1449.
Spyer, K. M. (1990). The central nervous organisation of reflex
circulatory control. In Central Regulation of Autonomic
Functions (A. D. Loewy and K. M. Spyer, Eds.), pp. 168–188.
Oxford Univ. Press, New York.
Carnitine Deficiency
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CARNITINE (specifically l-carnitine or levocarnitine)
is a simple, ubiquitous molecule that acts primarily
to transport acyl groups into and out of the
mitochondrion. Thus, it plays a key role in energy
metabolism in health and disease. Abnormalities in
carnitine metabolism have been identified in a wide
variety of medical disorders, including cardiovascu-
lar, pulmonary, and kidney diseases and diabetes.
Neurological manifestations of carnitine deficiency
occur in patients with metabolic and mitochondrial
disorders, neuromuscular disorders, and epilepsy.
METABOLISM
Humans synthesize levocarnitine from dietary pre-
cursors, primarily from trimethyl lysine derived from
the breakdown of protein. Trimethyl lysine is first
hydroxylated and then cleaved to remove a terminal
glycine group. The resulting molecule, g-trimethyl
aminobutyraldehyde, is then converted to g-butyr-
obetaine, which is then hydroxylated to form
levocarnitine. g-Butyrobetaine is synthesized in many
tissues in the body, but hydroxylation to form
levocarnitine occurs only in kidney, liver, testis, and
brain. The activity of the enzyme involved in this
final step in the pathway is relatively low in newborn
infants but increases rapidly during early childhood.
l-Carnitine is also obtained from the diet. Princi-
pal dietary sources include red meat, milk products,
fish, and poultry. Human milk is particularly high in
carnitine. Carnitine is absorbed from the gut by an
active transport process. It is then actively trans-
ported from the blood into other tissues (e.g., heart
and skeletal muscle) against a concentration gradi-
ent. Of total body carnitine, 98% is in muscle and
the concentration of carnitine in muscle is 40–60
times that in blood.
Carnitine can be measured in the blood in both the
free form and the esterified form. Normally, esterified
or acylcarnitine accounts for 15–25% of total blood
carnitine, and acetylcarnitine accounts for most of
this esterified carnitine. Carnitine is excreted by the
kidney and actively reabsorbed in the proximal
tubule. Blood levels of carnitine are regulated by
the renal reabsorption of filtered carnitine.
Within the cell, carnitine functions primarily to
transport acyl groups into and out of the mitochon-
drion. Long-chain fatty acids are transported into the
mitochondrion, where they undergo oxidation to
generate ATP. Intramitochondrial acyl groups are
esterified with carnitine and then transported out of
the mitochondrion. This regenerates free levels of
coenzyme A within the mitochondrion, so carnitine
plays an important role in regulating coenzyme A
metabolism as well. Removal of potentially toxic
acyl groups from the mitochondrion is another
important function of carnitine. Toxic acyl groups
may be caused by inborn errors of metabolism or by
treatment with drugs such as valproic acid. These
acylcarnitine esters are transported out of the
mitochondrion and ultimately excreted by the
kidney.
CARNITINE DEFICIENCY
Carnitine levels can be deficient in blood, tissue
(usually muscle), or both. The normal blood levels in
humans are 50–60 mmol/liter for total carnitine and
40–50 mmol/liter for free carnitine. Carnitine blood
levels are readily available from many commercial
laboratories. A free carnitine level in the blood of
o20 mmol/liter is considered evidence of carnitine
deficiency. The acylcarnitine level is the difference
between the total and the free carnitine levels. A ratio
of acylcarnitine to free carnitine of more than 0.4 is
considered abnormal and represents carnitine insuf-
ficiency.
Primary Carnitine Deficiency
Primary systemic carnitine deficiency is caused by a
genetically determined, autosomal recessive abnorm-
ality in the active transport of carnitine. Hetero-
zygotes have low levels of transport activity but are

usually asymptomatic. Homozygotes have extremely
low levels of transport activity and present with
progressive dilated cardiomyopathy or recurrent
encephalopathy. Patients with encephalopathy have
hypoglycemia, metabolic acidosis, and signs of liver
failure with hyperammonemia. The diagnosis is
suggested by very low carnitine levels in the blood
and confirmed by demonstration of negligible carni-
tine transport activity in cultured fibroblasts. Treat-
ment with 100–200 mg/kg/day of levocarnitine can
be lifesaving.
Primary muscle carnitine deficiency presents with
signs of a progressive myopathy with weakness and
exercise intolerance. Blood levels of carnitine are
normal but muscle biopsy tissue levels are low. It is
not clear whether this represents an isolated defect in
muscle carnitine transport, a heterozygous systemic
transport defect manifested primarily in muscle, or a
secondary carnitine deficiency with symptoms man-
ifest primarily in muscle. Treatment with levocarni-
tine is generally beneficial.
Secondary Carnitine Deficiency
Carnitine deficiency occurs in a wide variety of other
conditions and is considered secondary to those
conditions. Many inborn errors of metabolism cause
secondary carnitine deficiency, and the identification
of low carnitine levels in a patient should stimulate
an intensive evaluation for metabolic disease. The
most common causes are genetically determined
defects in fatty acid oxidation and amino acid
oxidation. Other causes include defects in mito-
chondrial function that may reflect genetic abnorm-
alities in mitochondrial DNA. Because of the
accumulation of acyl groups as by-products of these
metabolic defects, the relative or absolute concen-
tration of acylcarnitine is increased in the blood
and urine.
Patients may present with a variety of symptoms
and signs, including hypotonia, weakness, failure to
thrive, developmental delay, seizures, and hepatic or
renal abnormalities. Evaluation of these patients
should include measurement of carnitine levels in the
blood. Carnitine levels may be low but are not
usually as low as those in primary carnitine
deficiency. The ratio of acylcarnitine to free carnitine
may be raised (even when the actual levels are
normal) and is an important indicator of underlying
metabolic disease. Analysis of acylcarnitine species
(often following a carnitine load) may help identify
the specific acyl group present in excess and facilitate
diagnosis of the underlying metabolic disorder.
CARNITINE DEFICIENCY 511
Treatment is directed to the specific underlying
abnormality. Levocarnitine supplementation may be
an important component of the treatment program
that acts to restore normal carnitine levels, enhance
mitochondrial function, and facilitate removal of
toxic metabolites from the mitochondrion and from
the body.
Secondary carnitine deficiency occurs in some
medical conditions due to decreased biosynthesis,
decreased dietary intake, or removal of carnitine.
Patients with liver disease may have deficient
biosynthesis and may have reduced dietary intake
because of protein restrictions. Premature infants
often cannot synthesize carnitine adequately due to
low levels of g-butyrobetaine hydroxylase and thus
are dependent on dietary intake to maintain carnitine
metabolism. Breast milk is a good source of carnitine
for these infants. If that is not available, carnitine
supplementation is indicated. Patients on long-term
parenteral nutrition will develop carnitine deficiency
if carnitine is not included in the nutritional product.
Renal dialysis effectively removes carnitine and
results in carnitine deficiency, so replacement of
carnitine is generally indicated following each
dialysis session.
Certain drugs used to treat medical conditions can
result in secondary carnitine deficiency. Antibiotics
formulated with pivalic acid to enhance absorption
induce carnitine deficiency because the pivoxil
moiety is also absorbed and excreted as pivaloylcar-
nitine. Blood carnitine levels may decrease dramati-
cally during treatment with these antibiotics.
Although short-term treatment may be well toler-
ated, long-term treatment with these antibiotics
could be problematic and carnitine supplementation
is often recommended. Zidovidine, used to treat HIV
infection, induces a mitochondrial myopathy and is
associated with carnitine deficiency. Carnitine sup-
plementation is often recommended for HIV-infected
patients, particularly those receiving zidovidine. The
role of anticonvulsants, particularly valproic acid, in
causing carnitine deficiency is discussed separately in
this encyclopedia.
CARNITINE DEFICIENCY IN EPILEPSY
Blood carnitine levels are lower in patients with
epilepsy compared to healthy controls, and some
patients have levels that are low enough to represent
carnitine deficiency. Muscle tissue carnitine levels
may be low in patients with epilepsy even when
blood carnitine levels are normal. Carnitine levels
512 CARNITINE DEFICIENCY
are lowest in patients taking valproic acid in
combination with other anticonvulsant drugs, but
low levels and carnitine deficiency can occur in
patients taking valproic acid alone or taking other
anticonvulsant drugs. In patients with epilepsy,
carnitine deficiency can be caused by underlying
metabolic errors or mitochondrial diseases and can
also reflect inadequate nutritional intake. Carnitine
deficiency or insufficiency was found in many
patients with mental retardation residing in large
public institutions, including some who did not have
epilepsy and many who were not taking valproic
acid. This suggests that multiple mechanisms may be
present in some individuals.
Several factors may be involved in the mechanism
of valproic acid-associated carnitine deficiency. Val-
proic acid treatment increases renal excretion of
acylcarnitine, which may interfere with renal reab-
sorption of free carnitine. Valproic acid causes a
dose-dependent, reversible inhibition of carnitine
uptake from cultured fibroblasts. This effect on
carnitine transport could cause carnitine deficiency
by decreasing carnitine absorption from the gut as
well as by decreasing renal reabsorption of free
carnitine. Patients who are heterozygous for the
carnitine transport defect seen in primary systemic
carnitine deficiency (who already have a low level of
carnitine transport) could hypothetically be at
increased risk for hepatic failure from valproic acid
because of the additional reduction of carnitine
transport caused by valproic acid.
Valproic acid treatment can cause hyperammone-
mia when no other signs of hepatic dysfunction are
present. The mechanism may involve inhibition of
urea synthesis or increased renal formation of
ammonia. Mild elevations of ammonia are often
asymptomatic and of little clinical significance.
Greater elevations of ammonia may be associated
with lethargy or hypotonia. Treatment with levocar-
nitine often lowers the ammonia level even when
valproic acid treatment is continued, suggesting a
role for carnitine in the pathogenesis of this condi-
tion.
Valproic acid rarely causes progressive hepatic
failure, which is often fatal. Symptoms include
anorexia, vomiting, lethargy, coma, and seizures.
The risk of hepatic failure is highest (1 in 500 cases)
in children younger than 2 years of age with
neurological impairment who are taking valproic
acid as well as other anticonvulsants. However,
hepatic failure can also occur in adults and in
patients taking valproic acid alone. A family history
of unexplained hepatic failure warrants caution in
prescribing valproic acid since the patient may have a
genetically determined metabolic disorder or a defect
in carnitine transport. Survival from valproic acid-
induced hepatic failure has been shown to be
significantly greater in patients treated with intrave-
nous levocarnitine within the first 3 days of the
illness. Carnitine treatment is strongly recommended
for patients with hepatic failure caused by valproic
acid treatment. Carnitine treatment is also recom-
mended for children younger than 2 years of age
who are taking valproic acid to prevent hepatic
failure.
Risk factors for carnitine deficiency in patients
with epilepsy include young age, multiple neurologi-
cal disabilities, malnutrition, and use of valproic acid
in combination with other anticonvulsant drugs. Use
of the ketogenic diet may also be a risk factor. In the
absence of hepatic failure, symptoms of carnitine
deficiency may include listlessness, lethargy, anorex-
ia, constipation, hypotonia, or weakness. Carnitine
treatment is of no benefit in asymptomatic patients
with normal carnitine levels who do not have these
risk factors, but it may be beneficial in symptomatic
patients with low carnitine levels who have multiple
risk factors.
—David L. Coulter
See also–Epilepsy, Comorbidity; Hexosaminidase
Deficiency
Further Reading
Bohan, T. P., Helton, E., McDonald, I., et al. (2001). Effect of
l-carnitine treatment for valproate-induced hepatotoxicity.
Neurology 56, 1405–1409.
Bohles, H., Sewell, A. C., and Wenzel, D. (1996). The effect of
carnitine supplementation in valproate-induced hyperammone-
mia. Acta Paediatr. 85, 446–449.
Borum, P. R. (1995). Carnitine in neonatal nutrition. J. Child
Neurol. 10, 2S25–2S31.
Bryant, A. E., and Dreifuss, F. E. (1996). Valproic acid hepatic
fatalities. III. U.S. experience since 1986. Neurology 46,
465–469.
Carter, A. L. (Ed.) (1992). Current Concepts in Carnitine
Research. CRC Press, Boca Raton, FL.
Carter, A. L., Abner, T. O., and Lapp, D. F. (1995). Biosynthesis
and metabolism of carnitine. J. Child Neurol. 10, 2S3–2S7.
Coulter, D. L. (1995). Carnitine deficiency in epilepsy: Risk
factors and treatment. J. Child Neurol. 10, 2S32–2S39.
Coulter, D. L., and Allen, R. J. (1981). Hyperammonemia with
valproic acid therapy. J. Pediatr. 99, 317–319.
DeVivo, D. C., Bohan, T. P., Coulter, D. L., et al. (1998).
l-Carnitine supplementation in childhood epilepsy: Current
perspectives. Epilepsia 39, 1216–1225.

Ferrari, R., DiMauro, S., and Sherwood, G. (Eds.) (1992).
l-Carnitine and Its Role in Medicine: From Function to
Therapy. Academic Press, New York.
Mintz, M. (1995). Carnitine in HIV infection/AIDS. J. Child
Neurol. 10, 2S40–2S44.
Pons, R., and DeVivo, D. C. (1995). Primary and secondary
carnitine deficiency syndromes. J. Child Neurol. 10, 2S8–
2S24.
Sankar, R., and Sotero de Menezes, M. (1999). Metabolic and
endocrine aspects of the ketogenic diet. Epilepsy Res. 37,
191–201.
Shapira, Y., and Gutman, A. (1991). Muscle carnitine deficiency in
patients using valproic acid. J. Pediatr. 118, 646–649.
Tein, I., DiMauro, S., Xie, Z.-W., et al. (1993). Valproic acid
impairs carnitine uptake in cultured human skin fibroblasts: An
in vitro model for the pathogenesis of valproate-associated
carnitine deficiency. Pediatr. Res. 34, 281–287.
Carotid Angioplasty
and Stenting
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE REPAIR of a significantly narrowed carotid artery
has been proven to reduce the subsequent risk of
stroke more effectively than treatment with aspirin
alone. This benefit was demonstrated using open
surgical repair with removal of the responsible
atherosclerotic plaque along with the intima, the
inner layer of the artery. This procedure, known as
carotid endarterectomy (CEA), has become the
accepted standard of care for severe carotid stenosis.
The benefit of this procedure, however, must be
weighed against the potential risk of performing a
major operation, especially when additional factors
increase the surgical risk. Carotid angioplasty and
stenting (CAS) has emerged as an alternative to CEA
for the treatment of severe carotid stenosis.
CAS is particularly attractive in cases of carotid
stenosis in patients at high risk for complications
from CEA or from anesthesia. Patients of advanced
age, those with recent symptoms from the target
lesion, and those with significant medical problems
(such as heart disease) are considered at high risk for
CEA. Some authors believe that these patients
tolerate CAS better than CEA because CAS is usually
performed without anesthesia and involves a shorter
period of carotid occlusion. In addition, for patients
with carotid lesions located above the jaw line, prior
neck irradiation, or early post-CEA restenosis from
intimal hyperplasia (overgrowth of the intima), the
CAROTID ANGIOPLASTY AND STENTING 513
performance of CEA is technically very difficult and
therefore poses a higher risk of surgical complica-
tions.
CAS is performed entirely with fluoroscopy, which
is real-time x-ray imaging that allows the operator to
visualize the procedure within the carotid artery
without an incision in the neck. Using fluoroscopy,
the endovascular surgeon first performs angiography
to visualize the diseased artery and to identify the
location, length, and severity of the narrowing. With
digital angiographical imaging, the diameter of the
normal vessel, the severity of stenosis at the
narrowest point, and the length of the lesion are all
measured. These measurements dictate the size of the
devices used to repair the artery. In most cases, a
balloon catheter is inserted into the narrowed
segment of the artery and inflated for as few as 5
sec or up to 60 sec to dilate the artery. By filling the
balloon with contrast material, the inflated balloon is
easily visualized on fluoroscopy. Experience with
coronary artery angioplasty suggests that long-term
patency of an artery is improved by placing a metal
stent into the diseased segment. After removing the
balloon catheter, a stent is then advanced into dilated
arterial segment. The stent is deployed either by
balloon inflation or through self-expansion. Occa-
sionally, a second balloon is inflated within the
deployed stent to further expand the arterial lumen
and the stent.
Repair of carotid stenosis by CAS is fundamen-
tally different than that by CEA. In CEA, the plaque
is removed, whereas in CAS it is fractured by the
pressure of the balloon and held open by a metal
stent. Tissue response to the injured plaque and the
stent (which is perceived as a foreign body) results
in the growth of a new layer of endothelium (the
tissue that lines the lumen of all arteries) over the
stent and plaque. This produces a smooth arterial
wall with a normal or nearly normal diameter.
During the healing phase, however, the rough
surface of the stent and the fractured plaque are
prone to inducing blood clots, which may result in
embolic stroke or arterial occlusion. For this reason,
patients are typically treated with antiplatelet agents
at the time of CAS and for approximately 1 month
afterward. It is our practice to treat patients
undergoing CAS with a combination of aspirin
and either clopidogrel or ticlodipine at the time of
treatment and for 1 month afterward. Aspirin is
then continued indefinitely.
The primary risk of CAS, as in CEA, is stroke.
Stroke rates with CAS vary widely from less than 1 to

Ferrari, R., DiMauro, S., and Sherwood, G. (Eds.) (1992).
l-Carnitine and Its Role in Medicine: From Function to
Therapy. Academic Press, New York.
Mintz, M. (1995). Carnitine in HIV infection/AIDS. J. Child
Neurol. 10, 2S40–2S44.
Pons, R., and DeVivo, D. C. (1995). Primary and secondary
carnitine deficiency syndromes. J. Child Neurol. 10, 2S8–
2S24.
Sankar, R., and Sotero de Menezes, M. (1999). Metabolic and
endocrine aspects of the ketogenic diet. Epilepsy Res. 37,
191–201.
Shapira, Y., and Gutman, A. (1991). Muscle carnitine deficiency in
patients using valproic acid. J. Pediatr. 118, 646–649.
Tein, I., DiMauro, S., Xie, Z.-W., et al. (1993). Valproic acid
impairs carnitine uptake in cultured human skin fibroblasts: An
in vitro model for the pathogenesis of valproate-associated
carnitine deficiency. Pediatr. Res. 34, 281–287.
Carotid Angioplasty
and Stenting
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE REPAIR of a significantly narrowed carotid artery
has been proven to reduce the subsequent risk of
stroke more effectively than treatment with aspirin
alone. This benefit was demonstrated using open
surgical repair with removal of the responsible
atherosclerotic plaque along with the intima, the
inner layer of the artery. This procedure, known as
carotid endarterectomy (CEA), has become the
accepted standard of care for severe carotid stenosis.
The benefit of this procedure, however, must be
weighed against the potential risk of performing a
major operation, especially when additional factors
increase the surgical risk. Carotid angioplasty and
stenting (CAS) has emerged as an alternative to CEA
for the treatment of severe carotid stenosis.
CAS is particularly attractive in cases of carotid
stenosis in patients at high risk for complications
from CEA or from anesthesia. Patients of advanced
age, those with recent symptoms from the target
lesion, and those with significant medical problems
(such as heart disease) are considered at high risk for
CEA. Some authors believe that these patients
tolerate CAS better than CEA because CAS is usually
performed without anesthesia and involves a shorter
period of carotid occlusion. In addition, for patients
with carotid lesions located above the jaw line, prior
neck irradiation, or early post-CEA restenosis from
intimal hyperplasia (overgrowth of the intima), the
CAROTID ANGIOPLASTY AND STENTING 513
performance of CEA is technically very difficult and
therefore poses a higher risk of surgical complica-
tions.
CAS is performed entirely with fluoroscopy, which
is real-time x-ray imaging that allows the operator to
visualize the procedure within the carotid artery
without an incision in the neck. Using fluoroscopy,
the endovascular surgeon first performs angiography
to visualize the diseased artery and to identify the
location, length, and severity of the narrowing. With
digital angiographical imaging, the diameter of the
normal vessel, the severity of stenosis at the
narrowest point, and the length of the lesion are all
measured. These measurements dictate the size of the
devices used to repair the artery. In most cases, a
balloon catheter is inserted into the narrowed
segment of the artery and inflated for as few as 5
sec or up to 60 sec to dilate the artery. By filling the
balloon with contrast material, the inflated balloon is
easily visualized on fluoroscopy. Experience with
coronary artery angioplasty suggests that long-term
patency of an artery is improved by placing a metal
stent into the diseased segment. After removing the
balloon catheter, a stent is then advanced into dilated
arterial segment. The stent is deployed either by
balloon inflation or through self-expansion. Occa-
sionally, a second balloon is inflated within the
deployed stent to further expand the arterial lumen
and the stent.
Repair of carotid stenosis by CAS is fundamen-
tally different than that by CEA. In CEA, the plaque
is removed, whereas in CAS it is fractured by the
pressure of the balloon and held open by a metal
stent. Tissue response to the injured plaque and the
stent (which is perceived as a foreign body) results
in the growth of a new layer of endothelium (the
tissue that lines the lumen of all arteries) over the
stent and plaque. This produces a smooth arterial
wall with a normal or nearly normal diameter.
During the healing phase, however, the rough
surface of the stent and the fractured plaque are
prone to inducing blood clots, which may result in
embolic stroke or arterial occlusion. For this reason,
patients are typically treated with antiplatelet agents
at the time of CAS and for approximately 1 month
afterward. It is our practice to treat patients
undergoing CAS with a combination of aspirin
and either clopidogrel or ticlodipine at the time of
treatment and for 1 month afterward. Aspirin is
then continued indefinitely.
The primary risk of CAS, as in CEA, is stroke.
Stroke rates with CAS vary widely from less than 1 to
514 CAROTID ARTERY
more than 10%, but they are typically similar at
experienced centers to rates of stroke with CEA.
Stroke likely occurs as a result of emboli arising from
the plaque. This may occur during manipulation of a
guidewire or device through the lesion and especially
during balloon inflation and stent deployment. These
forceful manipulations may fracture or tear small
pieces of plaque from the vessel wall and allow
them to travel through the bloodstream until they
obstruct smaller cerebral arteries. The concept of
distal protection was developed to prevent, or
minimize, this risk. By inflating a balloon to occlude
the carotid artery distal to the lesion during plaque
manipulation, particles may be trapped as they are
fractured off of the plaque. By occluding the
proximal artery in the common carotid artery,
proximal to the bifurcation, with a second balloon
and deflating the distal balloon, flow is reversed in
the internal carotid artery and the particles are
washed back to the carotid bifurcation and then out
the external carotid artery, where their presence is
relatively harmless. Several devices designed specifi-
cally for distal protection are now in the develop-
ment and testing stage. These include balloon
occlusion devices with catheters designed to aspirate
debris trapped by the balloon, net-like filters that
capture debris without occluding blood flow, and
filters attached to a wire that serves to guide
angioplasty balloons or stents to the lesion. Their
refinement is likely to improve the safety of CAS in
the near future.
—Andrew J. Ringer and L. Nelson Hopkins
See also–Angiography; Carotid Artery;
Endovascular Therapy; Therapeutic
Neuroradiology, Angioplasty and Stenting;
Ultrasound, Carotid
Further Reading
Castaneda-Zuniga, W., Formanek, A., Tadavarthy, M., et al.
(1980). The mechanism of balloon angioplasty. Radiology 135,
565–571.
Executive Committee for the Asymptomatic Carotid
Atherosclerosis Study (1995). Endarterectomy for asympto-
matic carotid artery stenosis. J. Am. Med. Assoc. 273,
1421–1428.
North American Symptomatic Carotid Endarterectomy Trial
Collaborators (1991). Beneficial effect of carotid endarterect-
omy in symptomatic patients with high-grade carotid stenosis.
N. Engl. J. Med. 325, 445–453.
Theron, J. G., Payelle, G. G., Coskun, O., et al. (1996). Carotid
artery stenosis: Treatment with protected balloon angioplasty
and stent placement. Radiology 201, 627–636.
Carotid Artery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAROTID ARTERIES are the main channels for
blood to the head from the major arterial trunks at
the root of the neck. They are supplemented by the
left and right vertebral arteries. In most humans, the
right common carotid, together with the right
subclavian, arises from the innominate artery, and
the left common carotid arises from the aortic arch.
The common carotids, passing upward close to the
trachea, bifurcate into external and internal carotid
arteries at the level of the thyroid cartilage. The
origin of the internal carotid presents a slight
dilatation, the carotid sinus, which contains baro-
receptors, and its wall houses the carotid body,
which contains chemoreceptors. They affect heart
rate and cardiac output. The reactivity of the
common and internal carotid arteries is mediated
both by the autonomic system and by local blood
pressure and chemical stimuli. The external carotids
are slightly narrower than the internal carotids and
supply branches to all the organs and muscles of the
upper parts of the neck, face, scalp, bones, and the
meningeal coverings of the brain.
The internal carotid arteries ascend close to the
posterolateral walls of the oro- and nasopharynx
without supplying any large branches. Both then enter
the bony carotid canals in the skull base, which bend
anteromedially and reach the cranial cavity at the
foramina lacera, where the artery is closely invested by
the venous blood flowing (usually in a posterior
direction) in the cavernous sinus. The intracavernous
carotid makes a 1801 turn, called the carotid siphon,
which carries it to its passage through the dura mater
alongside the pituitary fossa and into the subarach-
noid space at approximately the point where it gives
off its first major branch, the ophthalmic artery. The
next branch, the posterior communicating artery, joins
the posterior cerebral caudally to the terminal part of
the internal carotid artery and thence the anterior
cerebral and its anterior communicating link. This
pathway with its mirror image forms the anastomotic
ring at the base of the brain, the circle of Willis.
The two vertebrals carry approximately as much
blood as one internal carotid. The four vessels
together provide approximately 35–80 ml of blood
per 100 g of brain per minute, with the gray matter
taking a much larger share than the white matter. For
a 1500-g brain, mean volume flow in one internal
514 CAROTID ARTERY
more than 10%, but they are typically similar at
experienced centers to rates of stroke with CEA.
Stroke likely occurs as a result of emboli arising from
the plaque. This may occur during manipulation of a
guidewire or device through the lesion and especially
during balloon inflation and stent deployment. These
forceful manipulations may fracture or tear small
pieces of plaque from the vessel wall and allow
them to travel through the bloodstream until they
obstruct smaller cerebral arteries. The concept of
distal protection was developed to prevent, or
minimize, this risk. By inflating a balloon to occlude
the carotid artery distal to the lesion during plaque
manipulation, particles may be trapped as they are
fractured off of the plaque. By occluding the
proximal artery in the common carotid artery,
proximal to the bifurcation, with a second balloon
and deflating the distal balloon, flow is reversed in
the internal carotid artery and the particles are
washed back to the carotid bifurcation and then out
the external carotid artery, where their presence is
relatively harmless. Several devices designed specifi-
cally for distal protection are now in the develop-
ment and testing stage. These include balloon
occlusion devices with catheters designed to aspirate
debris trapped by the balloon, net-like filters that
capture debris without occluding blood flow, and
filters attached to a wire that serves to guide
angioplasty balloons or stents to the lesion. Their
refinement is likely to improve the safety of CAS in
the near future.
—Andrew J. Ringer and L. Nelson Hopkins
See also–Angiography; Carotid Artery;
Endovascular Therapy; Therapeutic
Neuroradiology, Angioplasty and Stenting;
Ultrasound, Carotid
Further Reading
Castaneda-Zuniga, W., Formanek, A., Tadavarthy, M., et al.
(1980). The mechanism of balloon angioplasty. Radiology 135,
565–571.
Executive Committee for the Asymptomatic Carotid
Atherosclerosis Study (1995). Endarterectomy for asympto-
matic carotid artery stenosis. J. Am. Med. Assoc. 273,
1421–1428.
North American Symptomatic Carotid Endarterectomy Trial
Collaborators (1991). Beneficial effect of carotid endarterect-
omy in symptomatic patients with high-grade carotid stenosis.
N. Engl. J. Med. 325, 445–453.
Theron, J. G., Payelle, G. G., Coskun, O., et al. (1996). Carotid
artery stenosis: Treatment with protected balloon angioplasty
and stent placement. Radiology 201, 627–636.
Carotid Artery
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAROTID ARTERIES are the main channels for
blood to the head from the major arterial trunks at
the root of the neck. They are supplemented by the
left and right vertebral arteries. In most humans, the
right common carotid, together with the right
subclavian, arises from the innominate artery, and
the left common carotid arises from the aortic arch.
The common carotids, passing upward close to the
trachea, bifurcate into external and internal carotid
arteries at the level of the thyroid cartilage. The
origin of the internal carotid presents a slight
dilatation, the carotid sinus, which contains baro-
receptors, and its wall houses the carotid body,
which contains chemoreceptors. They affect heart
rate and cardiac output. The reactivity of the
common and internal carotid arteries is mediated
both by the autonomic system and by local blood
pressure and chemical stimuli. The external carotids
are slightly narrower than the internal carotids and
supply branches to all the organs and muscles of the
upper parts of the neck, face, scalp, bones, and the
meningeal coverings of the brain.
The internal carotid arteries ascend close to the
posterolateral walls of the oro- and nasopharynx
without supplying any large branches. Both then enter
the bony carotid canals in the skull base, which bend
anteromedially and reach the cranial cavity at the
foramina lacera, where the artery is closely invested by
the venous blood flowing (usually in a posterior
direction) in the cavernous sinus. The intracavernous
carotid makes a 1801 turn, called the carotid siphon,
which carries it to its passage through the dura mater
alongside the pituitary fossa and into the subarach-
noid space at approximately the point where it gives
off its first major branch, the ophthalmic artery. The
next branch, the posterior communicating artery, joins
the posterior cerebral caudally to the terminal part of
the internal carotid artery and thence the anterior
cerebral and its anterior communicating link. This
pathway with its mirror image forms the anastomotic
ring at the base of the brain, the circle of Willis.
The two vertebrals carry approximately as much
blood as one internal carotid. The four vessels
together provide approximately 35–80 ml of blood
per 100 g of brain per minute, with the gray matter
taking a much larger share than the white matter. For
a 1500-g brain, mean volume flow in one internal

carotid is 175–400 ml/min, depending on physiolo-
gical conditions, brain activity, and probably tem-
perature. The normal flow is pulsatile without a
retrograde phase, and even at the normal carotid
bifurcation in the neck there is little turbulence.
Some workers assume a mean flow over the cardiac
cycle of approximately 50 ml/100 g/min, giving a
mean intracarotid flow of 250 ml/min. However,
contrast angiography and digital analysis of cine or
video recordings indicate a much higher brief mid-
stream systolic flow velocity. Similar recording
techniques suggest diastolic volume flow of 19 ml/
100 g/min.
The common carotid artery usually has no named
branches but may give rise to the vertebral, superior
thyroid or its laryngeal branch, ascending pharyn-
geal, inferior thyroid, or the occipital branches. The
external carotid may alternatively provide the super-
ior thyroid, ascending pharyngeal, occipital, poster-
ior auricular, superficial temporal, and maxillary
branches.
The histological arrangement of the intima, media,
and adventitia of the different parts of the carotid
tree changes by degrees from the characteristic large
conducting type of vessel having an internal and an
external elastic lamina and substantial muscular
elements within the tunica media to that of the
smaller distributing vessels with very little external
elastic tissue. Near the upper end of the internal
carotid, its wall begins to resemble the resistance
vessels that ramify over and within the brain and are
notably poorly covered by adventitia.
Although sometimes unnamed, several small twigs
from external carotid branches run through the skull
base to meet similarly small meningeal branches
arising from the cavernous and subarachnoid parts of
the internal carotid. Such small paths can grow to
major routes under evolutionary pressures or in
individuals in response to slowly developing stenoses
caused by disease in more proximal large distributing
vessels. Of special interest in comparative functional
anatomy are the occipital branches, certain branches
of the maxillary artery, and the ascending pharyn-
geal.
EMBRYOLOGY
In humans the common carotid arteries develop from
that part of the aortic sac derived from fusion of the
third and fourth ventral aortic arches. The common
carotid, elongating in a cranial direction, continues
as the internal carotid (consisting of the ventral part
CAROTID ARTERY 515
of the third aortic arch and the cranial continuation
of the dorsal aorta). The part of the dorsal aorta
between the third and fourth aortic arches regresses
and disappears, as do the second arches.
The primitive internal carotid splits into a cranial
division, with the primitive olfactory artery supply-
ing the olfactory brain and a caudal division that
curves caudally and posteriorly to reach the ventral
aspect of the midbrain. Simultaneously, a plexus,
which later becomes the basilar artery, forms along
the ventral surface of the hindbrain and is fed by
transitory branches of the dorsal aorta. The most
important of these is the primitive trigeminal artery.
The external carotid artery appears as a new vessel
growing from the aortic sac at the ventral end of the
third arch.
COMPARATIVE FUNCTIONAL ANATOMY
Important deviations from the human pattern of
carotid artery anatomy can be correlated with the
physiological imperatives of other species. Consid-
eration of these has led to better understanding of the
human. Of continuing interest since ancient times is
the rete caroticum found in all cloven-footed
mammals (Artiodactyla) and members of the cat
family (Felidae) as well as in individual species from
other orders. Wherever this has been studied, it has
been apparent that the human cerebral arterial
system is the more primitive. The pathways of the
rete caroticum open at approximately the time of
birth simultaneously with the closure of all except
the intra-arachnoid final part of the internal carotid.
The rete consists of a mesh of interconnecting
arterioles, the tunica media of which consists of little
more than a single layer of smooth muscle covered
on both sides with endothelium. On one side flows
the venous blood of the cavernous sinus and on the
other arterial blood derived from anastomizing
branches and twigs of external carotid origin that
take over the brain’s blood supply. Functions of the
internal carotid exercising their evolutionary pres-
sure may explain these extreme variations of design.
The large primate brain, with its high energy
demand, may explain the caliber and singleness of
the human internal carotid. The plasticity of the
adaptable anlage of the cranial arterial supply is
attested by the ability of humans to survive when
both internal carotids are blocked by disease if this
occurs slowly enough to allow compensatory widen-
ing of potential anastomotic links between external
carotid branches and the cerebral circulation.
516 CAROTID ARTERY
THE NEED FOR AUTOREGULATION AND THE
MECHANISMS TO ACHIEVE IT
One probable evolutionary drive may be related to
posture. Constant blood supply to the brain despite
variable systemic arterial blood pressure in many
mammals including primates is obtained by auto-
regulation of volume flow. As systemic blood
pressure declines, within limits, supplying vessels
dilate and vice versa as systemic blood pressure
increases. In animals without carotid retia, of which
man is an example, most of the blood vessels that
react in this autoregulatory way are within or on the
surface of the brain inside the rigid box of the skull.
To compensate for the extra volume of intracranial
vasodilatation, cerebrospinal fluid (CSF) is driven out
of the head and into the spinal subarachnoid space.
To make room for the enlargement of the spinal
subarachnoid space, large extra-arachnoid veins are
compressed and blood from them moves to the
abdominal and thoracic venous system. It seems that
an essential condition for this phenomenon must be
central venous pressure sufficient to keep the spinal
veins turgid under all but extreme demands of
intracranial vasodilatation.
Consider a mammal, such as a goat or a horse, that
has evolved long legs and a pronograde posture. It
stands, walks, or runs on four legs of more or less
equal length. Its spine containing the spinal canal is
almost always further from the ground than its heart.
To keep spinal venous pressure high enough to
maintain turgid veins would require uneconomically
high central venous pressure and would add to the
already substantial demand of pumping pressure to
force the blood back from the feet. The goat,
however, has a very low central venous pressure as
well as a mechanism, involving its posterior vena
cava, to eliminate abdominal pressure fluctuations
from the thorax caused by breathing. Therefore, if it
cannot shift much CSF out of its head into the spinal
canal when its blood pressure declines, how does it
manage to autoregulate its cerebral blood flow?
Evolution has played a clever trick. It is a general
tendency in mammals’ arterial systems to protect the
functionality of the whole animal by ensuring against
sudden, very severe loss of blood pressure by making
the larger arterial trunks constrict in response to
hypotension (to preserve blood pressure) while the
smaller, more distal branches do the opposite,
autoregulating as described previously to preserve
blood volumetric flow. The evolutionary adjustment
has been to insert into the pathway to the cerebral
arteries a number of more distal branches of the
external carotid with autoregulatory responses. Be-
cause they are entirely outside the dura and even
outside the head, these branches make no demand on
the intracranial spaces as they dilate or constrict.
Autoregulation is preserved, but the flow adjustment
is carried on remotely. These suggestions are sup-
ported by observations in primates that the smaller
neck arteries dilate as blood pressure declines and in
goats that the vessels of the rete (also outside the
dura) are also autoregulatory. The human internal
carotid in the neck alters its caliber very little in
response to physiological conditions. Downstream,
however, when it has entered the subarachnoid space
it responds to both blood pressure and arterial CO2
tension in a fashion similar to but less extreme than
that of the middle and anterior cerebral arteries.
SELECTIVE COOLING OF THE BRAIN
Posture was clearly not the only evolutionary driving
force behind the development of the carotid rete.
Hayward and Baker showed that the arrangement of
the rete inside the cavernous sinus was a cooling
mechanism for the blood going to the brain, with heat
being removed from the venous blood during its
passage close to moist mucosal surfaces and facial
skin. Mammalian neural tissue is very sensitive to
increases in temperature, and the combination of
muscular effort and high environmental temperature
is potentially lethal. This is also true for humans. How
then do humans manage without a rete caroticum?
In the past few years, it has been shown that the
absence of a rete caroticum in primates does not
deprive monkey, and presumably man, of selective
brain cooling. Using a miniature thermocouple within
the internal carotid artery in monkeys, it has been
observed that in its passage up the neck close to the
tracheopharyngeal airway, the temperature of blood
decreases by approximately 21C. This keeps the
brain’s temperature at approximately the core tem-
perature of the body. If the cool air being breathed by
the animal is replaced by hot air, brain temperature
increases quickly. If the warm airflow is continued,
the increase in brain temperature may accelerate,
probably because brain metabolism is enhanced.
DISEASE AND ABNORMAL CONDITIONS OF
THE CAROTID ARTERY
Accidental failure to allow the carotid artery
selective brain cooling mechanisms to operate has
 CARPAL TUNNEL SYNDROME 517

been suggested as causal in sudden infant death

syndrome. Arteriosclerosis and atheroma are very
common in the main vessels of the neck. There are
predilections for disease at the origin of the internal
Carpal Tunnel Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

and external carotids or alternatively in the carotid

siphon. Cerebral ischemia may occur from severe MEDIAN NEUROPATHY at the carpal tunnel, or carpal
internal carotid stenosis, but probably because there tunnel syndrome (CTS), is the most common
are so many alternative vascular pathways, it peripheral nerve entrapment syndrome. It can be
generally requires at least 70% narrowing to confused clinically with brachial plexopathy, cervical
produce the conditions for ischemia. On the other radiculopathy, or thoracic outlet syndrome.
hand, transient ischemic attacks are common,
possibly because the wall of the vessel is roughened ANATOMY
or ulcerated and a source of platelet or more
The median nerve originates from fibers of C6–T1
substantial emboli. The role of metabolic/electrical
nerve roots. It receives contribution from both the
disturbance is uncertain. In contrast, narrowing of
lateral and the medial cord of the brachial plexus.
intracranial branches of the carotid may be more
From the lateral cord, fibers from C6 and C7 roots
obviously linked to local ischemic signs and
innervate and convey sensation from the thenar
symptoms. Depending on the position in relation
eminence, thumb, and index, middle, and ring finger.
to the circle of Willis, arteriosclerotic narrowing or
These fibers also supply the motor innervation of
spasm reducing caliber to 50% of normal after
proximal forearm muscles in the median nerve
subarachnoid hemorrhage may reduce cerebral
territory. The C8–T1 fibers from the medial cord
blood flow to 20 ml/100 g/min and result in
supply the motor fibers of the distal muscles in
(possibly recoverable) ischemia. Blood flow of 16
forearm as well as the intrinsic hand muscles.
ml/100 g/min is likely to cause cessation of
After forming from the lateral and medial cords,
neurological function.
the median nerve runs down the arm and does not
Other much less common diseases of the carotid
give off any motor or sensory branch until it is in the
arteries and their branches are post-traumatic or
forearm. After supplying muscles in the forearm, the
spontaneous dissection; the ocular manifestations of
palmar cutaneous sensory branch arises just prox-
Horner’s syndrome that may follow damage to the
imal to the wrist and carpal tunnel to supply
sympathetic nervous fibers in the internal carotid
sensation over the thenar eminence. The last branch
adventia; carotid sinus syndrome; giant cell or
of the median nerve then proceeds to enter the carpal
temporal arteritis; other rare forms of arteritis, such
tunnel in the wrist. The carpal tunnel is formed by
as Takayasu’s or pulseless disease; and chemodecto-
the carpal bones on the floor and sides, and its roof is
ma of the carotid body, which may accompany
formed by the transverse ligament. The contents of
similar tumors at other chemoreceptor sites.
the carpal tunnel include nine flexor tendons to the
—George H. du Boulay
digits and thumb as well as the median nerve. Once it
transverses the carpal tunnel, the median nerve
divides into motor and sensory divisions in the palm.
See also–Brain Evolution, Human; Carotid The motor component supplies the first and second
Angioplasty and Stenting; Cerebral Blood
lumbricals as well as the muscles in the thenar
Vessels: Arteries; Cerebral Metabolism and
eminence (opponens pollicis, abductor pollicis bre-
Blood Flow; Ultrasound, Carotid; Vertebrate
Nervous System, Development of vis, and superficial head of flexor pollicis brevis). The
sensory branch supplies the thumb, index, middle,
and lateral half of the ring finger. The index and
Further Reading middle fingers receive two digital branches (one
Boulin, D. J. (1980). Cerebral Vasospasm. Wiley, Chichester, UK. median and one lateral), whereas the thumb and ring
du Boulay, G. H., and Verity, P. M. (1973). The Cranial Arteries of
finger each have one branch.
Mammals. Heinemann, London.
du Boulay, G. H., Lawton, M., and Wallis, A. (1998). The story of
the internal carotid artery of mammals: From Galen to sudden PATHOGENESIS
infant death syndrome. Neuroradiology 40, 697–703.
Warwick, R., and Locllean, P. L. (1995). Gray’s Anatomy, 38th ed. CTS has been reported to have a population
Longman, London. incidence of 0.1% annually among adults, with a
 CARPAL TUNNEL SYNDROME 517

been suggested as causal in sudden infant death

syndrome. Arteriosclerosis and atheroma are very
common in the main vessels of the neck. There are
predilections for disease at the origin of the internal
Carpal Tunnel Syndrome
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

and external carotids or alternatively in the carotid

siphon. Cerebral ischemia may occur from severe MEDIAN NEUROPATHY at the carpal tunnel, or carpal
internal carotid stenosis, but probably because there tunnel syndrome (CTS), is the most common
are so many alternative vascular pathways, it peripheral nerve entrapment syndrome. It can be
generally requires at least 70% narrowing to confused clinically with brachial plexopathy, cervical
produce the conditions for ischemia. On the other radiculopathy, or thoracic outlet syndrome.
hand, transient ischemic attacks are common,
possibly because the wall of the vessel is roughened ANATOMY
or ulcerated and a source of platelet or more
The median nerve originates from fibers of C6–T1
substantial emboli. The role of metabolic/electrical
nerve roots. It receives contribution from both the
disturbance is uncertain. In contrast, narrowing of
lateral and the medial cord of the brachial plexus.
intracranial branches of the carotid may be more
From the lateral cord, fibers from C6 and C7 roots
obviously linked to local ischemic signs and
innervate and convey sensation from the thenar
symptoms. Depending on the position in relation
eminence, thumb, and index, middle, and ring finger.
to the circle of Willis, arteriosclerotic narrowing or
These fibers also supply the motor innervation of
spasm reducing caliber to 50% of normal after
proximal forearm muscles in the median nerve
subarachnoid hemorrhage may reduce cerebral
territory. The C8–T1 fibers from the medial cord
blood flow to 20 ml/100 g/min and result in
supply the motor fibers of the distal muscles in
(possibly recoverable) ischemia. Blood flow of 16
forearm as well as the intrinsic hand muscles.
ml/100 g/min is likely to cause cessation of
After forming from the lateral and medial cords,
neurological function.
the median nerve runs down the arm and does not
Other much less common diseases of the carotid
give off any motor or sensory branch until it is in the
arteries and their branches are post-traumatic or
forearm. After supplying muscles in the forearm, the
spontaneous dissection; the ocular manifestations of
palmar cutaneous sensory branch arises just prox-
Horner’s syndrome that may follow damage to the
imal to the wrist and carpal tunnel to supply
sympathetic nervous fibers in the internal carotid
sensation over the thenar eminence. The last branch
adventia; carotid sinus syndrome; giant cell or
of the median nerve then proceeds to enter the carpal
temporal arteritis; other rare forms of arteritis, such
tunnel in the wrist. The carpal tunnel is formed by
as Takayasu’s or pulseless disease; and chemodecto-
the carpal bones on the floor and sides, and its roof is
ma of the carotid body, which may accompany
formed by the transverse ligament. The contents of
similar tumors at other chemoreceptor sites.
the carpal tunnel include nine flexor tendons to the
—George H. du Boulay
digits and thumb as well as the median nerve. Once it
transverses the carpal tunnel, the median nerve
divides into motor and sensory divisions in the palm.
See also–Brain Evolution, Human; Carotid The motor component supplies the first and second
Angioplasty and Stenting; Cerebral Blood
lumbricals as well as the muscles in the thenar
Vessels: Arteries; Cerebral Metabolism and
eminence (opponens pollicis, abductor pollicis bre-
Blood Flow; Ultrasound, Carotid; Vertebrate
Nervous System, Development of vis, and superficial head of flexor pollicis brevis). The
sensory branch supplies the thumb, index, middle,
and lateral half of the ring finger. The index and
Further Reading middle fingers receive two digital branches (one
Boulin, D. J. (1980). Cerebral Vasospasm. Wiley, Chichester, UK. median and one lateral), whereas the thumb and ring
du Boulay, G. H., and Verity, P. M. (1973). The Cranial Arteries of
finger each have one branch.
Mammals. Heinemann, London.
du Boulay, G. H., Lawton, M., and Wallis, A. (1998). The story of
the internal carotid artery of mammals: From Galen to sudden PATHOGENESIS
infant death syndrome. Neuroradiology 40, 697–703.
Warwick, R., and Locllean, P. L. (1995). Gray’s Anatomy, 38th ed. CTS has been reported to have a population
Longman, London. incidence of 0.1% annually among adults, with a
518 CARPAL TUNNEL SYNDROME

lifetime estimated risk of 10% and the condition is PHYSICAL FINDINGS

bilateral in approximately half of patients. A recent
On physical exam, sensation can be normal in early
population study in Sweden reports the overall
stages of CTS. When the condition is more advanced,
prevalence to be approximately 2.7%. Many condi-
there can be hypesthesia in the median nerve
tions are associated with CTS: structural/anatomic
distribution. Classically, the sensory deficit localizes
(ganglion, lipoma, and neuroma), inflammatory
to the radial aspects of the palm splitting the ring
(rheumatoid arthritis, gout, tenosynovitis, and scler-
finger. Because the region of the thenar eminence is
aderma), neuropathic/ischemic (diabetes, alcoholism,
supplied by the palmar cutaneous sensory branch,
and amyloidosis), or shifts in fluid balance (preg-
which originates before the carpal tunnel, the sensory
nancy, hypothyroidism, and obesity). In other words,
exam is normal. On motor exam, thumb abduction
any process that can increase the volume within the
and opposition are usually normal unless the condi-
carpal tunnel can increase the pressure within the
tion is severe or advanced, in which case thenar
canal. This increased pressure can then lead to
atrophy may be present.
compression or ischemia of the median nerve.
Other tests commonly performed in examination
Phalen, an orthopedic surgeon who popularized
for CTS include the Tinel and Phalen tests. The Tinel
the diagnosis and treatment of CTS with a series of
sign is produced by tapping the median nerve over
publications starting in the 1950s, postulated that
the volar skin crease. It is positive if it causes tingling
increased pressure in the carpal tunnel occurs with
or electric shock sensation extending into any or all
persistent wrist flexion or extension during sleep. This
of the median nerve innervated digits. The test is
increased pressure in turn leads to nerve ischemia,
neither sensitive nor specific. Tinel sign may be
resulting in paresthesia in the nerve distribution.
positive in approximately half of patients with CTS,
The question of whether CTS can be a result of
but it may be also positive in up to half of the
occupation-related hand or wrist overuse is contro-
asymptomatic group.
versial. Some authors have reported occupation and
In the Phalen test, patients holding the wrist
heavy manual labor as a risk factor for CTS, but
passively flexed for 30–60 sec can elicit pain and
others have disputed the association. Studies of nerve
numbness due to CTS. Phalen found this test positive
conduction of workers show no consistent associa-
in 80% of those he tested, with fewer false positives.
tion between prevalence of CTS and the type of
The belief is that this maneuver further compresses
occupational activity or duration of employment.
the median nerve against the proximal edge of the
One study of medical workers who are frequent
transverse carpal ligament and the adjacent flexor
computer users showed no difference in frequency of
tendons.
CTS when compared with the general population.
Another clinical maneuver that can elicit symp-
toms of CTS is a direct compression of the median
CLINICAL PRESENTATION nerve applied for up to 30 sec using both thumbs or a
mechanical device. The time it takes for the patient
Patients with CTS typically complain of nocturnal
to develop pain, numbness, or paresthesia is noted,
paresthesias or burning pain in the territory supplied
with the sensitivity and specificity of the test reported
by the nerve. It is a reliable symptom, although its
to be 87 and 90%, respectively.
cause is uncertain. Some patients may complain of
stiffness in the hand as a presenting symptom rather
than pain. The sensation of pain or discomfort often
ELECTROPHYSIOLOGICAL TESTING
spread to the forearm, elbow, and even to the
shoulder and neck area. Sometimes, the pain may Nerve conduction studies and electromyography
be localized to the shoulder and forearm instead of (EMG) are performed routinely for evaluation of
the hand and wrist. Most commonly, the area of CTS. The aim of the study is to document focal lesion
discomfort involves the thumb, index and middle of the median nerve at the wrist as the cause of the
fingers, and the radial half of the ring finger. Patients symptoms and to eliminate possible causes, such as
also complain of stiffness and weakness in the hands, peripheral neuropathy, proximal median neuropathy,
especially with activity. Weakness and thenar atro- or cervical radiculopathy. In most cases of CTS,
phy are late findings in CTS, although they may be demyelination of the nerve is present at the site of the
presenting symptoms because the sensory loss is compression, with secondary axonal loss in advanced
unnoticed by the patient. cases.

On sensory conduction testing, findings include
slow conduction velocity and low amplitudes in
sensory nerve action potentials. Often, these sensory
changes are the first abnormality documented in
early CTS. As the condition worsens, motor conduc-
tion studies can show prolonged distal latency, with
reduced or absent compound motor action potential
in advanced or severe cases. If the largest and fastest
fibers of the median nerve are blocked or have
undergone Wallerian degeneration due to CTS, there
can be slowed motor conduction in the forearm
segment. The minimum F wave latency may also be
prolonged when compared to that of the ulnar nerve
because the signal must also traverse the carpal
tunnel.
Although decreased sensory and motor conduction
amplitudes and velocities, as well as prolonged
motor distal latencies, can diagnose many cases of
CTS, these values can be normal in early or mild
stages. In these situations, special studies may be
required. Usually, further studies using internal
comparison to the ulnar or, less frequently, the radial
nerve of the same hand are performed. These studies
include the median (second lumbrical) versus the
ulnar (interossei) distal motor latencies; the median
versus the radial sensory latencies from the thumb,
recording at the wrist; the median versus the ulnar
wrist to digit 4 sensory latencies; and the digit-to-
palm and palm-to-wrist conduction study of the
median nerve, which can also differentiate between
peripheral neuropathy and conduction block in CTS.
Each of these comparison studies measures identical
distances between stimulating and recording electro-
des for the median and the compared nerve, which
then ideally minimizes effects of other variables
known to affect conduction studies, such as age and
temperature. These internal comparison studies can
detect milder cases of CTS by documenting focal
slowing of the distal median nerve. These studies can
also indicate the degree of secondary axonal injuries
or loss based on motor and sensory amplitudes,
which has implications in the degree of injury and
prognosis, even with appropriate treatment. How-
ever, only the digit-to-palm and palm-to-wrist
sensory and motor nerve study can document
conduction block across the carpal tunnel, which
signifies demyelination and has a better prognosis
than axonal degeneration.
Using needle electromyography to evaluate CTS
can help differentiate this condition from others that
can cause similar complaints, such as high median
neuropathy or cervical radiculopathy (usually C6 or
CARPAL TUNNEL SYNDROME 519
C7), which can cause hand pain and paresthesia. It
can also assess the severity of CTS regarding any
acute or chronic denervation with axonal loss.
If the median innervated muscles of the thenar
eminence (opponens pollicis or abductor pollicis
brevis) are abnormal but those innervated by
proximal median nerve and ulnar innervated C8–
T1 muscles are normal, then the diagnosis of distal
median neuropathy/CTS is confirmed. In most
situations, EMG study is normal unless the CTS is
severe, with axonotmesis. Very rarely is there
denervation on EMG with normal conduction
studies, and presumably this indicates primary
axonotmesis, supporting the notion that both EMG
and nerve conduction studies are equally important
in CTS evaluation.
OTHER DIAGNOSTIC TESTS
CTS is usually idiopathic, although there are many
medical conditions associated with it, such as
diabetes, hypothyroidism, rheumatoid arthritis, and
amyloidosis. However, routine use of screening tests,
such as rheumatoid factor, thyroid function tests, and
blood glucose, usually has a low yield, and the
decision whether to perform such tests should be
made on an individual basis based on patient’s
medical history, presenting symptoms, or other risk
factors.
Magnetic resonance imaging allows detailed views
of wrist anatomy. It is rarely used in routine clinical
diagnosis of CTS, but it can be useful if CTS is
suspected to be caused by a mass lesion, such as
ganglia or tumors (neurofibroma and schwannoma).
DIFFERENTIAL DIAGNOSIS
As mentioned earlier, other disorders have presenting
symptoms similar to those of CTS. Peripheral causes
include proximal median neuropathy, brachial plexo-
pathy, and cervical radiculopathy. Compression of
C6 and C7 cervical roots is the most common
disorder mimicking CTS. Pain and paresthesia in the
arm and hand are common with C6 and C7 radiculo-
pathy. However, pain in the neck and shoulders is
much less common in CTS, and pain that is
exacerbated by neck movement or radiates to the
chest wall or scapular indicates cervical radiculo-
pathy. Clinically, patients with cervical radiculopathy
can have worsening symptoms during the day with
arm use, whereas symptoms of CTS tend to exacer-
bate at bedtime. On exam and EMG studies,
520 CARPAL TUNNEL SYNDROME
attention is paid to C6 and C7 innervated muscles to
detect weakness or denervation. There can also be
diminished tendon reflex when compared to the
unaffected side—the biceps reflex when C6 is
involved and the triceps reflex if C7 root is affected.
Proximal median neuropathy around the elbow
causes paresthesia and numbness including the
thenar eminence, and muscles affected include those
in the forearm responsible for thumb flexion (flexor
pollicis longus), arm pronation (pronator teres and
quadratus), as well as wrist flexion (flexor carpi
radialis). Detection of brachial plexopathy can be
accomplished clinically if, on exam, sensory and
motor deficits attributable to multiple nerves are
demonstrated, with electrophysiological confirma-
tion based on nerve conduction testing and EMG
findings.
Occasionally, symptoms from some central ner-
vous system disorders can be confused with those of
CTS, including focal seizures and transient ischemic
attacks. However, pain is usually not present in these
conditions.
TREATMENT
In cases of acute CTS caused by fractures, hemato-
ma, or compartment syndrome, appropriate surgical
intervention or repair are necessary and may include
carpal tunnel releases to protect the function of the
median nerve.
In idiopathic CTS, symptoms of patients with mild
cases can be relieved by the use of a neutral wrist
splint during sleep. Addition of a nonsteroidal anti-
inflammatory drug for 2 or 3 weeks can also decrease
pain in the wrist. Most of the improvement from
splints is seen by 2 weeks.
If symptoms recur or persist after a trial of
splinting for a few weeks, the next step of treatment
may be direct injection of corticosteroids into the
carpal tunnel. Local steroid injections have been
shown to provide better symptom relief than a short
course of oral steroids. A subgroup of patients
indicated for local steroid injection includes the
elderly and poor surgical candidates with complaints
of pain. Steroid injections can relieve pain within a
few days and can last from a few weeks to 6 months.
Results from different authors indicate good to
complete relief of symptoms in up to 81% of
patients. Disadvantages of steroid injections are that
effects are temporary and more than two or three
injections are not advised due to danger of focal
tendon damage and rupture. Steroid injections can be
very useful in conditions in which CTS is expected to
be of limited duration, such as during pregnancy.
If there is evidence of a mass lesion, thenar
atrophy, denervation on EMG, or persistent or
recurrent symptoms despite conservative therapies,
then the definitive treatment is surgical decompres-
sion of the carpal tunnel by cutting the transverse
carpal ligament. Most commonly, it is done through
a longitudinal incision extending from the wrist to
the palm, with open carpal tunnel release (OCTR).
Endoscopic carpal tunnel release (ECTR) and mini-
mal OCTR are gaining popularity because of less
postoperative discomfort. Both techniques have been
shown to have similar long-term results in relieving
median nerve compression. Surgical complication
rates of both OCTR and ECTR are 1% when
performed by experienced surgeons. Complications
include injuries to median, ulnar, and digital nerves,
arteries, or flexor tendons, as well as incomplete
release due to incomplete ligation of the transverse
carpal ligament. Complications appear to be more
severe and more difficult to recognize in ECTR.
Postoperative care in carpal tunnel release includes
wrist splinting in a neutral position for several weeks.
However, a prospective study found that patients
who did not receive wrist splinting post-op had
earlier functional recovery than those splinted for 2
weeks, without an increase in complications.
With treatment, the prognosis of CTS is very good.
Many patients present early in the disorder due to
pain and paresthesia, before any muscle atrophy or
axonal loss have occurred. Patients whose main
complaints are intermittent pain and paresthesia
without any fixed motor or sensory deficits usually
respond well to conservative treatment. Those with
persistent symptoms despite conservative manage-
ment have good symptom relief with surgery, with
improvement in 85–90% of patients within days of
operation. If persistent sensory or motor deficits are
present at the time of surgery, recovery postsurgery
will depend on whether the deficits are caused by
demyelination at the site of compression, leading to
conduction block, secondary axonal loss, or a
combination of the two. If the cause is conduction
block, then remyelination postdecompression is
usually complete after a few weeks. If the deficits
are secondary to axonal loss, then recovery is
expected to be slow over several months. In
advanced cases in which thenar atrophy is promi-
nent, motor and sensory recovery is usually incom-
plete, although pain and paresthesia often improve.
—Dora Leung

See also–Brachial Plexopathies; Median Nerves
and Neuropathy; Neuropathies, Entrapment;
Neuropathies, Instrumental; Radiculopathy;
Sensation, Assessment of; Tarsal Tunnel
Syndrome; Thoracic Outlet Syndromes; Writer’s
Cramp/Tremor
Further Reading
American Academy of Neurology, American Association of
Electrodiagnostic Medicine, American Academy of Physical
Medicine and Rehabilitation (1993). Practice parameter for
electrodiagnostic studies in carpal tunnel syndrome. Neurology
43, 2404–2405.
Atroshi, I., Gummesson, C., Johnsson, R., et al. (1999). Prevalence
of carpal tunnel syndrome in a general population. J. Am. Med.
Assoc. 282, 153–158.
Campbell, W. W. (1998). Entrapment neuropathies. In Prognosis
in Neurology (J. Gilchrist, Ed.), pp. 307–312. Butterworth-
Heinemann, Boston.
Demopulos, G. A., and Urbaniak, J. R. (1996). Carpal tunnel
release: Comparing the options. J. Musculskel. Med. 13, 51.
Murphy, R. X., Chernofsky, M. A., Osborne, M. A., et al. (1993).
Magnetic resonance imaging in the evaluation of persistent
carpal tunnel syndrome. J. Hand Surg. 18, 113.
Phalen, G. S. (1976). Reflections on 21 years’ experience with
carpal tunnel syndrome. J. Am. Med. Assoc. 212, 1365.
Preston, D. C. (1999). Distal median neuropathies. Neurol. Clin.
17, 407–424.
Quality Standards Subcommittee of the American Academy of
Neurology (1993). Practice parameter for carpal tunnel
syndrome. Neurology 43, 2406–2409.
Stevens, J. C., Sun, S., Beard, C. M., et al. (1988). Carpal tunnel
syndrome in Rochester, Minnesota, 1961 to 1980. Mayo Clinic
Proc. 38, 134–138.
Stevens, J. C., Witt, J. C., Smith, B. E., et al. (2001). The frequency
of carpal tunnel syndrome in computer users at a medical
facility. Neurology 56, 1568–1570.
Wong, S. M., Hui, A. C. F., Tang, A., et al. (2001). Local vs
systemic corticosteroids in the treatment of carpal tunnel
syndrome. Neurology 56, 1565–1567.
Catalepsy
see Catatonia
Cataplexy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CATAPLEXY is a classic symptom of the ‘‘narcolepsy
tetrad’’ described by Yoss and Daly. The cardinal
features of narcolepsy are daytime somnolence,
hypnagogic hallucinations, sleep paralysis, and cat-
aplexy. Cataplexy is characterized by the sudden loss
CATAPLEXY 521
of muscle tone while awake, typically triggered by a
strong positive emotion such a laughter or surprise. It
can also be triggered less commonly by anger or fear.
Cataplexy is virtually a pathognomonic symptom of
narcolepsy. When an experienced clinician witnesses
a cataplextic attack, confirmatory sleep laboratory
testing for narcolepsy might not be necessary.
Narcoleptic patients remain conscious during the
attack and are able to remember the details of the
event afterwards. The episodes are typically brief and
may last only a few seconds. Some patients can have
other narcoleptic symptoms manifest during an
episode of cataplexy, such as hypnagogic hallucina-
tions and sleep paralysis, or they may simply fall
asleep.
Cataplexy may involve only certain muscles or the
entire voluntary musculature. Typically, the jaw sags,
the head falls forward, the arms drop to the side, and
the knees buckle. The severity and extent of
cataplectic attacks can range from a state of absolute
powerlessness, which seems to involve the entire
body, to no more than a fleeting sensation of
weakness. Although the intraocular ciliary muscles
are supposedly not involved, the patient may
complain of blurred vision. Respiration may become
irregular during an attack, which may be related to
weakness of the abdominal or intercostal muscles.
Complete loss of muscle tone, which results in a fall
with risk of serious injuries, including skull and other
bone fractures, may be noted during a cataplectic
attack. The attacks may also be subtle and not
noticed by nearby individuals. An attack may consist
only of a slight buckling of the knees. Patients may
perceive this abrupt and short-lasting weakness and
may simply sit or stand against a wall. Speech may be
slurred owing to intermittent weakness affecting the
arytenoid muscles. If the weakness involves only the
jaw or speech, the subject may present with wide
masticatory movement or odd attacks of stuttering.
If it involves the upper limbs, the patient will
complain of ‘‘clumsiness,’’ reporting activity such as
dropping cups or plates or spilling liquids when
surprised or laughing. A patient, particularly a child,
may present with repetitive falls that cannot be easily
explained. A clinical suspicion of atonic seizures or
drop attacks may lead to a misdiagnosis. The
duration of each cataplectic attack, partial or total,
is highly variable and usually ranges from a few
seconds to 2 min and rarely up to 30 min.The term
‘‘status cataplecticus’’ can be applied to prolonged
attacks. Attacks can be elicited by emotion, stress,
fatigue, or heavy meals. Laughter and anger seem to

See also–Brachial Plexopathies; Median Nerves
and Neuropathy; Neuropathies, Entrapment;
Neuropathies, Instrumental; Radiculopathy;
Sensation, Assessment of; Tarsal Tunnel
Syndrome; Thoracic Outlet Syndromes; Writer’s
Cramp/Tremor
Further Reading
American Academy of Neurology, American Association of
Electrodiagnostic Medicine, American Academy of Physical
Medicine and Rehabilitation (1993). Practice parameter for
electrodiagnostic studies in carpal tunnel syndrome. Neurology
43, 2404–2405.
Atroshi, I., Gummesson, C., Johnsson, R., et al. (1999). Prevalence
of carpal tunnel syndrome in a general population. J. Am. Med.
Assoc. 282, 153–158.
Campbell, W. W. (1998). Entrapment neuropathies. In Prognosis
in Neurology (J. Gilchrist, Ed.), pp. 307–312. Butterworth-
Heinemann, Boston.
Demopulos, G. A., and Urbaniak, J. R. (1996). Carpal tunnel
release: Comparing the options. J. Musculskel. Med. 13, 51.
Murphy, R. X., Chernofsky, M. A., Osborne, M. A., et al. (1993).
Magnetic resonance imaging in the evaluation of persistent
carpal tunnel syndrome. J. Hand Surg. 18, 113.
Phalen, G. S. (1976). Reflections on 21 years’ experience with
carpal tunnel syndrome. J. Am. Med. Assoc. 212, 1365.
Preston, D. C. (1999). Distal median neuropathies. Neurol. Clin.
17, 407–424.
Quality Standards Subcommittee of the American Academy of
Neurology (1993). Practice parameter for carpal tunnel
syndrome. Neurology 43, 2406–2409.
Stevens, J. C., Sun, S., Beard, C. M., et al. (1988). Carpal tunnel
syndrome in Rochester, Minnesota, 1961 to 1980. Mayo Clinic
Proc. 38, 134–138.
Stevens, J. C., Witt, J. C., Smith, B. E., et al. (2001). The frequency
of carpal tunnel syndrome in computer users at a medical
facility. Neurology 56, 1568–1570.
Wong, S. M., Hui, A. C. F., Tang, A., et al. (2001). Local vs
systemic corticosteroids in the treatment of carpal tunnel
syndrome. Neurology 56, 1565–1567.
Catalepsy
see Catatonia
Cataplexy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CATAPLEXY is a classic symptom of the ‘‘narcolepsy
tetrad’’ described by Yoss and Daly. The cardinal
features of narcolepsy are daytime somnolence,
hypnagogic hallucinations, sleep paralysis, and cat-
aplexy. Cataplexy is characterized by the sudden loss
CATAPLEXY 521
of muscle tone while awake, typically triggered by a
strong positive emotion such a laughter or surprise. It
can also be triggered less commonly by anger or fear.
Cataplexy is virtually a pathognomonic symptom of
narcolepsy. When an experienced clinician witnesses
a cataplextic attack, confirmatory sleep laboratory
testing for narcolepsy might not be necessary.
Narcoleptic patients remain conscious during the
attack and are able to remember the details of the
event afterwards. The episodes are typically brief and
may last only a few seconds. Some patients can have
other narcoleptic symptoms manifest during an
episode of cataplexy, such as hypnagogic hallucina-
tions and sleep paralysis, or they may simply fall
asleep.
Cataplexy may involve only certain muscles or the
entire voluntary musculature. Typically, the jaw sags,
the head falls forward, the arms drop to the side, and
the knees buckle. The severity and extent of
cataplectic attacks can range from a state of absolute
powerlessness, which seems to involve the entire
body, to no more than a fleeting sensation of
weakness. Although the intraocular ciliary muscles
are supposedly not involved, the patient may
complain of blurred vision. Respiration may become
irregular during an attack, which may be related to
weakness of the abdominal or intercostal muscles.
Complete loss of muscle tone, which results in a fall
with risk of serious injuries, including skull and other
bone fractures, may be noted during a cataplectic
attack. The attacks may also be subtle and not
noticed by nearby individuals. An attack may consist
only of a slight buckling of the knees. Patients may
perceive this abrupt and short-lasting weakness and
may simply sit or stand against a wall. Speech may be
slurred owing to intermittent weakness affecting the
arytenoid muscles. If the weakness involves only the
jaw or speech, the subject may present with wide
masticatory movement or odd attacks of stuttering.
If it involves the upper limbs, the patient will
complain of ‘‘clumsiness,’’ reporting activity such as
dropping cups or plates or spilling liquids when
surprised or laughing. A patient, particularly a child,
may present with repetitive falls that cannot be easily
explained. A clinical suspicion of atonic seizures or
drop attacks may lead to a misdiagnosis. The
duration of each cataplectic attack, partial or total,
is highly variable and usually ranges from a few
seconds to 2 min and rarely up to 30 min.The term
‘‘status cataplecticus’’ can be applied to prolonged
attacks. Attacks can be elicited by emotion, stress,
fatigue, or heavy meals. Laughter and anger seem to
522 CATAPLEXY
be the most common triggers, but a feeling of elation
while listening to music, reading a book, or watching
a movie can also induce the attacks. Merely
remembering a funny situation may induce cata-
plexy, and it may also occur without obvious
precipitating acts or emotions. In children it often
occurs while playing with others.
A canine animal model for narcolepsy has helped
in understanding the pathophysiology of cataplexy.
A pathway similar to the one leading to rapid eye
movement (REM) atonia is strongly suspected in
cataplexy. Cholinergic mechanisms are also impor-
tant. Physostigmine increases cataplexy and it is
blocked by atropine in narcoleptic animals. Cata-
plexy is associated with an inhibition of mono-
synaptic H-reflexes and tendon reflexes. H-reflex
activity is fully suppressed physiologically during
REM sleep, which emphasizes the relationship
between the motor inhibition of REM sleep and the
sudden atonia and areflexia seen during a cataplectic
attack. Noradrenergic pathways are especially im-
portant in cataplexy. REM sleep-off cells in the locus
coeruleus stop discharging immediately prior to and
during a cataplectic attack in dogs. Narcolepsy in
dogs was found to be caused by a mutation in a
hypocretin receptor subtype. This finding led to the
discovery of hypocretin deficiency in human narco-
lepsy. Hypocretin cells in the lateral hypothalamus
have projections to the locus coeruleus. Sigel
reported that the impaired function of the hypocretin
system may lead to decreased tonic activation of the
locus coeruleus, which may explain cataplexy.
Isolated cataplexy without narcolepsy is extremely
rare. It may occur in patients with discrete structural
lesions involving the pontomedullary region, such as
in multiple sclerosis or in neoplasms. Episodes of
hyperekplexia may at first be confused with cata-
plexy, but they are not usually elicited with positive
emotion and are not associated with atonia.
The management of cataplexy is ideally part of a
comprehensive narcolepsy treatment plan. Successful
treatment typically must combine both behavioral
and pharmacological treatments. The situation is
analogous to other chronic conditions such as
juvenile diabetes mellitus, where a combination of
diet with medication can control the disease. Patients
with narcolepsy–cataplexy will benefit from the
healthy sleep habits referred to as sleep hygiene.
Some patients with narcolepsy with relatively mild
cataplexy may prefer not to take medication for their
cataplexy. In part, this may be due to avoidance of
medication side effects. Also, some patients learn to
anticipate the attacks. Finally, cataplexy does not
typically progress in severity over time and some-
times may improve over the course of the disease.
Cataplexy does not usually respond to the
stimulant medications used to treat the sleepiness of
narcolepsy. Narcoleptics typically will take a medi-
cation to improve alertness and a different medica-
tion to avoid cataplexy attacks. Pharmacological
treatment options for cataplexy may change with the
recent discovery of a gene responsible for narcolepsy.
Cataplexy seems to respond best to medications with
noradrenergic reuptake blocking properties. Medica-
tion types that have been used effectively include
tricyclic antidepressants such as clomipramine, pro-
triptyline, and impramine. Selective serotonin reup-
take inhibitors, such as fluoxetine and venlafaxine,
are effective and have less undesirable side effects
than the tricyclic antidepressants. Two of these
medications have been more commonly used—
clomipramine and fluoxetine. Both of these drugs
have active noradrenergic reuptake blocking meta-
bolites (desmethylclomipramine and norfluoxetine).
It is through these metabolites that the therapeutic
effect may be mediated. Some patients have benefited
from monoamine oxidase inhibitors such as phenel-
zine and would preclude the use of stimulants to treat
marcolepsy.
The novel agent g-hydroxybutyrate (GHB) has
been found to be very effective and well tolerated in
the treatment of cataplexy among narcoleptics. This
is a precursor to g-aminobutyric acid. This medica-
tion usually does not improve daytime sleepiness.
The medication does increase slow-wave sleep with-
out changing the amount of REM sleep. The dosage
is usually approximately 2 or 3 g given at bedtime.
GHB is a very controversial compound in the United
States. It has become a popular drug of abuse among
some segments of society and has been given the
notorious nickname of the ‘‘date rape drug.’’ The
medication has strong sedating properties, particu-
larly when mixed with alcohol. Attempts to classify
GHB in the same category as heroin, cocaine, and
other street drugs have been made. It has been shown
to have medical benefit in cataplexy but should be
used with caution in patients with a known history of
substance abuse.
—Rafael Pelayo and Ravinder Shergill
See also–Excessive Daytime Sleepiness;
Narcolepsy; REM (Rapid Eye Movement) Sleep;
Sleep Disorders; Sleep Paralysis

Further Reading
Baker, T. L., and Dement, W. C. (1985). Canine narcolepsy–
cataplexy syndrome: Evidence for an inherited monoaminergic–
cholinergic imbalance. In Brain Mechanisms of Sleep (D. J.
McGinty, R. Drucker-Colin, and A. Morrison, et al., Eds.), pp.
199–234. Raven Press, New York.
Diagnostic Classification Steering Committee (M. J. Thorpy,
Chairman) (1990). International Classification of Sleep Dis-
orders Diagnostic and Coding Manual. American Association
of Sleep Disorders, Rochester, MI.
Guilleminault, C., and Pelayo, R. (1998). Narcolepsy in pre-
pubertal children. Ann. Neurol. 43, 135–142.
Guilleminault, C., Heinzer, R., Mignot, E., et al. (1998).
Investigations into the neurologic basis of narcolepsy. Neurol-
ogy 50, S8–S15.
Lin, L., Faraco, J., Li, R., et al. (1999). The sleep disorder canine
narcolepsy is caused by a mutation in the hypocretin (orexin)
receptor 2 gene. Cell 98, 365–376.
Mignot, E., Renaud, A., Nishino, S., et al. (1993). Canine
cataplexy is preferentially controlled by adrenergic
mechanisms: Evidence using monoamine selective uptake
inhibitors and release enhancers. Psychopharmacology 113,
76–82.
Nishino, S., Arrigoni, J., Shelton, J., et al. (1993). Desmethyl
metabolites of serotonergic uptake inhibitors are more potent
for suppressing canine cataplexy than their parent compounds.
Sleep 16, 706–712.
Nishino, S., Ripley, B., Overeem, S., et al. (2000). Hypocretin
(orexin) deficiency in human narcolepsy. Lancet 355, 39–40.
Sigel, J. M. (2000). Narcolepsy. Sci. Am. 282, 76–81.
Wu, M. F., Gulyani, S. A., Yau, E., et al. (1999). Locus coeruleus
neurons: Cessation of activity during cataplexy. Neuroscience
91, 1389–1399.
Yoss, R. E., and Daly, D. D. (1968). On the treatment of
narcolepsy. Med. Clin. North Am. 52, 781–787.
Catatonia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CATATONIA is a syndrome of abnormal motor
function manifesting as either a stupor or excitement.
Many clinicians equate stupor with catatonia.
Gelenberg defined catatonia as a symptom complex
and stupor as one of the features of the catatonic
syndrome. A number of diverse organic and psychia-
tric etiologies can cause this syndrome. It is often
associated with schizophrenia, affective illnesses,
psychoses, intrinsic brain and metabolic disorders,
and drug-induced syndromes.
CLINICAL FEATURES
Clinical presentation of this syndrome varies de-
pending on whether a patient is presenting an
CATATONIA 523
excitatory or stuporous form. A patient in a
catatonic stupor (psychogenic) is capable of assim-
ilating all the external stimuli but cannot react to
these stimuli by motor activity. The three cardinal
clinical features of stupor are clear consciousness
associated with varying degrees of mutism and
akinesia. Mutism, negativism, posturing, and waxy
flexibility are typical characteristic signs that identi-
fy the stupor syndrome. This is in contrast to the use
of stupor by neurologists to define conditions of
reduced consciousness and responsivity associated
with diffuse organic dysfunction. Catatonia can also
manifest in excessive psychomotor activity as noted
in catatonic excitement. In addition, an acute
clinical form, lethal catatonia, presents with psy-
chosis, delirium, tremulousness, rigidity, tachycar-
dia, hyperpyrexia, hypertension, and diaphoresis
with extreme hyperactivity and/or stupor. This
condition responds to treatment but may be fatal
when not recognized. Exhaustion secondary to
relentless psychomotor excitement may be the cause
of lethal catatonia.
DIFFERENTIAL DIAGNOSIS
A catatonic syndrome strikingly similar to catatonic
stupor may develop during intramuscular or oral
neuroleptic therapy, thereby posing a serious diag-
nostic and management dilemma. Although cata-
tonic schizophrenia is becoming less frequent,
neuroleptic-induced catatonia is becoming more
prevalent. A related condition is neuroleptic malig-
nant syndrome, which presents a similar clinical
picture but also includes hyperthermia and an
autonomic discharge.
Patients with bipolar disorder may exhibit severe
manic excitement with confusion, which is indis-
tinguishable from catatonic excitement.
TREATMENT
For every case of catatonia, a full neurological and
general medical investigation should be performed,
including neuroimaging and electroencephalogram
examinations. Medical and/or neurological disorders
underlying catatonia should be treated as aggres-
sively as possible. The pharmacological treatment
includes administration of antipsychotic agents along
with benzodiazepines. Benzodiazepines such as
lorazepam, clonazepam, and diazepam are usually
employed for diagnosis and for rapid and temporary

Further Reading
Baker, T. L., and Dement, W. C. (1985). Canine narcolepsy–
cataplexy syndrome: Evidence for an inherited monoaminergic–
cholinergic imbalance. In Brain Mechanisms of Sleep (D. J.
McGinty, R. Drucker-Colin, and A. Morrison, et al., Eds.), pp.
199–234. Raven Press, New York.
Diagnostic Classification Steering Committee (M. J. Thorpy,
Chairman) (1990). International Classification of Sleep Dis-
orders Diagnostic and Coding Manual. American Association
of Sleep Disorders, Rochester, MI.
Guilleminault, C., and Pelayo, R. (1998). Narcolepsy in pre-
pubertal children. Ann. Neurol. 43, 135–142.
Guilleminault, C., Heinzer, R., Mignot, E., et al. (1998).
Investigations into the neurologic basis of narcolepsy. Neurol-
ogy 50, S8–S15.
Lin, L., Faraco, J., Li, R., et al. (1999). The sleep disorder canine
narcolepsy is caused by a mutation in the hypocretin (orexin)
receptor 2 gene. Cell 98, 365–376.
Mignot, E., Renaud, A., Nishino, S., et al. (1993). Canine
cataplexy is preferentially controlled by adrenergic
mechanisms: Evidence using monoamine selective uptake
inhibitors and release enhancers. Psychopharmacology 113,
76–82.
Nishino, S., Arrigoni, J., Shelton, J., et al. (1993). Desmethyl
metabolites of serotonergic uptake inhibitors are more potent
for suppressing canine cataplexy than their parent compounds.
Sleep 16, 706–712.
Nishino, S., Ripley, B., Overeem, S., et al. (2000). Hypocretin
(orexin) deficiency in human narcolepsy. Lancet 355, 39–40.
Sigel, J. M. (2000). Narcolepsy. Sci. Am. 282, 76–81.
Wu, M. F., Gulyani, S. A., Yau, E., et al. (1999). Locus coeruleus
neurons: Cessation of activity during cataplexy. Neuroscience
91, 1389–1399.
Yoss, R. E., and Daly, D. D. (1968). On the treatment of
narcolepsy. Med. Clin. North Am. 52, 781–787.
Catatonia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CATATONIA is a syndrome of abnormal motor
function manifesting as either a stupor or excitement.
Many clinicians equate stupor with catatonia.
Gelenberg defined catatonia as a symptom complex
and stupor as one of the features of the catatonic
syndrome. A number of diverse organic and psychia-
tric etiologies can cause this syndrome. It is often
associated with schizophrenia, affective illnesses,
psychoses, intrinsic brain and metabolic disorders,
and drug-induced syndromes.
CLINICAL FEATURES
Clinical presentation of this syndrome varies de-
pending on whether a patient is presenting an
CATATONIA 523
excitatory or stuporous form. A patient in a
catatonic stupor (psychogenic) is capable of assim-
ilating all the external stimuli but cannot react to
these stimuli by motor activity. The three cardinal
clinical features of stupor are clear consciousness
associated with varying degrees of mutism and
akinesia. Mutism, negativism, posturing, and waxy
flexibility are typical characteristic signs that identi-
fy the stupor syndrome. This is in contrast to the use
of stupor by neurologists to define conditions of
reduced consciousness and responsivity associated
with diffuse organic dysfunction. Catatonia can also
manifest in excessive psychomotor activity as noted
in catatonic excitement. In addition, an acute
clinical form, lethal catatonia, presents with psy-
chosis, delirium, tremulousness, rigidity, tachycar-
dia, hyperpyrexia, hypertension, and diaphoresis
with extreme hyperactivity and/or stupor. This
condition responds to treatment but may be fatal
when not recognized. Exhaustion secondary to
relentless psychomotor excitement may be the cause
of lethal catatonia.
DIFFERENTIAL DIAGNOSIS
A catatonic syndrome strikingly similar to catatonic
stupor may develop during intramuscular or oral
neuroleptic therapy, thereby posing a serious diag-
nostic and management dilemma. Although cata-
tonic schizophrenia is becoming less frequent,
neuroleptic-induced catatonia is becoming more
prevalent. A related condition is neuroleptic malig-
nant syndrome, which presents a similar clinical
picture but also includes hyperthermia and an
autonomic discharge.
Patients with bipolar disorder may exhibit severe
manic excitement with confusion, which is indis-
tinguishable from catatonic excitement.
TREATMENT
For every case of catatonia, a full neurological and
general medical investigation should be performed,
including neuroimaging and electroencephalogram
examinations. Medical and/or neurological disorders
underlying catatonia should be treated as aggres-
sively as possible. The pharmacological treatment
includes administration of antipsychotic agents along
with benzodiazepines. Benzodiazepines such as
lorazepam, clonazepam, and diazepam are usually
employed for diagnosis and for rapid and temporary
524 CATECHOLAMINES AND BEHAVIOR
symptomatic treatment. Electroconvulsive therapy
(ECT) has been the most effective treatment for
catatonic syndrome. This modality should be used
only in treatment-refractory or life-threatening cases.
On the other hand, for functional lethal catatonia,
ECT may be the treatment of choice because
neuroleptics are likely to make it worse.
If catatonic symptoms appear or worsen shortly
after initiation of neuroleptic therapy, a neuroleptic-
induced catatonia should be presumed. To avert
potential pathological sequelae, the antipsychotic
drug should be discontinued immediately. Generally,
catatonic symptoms may persist for a few days after
neuroleptic withdrawal because of their long elim-
ination half-life. Usually, the symptoms resolve
within several days to a few weeks after drug
discontinuation.
—Jambur Ananth
See also–Antipsychotic Pharmacology; Bipolar
Disorders; Electroconvulsive Therapy; Mania;
Schizophrenia, Biology of; Stupor; Substance
Abuse
Acknowledgment
I thank Rajesh Devaraj for his help in preparing this entry.
Further Reading
American Psychiatric Association Task Force on Electro-
convulsive Therapy (1990). The Practice of Electro-
convulsive Therapy: Recommendations for Treatment,
Training and Privileging. American Psychiatric Association,
Washington, DC.
Caroff, S. N. (1980). The neuroleptic malignant syndrome. J. Clin.
Psychiatr. 41, 79–83.
Carroll, B. T., Anfinson, T. J., Kennedy, J. C., et al. (1994).
Catatonic disorder due to general medical conditions. J.
Neuropsychol. Clin. Neurosci. 6, 122–133.
Gelenberg, A. J. (1976). The catatonic syndrome. Lancet 1, 1339–
1341.
Krauthamer, C., and Klerman, G. L. (1978). Secondary mania:
Manic syndromes associated with antecedent physical illness or
drugs. Arch. Gen. Psychiatr. 35, 1333–1339.
Levenson, J. (1985). Neuroleptic malignant syndrome. Am. J.
Psychiatr. 142, 1137–1145.
Philbrick, K. L., and Rummans, T. A. (1994). Malignant catatonia.
J. Neuropsychiatr. Clin. Neurosci. 6, 1–13.
Stoudemire, A., and Luther, J. S. (1984). Neuroleptic
malignant syndrome and neuroleptic-induced catatonia:
Differential diagnosis and treatment. Int. J. Psychiatr. Med.
14, 57–63.
Taylor, M. A. (1990). Catatonia. A review of the behavioral
neurologic syndrome. Neuropsychiatr. Neuropsychol. Behav.
Neurol. 3, 48–72.
Catecholamines and Behavior
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CATECHOLAMINES dopamine (DA), norepineph-
rine (NE), and epinephrine are neurotransmitters
and/or hormones found in the central nervous system
(CNS) and in the periphery. They are produced from
the amino acid precursor tyrosine by a sequence of
enzymatic steps (Fig. 1). Dopamine serves as a
neurotransmitter in several important pathways in
the CNS. Norepinephrine cell bodies are found in the
lateral tegmental nuclei and locus ceruleus in the
brainstem and in postganglionic, sympathetic neu-
rons. Epinephrine is a hormone released from the
adrenal gland that stimulates catecholamine recep-
tors in a variety of peripheral organs. It is also found
in small amounts in the CNS, mostly in the
brainstem.
The enzymatic processes involved in the formation
of catecholamines have been characterized, with the
identification of tyrosine hydroxylase (TH) as the
rate-limiting enzyme in their biosynthesis (Fig. 1).
Tyrosine hydroxylase catalyzes the addition of a
hydroxyl group to the meta position of tyrosine, thus
forming 3,4-dihydroxy-l-phenylalanine (l-DOPA).
The removal of the carboxyl group from l-DOPA
by DOPA decarboxylase results in the formation of
dopamine. Dopamine is in turn converted to NE by
the addition of a hydroxyl group to the B carbon on
the side chain of DA. In cells that synthesize
epinephrine, the final step in the pathway is catalyzed
by the enzyme phenylethanolamine N-methyltrans-
ferase.
As neurotransmitters, catecholamines exert their
effect by being synthesized in presynaptic neurons
and then released from them to bind to receptors on
postsynaptic neurons, where they alter the mem-
brane potential. After being synthesized, they are
concentrated in storage vesicles that are present in a
high density within nerve terminals. The concentra-
tion of catecholamines within the vesicles is an ATP-
dependent process linked to a proton pump. The
release of catecholamines into the extra neuronal
space is dependent on fusion of vesicles with the
neuronal membrane. Finally, they are removed from
the synaptic site by various mechanisms, including
reuptake, biochemical inactivation, and diffusion.
Once catecholamines are released into the synaptic
space, their actions are terminated by transport
pumps located on the presynaptic neurons. The
524 CATECHOLAMINES AND BEHAVIOR
symptomatic treatment. Electroconvulsive therapy
(ECT) has been the most effective treatment for
catatonic syndrome. This modality should be used
only in treatment-refractory or life-threatening cases.
On the other hand, for functional lethal catatonia,
ECT may be the treatment of choice because
neuroleptics are likely to make it worse.
If catatonic symptoms appear or worsen shortly
after initiation of neuroleptic therapy, a neuroleptic-
induced catatonia should be presumed. To avert
potential pathological sequelae, the antipsychotic
drug should be discontinued immediately. Generally,
catatonic symptoms may persist for a few days after
neuroleptic withdrawal because of their long elim-
ination half-life. Usually, the symptoms resolve
within several days to a few weeks after drug
discontinuation.
—Jambur Ananth
See also–Antipsychotic Pharmacology; Bipolar
Disorders; Electroconvulsive Therapy; Mania;
Schizophrenia, Biology of; Stupor; Substance
Abuse
Acknowledgment
I thank Rajesh Devaraj for his help in preparing this entry.
Further Reading
American Psychiatric Association Task Force on Electro-
convulsive Therapy (1990). The Practice of Electro-
convulsive Therapy: Recommendations for Treatment,
Training and Privileging. American Psychiatric Association,
Washington, DC.
Caroff, S. N. (1980). The neuroleptic malignant syndrome. J. Clin.
Psychiatr. 41, 79–83.
Carroll, B. T., Anfinson, T. J., Kennedy, J. C., et al. (1994).
Catatonic disorder due to general medical conditions. J.
Neuropsychol. Clin. Neurosci. 6, 122–133.
Gelenberg, A. J. (1976). The catatonic syndrome. Lancet 1, 1339–
1341.
Krauthamer, C., and Klerman, G. L. (1978). Secondary mania:
Manic syndromes associated with antecedent physical illness or
drugs. Arch. Gen. Psychiatr. 35, 1333–1339.
Levenson, J. (1985). Neuroleptic malignant syndrome. Am. J.
Psychiatr. 142, 1137–1145.
Philbrick, K. L., and Rummans, T. A. (1994). Malignant catatonia.
J. Neuropsychiatr. Clin. Neurosci. 6, 1–13.
Stoudemire, A., and Luther, J. S. (1984). Neuroleptic
malignant syndrome and neuroleptic-induced catatonia:
Differential diagnosis and treatment. Int. J. Psychiatr. Med.
14, 57–63.
Taylor, M. A. (1990). Catatonia. A review of the behavioral
neurologic syndrome. Neuropsychiatr. Neuropsychol. Behav.
Neurol. 3, 48–72.
Catecholamines and Behavior
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CATECHOLAMINES dopamine (DA), norepineph-
rine (NE), and epinephrine are neurotransmitters
and/or hormones found in the central nervous system
(CNS) and in the periphery. They are produced from
the amino acid precursor tyrosine by a sequence of
enzymatic steps (Fig. 1). Dopamine serves as a
neurotransmitter in several important pathways in
the CNS. Norepinephrine cell bodies are found in the
lateral tegmental nuclei and locus ceruleus in the
brainstem and in postganglionic, sympathetic neu-
rons. Epinephrine is a hormone released from the
adrenal gland that stimulates catecholamine recep-
tors in a variety of peripheral organs. It is also found
in small amounts in the CNS, mostly in the
brainstem.
The enzymatic processes involved in the formation
of catecholamines have been characterized, with the
identification of tyrosine hydroxylase (TH) as the
rate-limiting enzyme in their biosynthesis (Fig. 1).
Tyrosine hydroxylase catalyzes the addition of a
hydroxyl group to the meta position of tyrosine, thus
forming 3,4-dihydroxy-l-phenylalanine (l-DOPA).
The removal of the carboxyl group from l-DOPA
by DOPA decarboxylase results in the formation of
dopamine. Dopamine is in turn converted to NE by
the addition of a hydroxyl group to the B carbon on
the side chain of DA. In cells that synthesize
epinephrine, the final step in the pathway is catalyzed
by the enzyme phenylethanolamine N-methyltrans-
ferase.
As neurotransmitters, catecholamines exert their
effect by being synthesized in presynaptic neurons
and then released from them to bind to receptors on
postsynaptic neurons, where they alter the mem-
brane potential. After being synthesized, they are
concentrated in storage vesicles that are present in a
high density within nerve terminals. The concentra-
tion of catecholamines within the vesicles is an ATP-
dependent process linked to a proton pump. The
release of catecholamines into the extra neuronal
space is dependent on fusion of vesicles with the
neuronal membrane. Finally, they are removed from
the synaptic site by various mechanisms, including
reuptake, biochemical inactivation, and diffusion.
Once catecholamines are released into the synaptic
space, their actions are terminated by transport
pumps located on the presynaptic neurons. The

Figure 1
The biosynthetic pathway for catecholamines (reproduced with
permission from Siegel et al., 1998, Basic Neurochemistry:
Molecular, Cellular and Medical Aspects, pp. 243–261.
Lippincott–Raven, Philadelphia).
transport pumps are highly selective, specific for one
catecholamine but not for any other neurotransmit-
ter. They are often referred to as ‘‘reuptake pumps.’’
For example, the NE reuptake pump terminates the
synaptic action of NE by removing NE from the
synapse and transporting it back into the presynaptic
nerve terminal. Once inside the nerve terminal, NE
can be either stored again in vesicles for later use or
destroyed by catecholamine-destroying enzymes.
CATECHOLAMINES AND BEHAVIOR 525
The two principal enzymes that act on catechola-
mines to turn them into inactive metabolites are
monoamine oxidase (MAO) and catechol-O-methyl-
transferase (COMT). MAO is located in mitochon-
dria in the presynaptic neuron and elsewhere and
deactivates by oxidatively deaminating catechola-
mines to their corresponding aldehydes. COMT, on
the other hand, is thought to be located largely
outside of the presynaptic nerve terminal and
deactivates by methylating the 3-hydroxyl group on
the catechol ring. Both the reuptake mechanism and
the catecholamine-inactivating enzymes are targets in
the treatment of depression and anxiety, where drugs
are designed to decrease or increase the concentra-
tion of catecholamines in the synaptic space.
Similarly, blockers of postsynaptic catecholamine
receptors are designed to reduce the synaptic action
of catecholamines at their specific receptors.
DOPAMINE HYPOTHESIS OF PSYCHOSIS
Psychosis is a difficult term to define concisely and is
often associated with negative connotations of being
crazy, violent, or deranged. With psychosis, a wide
range of symptoms are often present, including
delusions, hallucinations, disorganized speech, dis-
organized behavior, and gross distortion of reality
testing. In diagnostic classification systems such as
the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) and the International Classifi-
cation of Diseases (ICD-10), there are disorders that
have psychosis as a defining feature and others that
have psychosis as an associated feature.
Schizophrenia is the most common psychotic
illness with the presence of psychosis as a diagnostic
criteria. Schizophrenia includes a mixture of both
positive and negative symptoms. Although positive
symptoms imply an excess of functions, such as the
presence of delusions, hallucinations, and disorga-
nized speech or behavior, negative symptoms imply
diminution of functions with affective flattening and
loss of will or drive. It has been observed for more
than two decades that DA as a neurotransmitter in
the brain may play a role in the production of
positive psychotic symptoms. Both amphetamines
and cocaine, when used repetitively, release DA in
large amounts and can lead to psychotic symptoms.
On the other hand, antipsychotic drugs can be used
to treat or diminish positive psychotic symptoms and
are known to be blockers of postsynaptic DA
receptors.
526 CATECHOLAMINES AND BEHAVIOR
Dopamine is a neurotransmitter in four well-
defined neuronal pathways in the brain: the meso-
limbic pathway, from the ventral tegmental area
(VTA) to the nucleus accumbens; the nigrostriatal
pathway, from the substantia nigra pars compacta to
the striatum; the mesocortical pathway, from the
VTA to the cerebral cortex; and the tuberinfundib-
ular pathway, from the arcuate nucleus to the median
eminence. Of the four pathways, the mesolimbic
dopamine pathway is thought to control behaviors
and to produce psychotic symptoms when over-
active. Although drugs that block postsynaptic
dopaminergic receptors in this pathway diminish
psychotic symptoms, they also block dopaminergic
action in the nigrostriatal pathway that controls
movements. This can result in akathisia (a form of
restlessness), dystonia, tremor, rigidity, akinesia,
bradykinesia, and/or tardive dyskinesia.
In addition to its role in the production of
psychotic symptoms, DA has also been implicated
in some forms of depression and mania. Dopamine
receptor agonists have been reported to have some
antidepressant effects and a number of antidepressant
drugs also have DA agonist activities. In Parkinson’s
disease, in which DA is depleted, patients often
develop depression in association with the movement
disorder. In animal studies of depression, it has been
shown that a single unavoidable/uncontrollable
aversive experience leads to inhibition of DA release
in the accumbens as well as to impaired responding to
rewarding and aversive stimuli. Evidence linking DA
to mania includes observations that DA agonists can
produce behaviors that simulate mania, whereas DA
antagonists are useful treatment agents for mania.
Multiple problems exist, however, when postulating a
role for DA in the mood disorders. Most notably,
antipsychotic medications used to treat psychosis
block DA receptors but are not generally associated
with the production of depressive symptoms. Other
neurotransmitters, including NE and serotonin, have
been implicated in playing a primary role in mood
disorders.
MONOAMINE HYPOTHESIS
OF MOOD DISORDERS
Mood disorders, similar to psychosis, are best
considered as syndromes consisting of signs and
symptoms that include abnormal moods and related
psychomotor disturbances lasting a period of weeks
to months. Included in the spectrum of mood
disorders are major depressive disorder, bipolar
disorder, dysthymia, and cyclothymia. According
to the DSM-IV, a major depressive episode refers to
the presence of the following signs and symptoms:
depressed mood, anhedonia, guilt, psychomotor
retardation or agitation, recurrent thoughts of
death, and disturbances in weight, sleep, energy,
and concentration. On the contrary, a manic
episode refers to the presence of the following
symptoms: elevated or irritable mood, inflated
self-esteem, decreased sleep, pressured speech, flight
of ideas, distractibility, increase in goal-directed
activity, or excessive involvement in pleasurable
activities.
Initial work suggesting a relationship between
neurotransmitters in the etiology of depression
hypothesized that depression was due to an absolute
or relative decrease in catecholamines, particularly
NE, at central adrenergic receptor sites. Conversely,
it was theorized that mania is caused by a functional
excess of catecholamines at critical synapses in the
brain. As other biogenic amines in the brain have
also been linked to depression and mania, notably
serotonin and DA, this hypothesis has broadened to
become the monoamine hypothesis of mood dis-
orders. It was noted in the 1960s that drugs such as
reserpine that depleted presynaptic stores of NE,
5-HT, and DA could cause depression. Moreover,
observations that MAOIs inhibit the metabolism of
monoamines and that the tricyclic antidepressants
that block the reuptake of monoamines are effective
antidepressants led to the hypothesis that one of the
monoamines might be deficient in the underlying
abnormality in depression. Problems exist, however,
when pharmacological studies and cellular actions of
psychotropic drugs are used to infer the underlying
cause for depression. Attempts to correlate levels of
metabolites of monoamines in the cerebrospinal
fluid, blood, or urine with affective states have failed
to yield consistent results. Although certain drugs
(e.g., cocaine) that boost monoamines are not
antidepressants, others that fail to boost mono-
amines (e.g., mianserin) are antidepressants. Lastly,
a major difficulty with the monoamine hypothesis is
the significant delay in the onset of antidepressants’
therapeutic actions (often 2–6 weeks) compared to
their immediate cellular effect in boosting mono-
amine levels. Due to these and other difficulties, the
focus of hypotheses for the biological etiology of
mood disorders shifted from the neurotransmitters to
their receptors.
In the neurotransmitter receptor hypothesis of
depression, it is posited that an abnormality in the

functioning of receptors for monoamine neurotrans-
mitters leads to depression. Although the depletion
of monoamine neurotransmitters might be the
original disturbance, the result is the compensatory
upregulation of postsynaptic neurotransmitter recep-
tors. This upregulation is correlated with the
production of the depressive illness, although direct
evidence is generally lacking. Postmortem studies,
however, do show increased numbers of serotonin-2
receptors in the frontal cortex of patients who
commit suicide. Although indirect studies of neuro-
transmitter receptor function suggest abnormalities
in various neurotransmitter receptors rather than any
specific type, molecular techniques aimed at explor-
ing abnormalities in gene expression of receptors and
enzymes have yet to identify molecular lesions of
mood disorders. Interestingly, alterations in the levels
of tyrosine hydroxylase, the rate-limiting enzyme in
NA synthesis, have been found in the locus ceruleus
of suicide victims. In animal studies, chronic but not
acute treatment with antidepressants from each
major class results in a reduction in tyrosine
hydroxylase mRNA expression in rats. This evidence
suggests that, in addition to receptor blockade, the
site of action of antidepressants may occur at the
level of gene expression.
In summary, during the past few decades, attempts
to elucidate the pathophysiology underlying psychia-
tric disorders have implicated catecholamines as
playing a significant role in the neurobiology of
behavior. By understanding the synthesis, neuro-
transmission, and mechanisms of inactivation of the
catecholamines, effective pharmacological agents
have been specifically designed to affect their action
at the molecular level. Despite improved drug
treatment of psychiatric disorders, the complex
interactions between and the specific contribution
of the catecholamines, other neurotransmitters,
receptor systems, and the neuroendocrine system
remain to be determined. Continuous advances in
research methods, including gene mapping, molecu-
lar biology, and brain imaging techniques, will result
in further clarification in the near future.
—Nancy Sheng-Shih Wu
See also–Amphetamine Toxicity; Antipsychotic
Pharmacology; Behavior, Neural Basis of;
Behavior, Neuropathology of; Cocaine;
Depression; Dopamine; Mania; Mood Disorders,
Biology; Mood Stabilizer Pharmacology;
Neurotransmitters, Overview; Schizophrenia,
Biology of
CAUDA EQUINA 527
Further Reading
American Psychiatric Association (1996). Diagnostic and Statis-
tical Manual, 4th ed. American Psychiatric Association,
Washington, DC.
Cabib, S., and Puglisi-Allegra, S. (1996). Stress, depression and the
mesolimbic dopamine system. Psychopharmacology 128, 331–
342.
Kuhar, M. J., Couceyro, P. R., and Lambert, P. D. (1999).
Catecholamines. In Basic Neurochemistry: Molecular, Cellular
and Medical Aspects (G. J. Siegal, Ed.), pp. 243–261.
Lippincott–Raven, Philadelphia.
Redmond, A. M., and Leonard, B. E. (1997). An evaluation of the
role of the noradrenergic system in the neurobiology of
depression: A review. Hum. Psychopharmacol. 12, 407–430.
Schildkraut, J. J. (1965). The catecholamine hypothesis of affective
disorders: A review of supporting evidence. Am. J. Psychiatr.
122, 509–522.
Sian, J., Youdim, B. H., Riederer, P., et al. (1999). Neurotrans-
mitters and disorders of the basal ganglia. In Basic Neurochem-
istry: Molecular, Cellular and Medical Aspects (G. J. Siegal,
Ed.), pp. 917–947. Lippincott–Raven, Philadelphia.
Stahl, S. M. (1996). Essential Psychopharmacology. Cambridge
Univ. Press, Cambridge, UK.
Cauda Equina
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAUDA EQUINA includes the lumbosacral nerve
rootlets that leave the spinal cord near its terminus.
The rootlets leave the terminus in close succession
and pass vertically downward; their length increases
downward since the spinal cord ends opposite the
T12 or L1 vertebral bodies. The brain and cord and
cauda equina are bathed in cerebrospinal fluid that
fills the subarachnoid space. Renaissance anatomists
likened the multiple nerve rootlets emanating from
the spinal cord to a ‘‘horse’s tail,’’ thus the cauda
equina nomenclature that has persisted for more than
four centuries. The spinal cord in turn is tethered to
the spinal dura by pial extensions from the cord
known as dentate ligaments. These ligaments pass
through the cerebrospinal fluid-filled subarachnoid
compartment and the arachnoid before inserting into
the dural sac. The extensions of the cord pia mater
that descends caudally to attach or tether the distal
cord to the lowest sacrococcygeal segment of the
dural sac are known as the filum terminale. The filum
terminale is not a functioning neural tissue and
therefore is not part of the cauda equina, but it
travels caudally with the cauda equina rootlets and is
imaged whenever the cauda equina is studied radio-
graphically. Blood supply to the cauda equina is
derived from the ventral spinal cord artery and the

functioning of receptors for monoamine neurotrans-
mitters leads to depression. Although the depletion
of monoamine neurotransmitters might be the
original disturbance, the result is the compensatory
upregulation of postsynaptic neurotransmitter recep-
tors. This upregulation is correlated with the
production of the depressive illness, although direct
evidence is generally lacking. Postmortem studies,
however, do show increased numbers of serotonin-2
receptors in the frontal cortex of patients who
commit suicide. Although indirect studies of neuro-
transmitter receptor function suggest abnormalities
in various neurotransmitter receptors rather than any
specific type, molecular techniques aimed at explor-
ing abnormalities in gene expression of receptors and
enzymes have yet to identify molecular lesions of
mood disorders. Interestingly, alterations in the levels
of tyrosine hydroxylase, the rate-limiting enzyme in
NA synthesis, have been found in the locus ceruleus
of suicide victims. In animal studies, chronic but not
acute treatment with antidepressants from each
major class results in a reduction in tyrosine
hydroxylase mRNA expression in rats. This evidence
suggests that, in addition to receptor blockade, the
site of action of antidepressants may occur at the
level of gene expression.
In summary, during the past few decades, attempts
to elucidate the pathophysiology underlying psychia-
tric disorders have implicated catecholamines as
playing a significant role in the neurobiology of
behavior. By understanding the synthesis, neuro-
transmission, and mechanisms of inactivation of the
catecholamines, effective pharmacological agents
have been specifically designed to affect their action
at the molecular level. Despite improved drug
treatment of psychiatric disorders, the complex
interactions between and the specific contribution
of the catecholamines, other neurotransmitters,
receptor systems, and the neuroendocrine system
remain to be determined. Continuous advances in
research methods, including gene mapping, molecu-
lar biology, and brain imaging techniques, will result
in further clarification in the near future.
—Nancy Sheng-Shih Wu
See also–Amphetamine Toxicity; Antipsychotic
Pharmacology; Behavior, Neural Basis of;
Behavior, Neuropathology of; Cocaine;
Depression; Dopamine; Mania; Mood Disorders,
Biology; Mood Stabilizer Pharmacology;
Neurotransmitters, Overview; Schizophrenia,
Biology of
CAUDA EQUINA 527
Further Reading
American Psychiatric Association (1996). Diagnostic and Statis-
tical Manual, 4th ed. American Psychiatric Association,
Washington, DC.
Cabib, S., and Puglisi-Allegra, S. (1996). Stress, depression and the
mesolimbic dopamine system. Psychopharmacology 128, 331–
342.
Kuhar, M. J., Couceyro, P. R., and Lambert, P. D. (1999).
Catecholamines. In Basic Neurochemistry: Molecular, Cellular
and Medical Aspects (G. J. Siegal, Ed.), pp. 243–261.
Lippincott–Raven, Philadelphia.
Redmond, A. M., and Leonard, B. E. (1997). An evaluation of the
role of the noradrenergic system in the neurobiology of
depression: A review. Hum. Psychopharmacol. 12, 407–430.
Schildkraut, J. J. (1965). The catecholamine hypothesis of affective
disorders: A review of supporting evidence. Am. J. Psychiatr.
122, 509–522.
Sian, J., Youdim, B. H., Riederer, P., et al. (1999). Neurotrans-
mitters and disorders of the basal ganglia. In Basic Neurochem-
istry: Molecular, Cellular and Medical Aspects (G. J. Siegal,
Ed.), pp. 917–947. Lippincott–Raven, Philadelphia.
Stahl, S. M. (1996). Essential Psychopharmacology. Cambridge
Univ. Press, Cambridge, UK.
Cauda Equina
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAUDA EQUINA includes the lumbosacral nerve
rootlets that leave the spinal cord near its terminus.
The rootlets leave the terminus in close succession
and pass vertically downward; their length increases
downward since the spinal cord ends opposite the
T12 or L1 vertebral bodies. The brain and cord and
cauda equina are bathed in cerebrospinal fluid that
fills the subarachnoid space. Renaissance anatomists
likened the multiple nerve rootlets emanating from
the spinal cord to a ‘‘horse’s tail,’’ thus the cauda
equina nomenclature that has persisted for more than
four centuries. The spinal cord in turn is tethered to
the spinal dura by pial extensions from the cord
known as dentate ligaments. These ligaments pass
through the cerebrospinal fluid-filled subarachnoid
compartment and the arachnoid before inserting into
the dural sac. The extensions of the cord pia mater
that descends caudally to attach or tether the distal
cord to the lowest sacrococcygeal segment of the
dural sac are known as the filum terminale. The filum
terminale is not a functioning neural tissue and
therefore is not part of the cauda equina, but it
travels caudally with the cauda equina rootlets and is
imaged whenever the cauda equina is studied radio-
graphically. Blood supply to the cauda equina is
derived from the ventral spinal cord artery and the
528 CAUDA EQUINA SYNDROME AND NEUROGENIC CLAUDICATION
posterior spinal column arcade, whose major blood
supply enters the thoracolumbar canal via the artery
magna of Adamkiewicz through a single foramen
that varies in different individuals and is most com-
monly between the T10 and usually on the left side.
Disorders of the cauda equina are classified as
developmental, postinfectious, posttraumatic, and
tumorous. Developmental delay closure of the neural
tube results in paraplegia due to failure of the cauda
equina to innervate the lumbosacral segments of the
body. In less extreme cases, the spinal cord terminus
and the cauda equina are tethered down by a short,
stubby filum terminale leading to chronic neurologi-
cal sequelae as the child grows into adulthood.
Postinfectious (bacterial, viral, or chemical) adhe-
sions may result in clumping of the nerve rootlets and
major progressive motor and sensory deficits, includ-
ing lower sacral nerve root dysfunction with bowel
and bladder paresis. A clumping of the rootlets in
this fashion is clinically referred to as arachnoiditis.
Other leading causes of arachnoiditis occur after
major vertebral trauma or a not uncommon sequelae
of multiple surgeries performed on the degenerative
lumbar spine. Tumors are relatively rare (o2 per
100,000 people per year), with the most common
being schwannoma. Tumors of the nonneural tissue
account for the other common lesion found in this
location, the myxopapillary ependymoma of the
filum terminale. Meningiomas, which grow from
the arachnoid cells and are usually attached to the
dura matter, are the least common tumors in this
location. Metastatic drop deposits from central
nervous system tumors higher up in the neuraxis
can grow within the cauda equina rootlets and rarely
cancerous tumors may metastasize to the cauda
equina from outside of the central nervous system.
—Michael H. Lavyne
See also–Arachnoiditis; Cauda Equina Syndrome
and Neurogenic Claudication; Leptomeninges:
Arachnoid and Pia; Spinal Cord Anatomy; Spinal
Roots
Cauda Equina Syndrome and
Neurogenic Claudication
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN HUMANS, the spinal cord ends at the level of L1–
L2, at which point the spinal cord divides into the
nerve roots of the lumbosacral spine. These nerve
rootlets are abundant in number and fan out in such
a way as to appear grossly as a horse’s tail, hence the
Latin name cauda equina. Compression of the
lumbosacral nerve roots from disorders such as
lumbar stenosis, herniated disk material, tumors,
and trauma can lead to neurogenic claudication,
cauda equina syndrome, or both. The signs and
symptoms of these two entities are related.
Patients with neurogenic claudication primarily
complain of pain radiating down the legs as well as
weakness, numbness, and tingling in the lower
extremities. Since pain is such a dominant compo-
nent of neurogenic claudication, this syndrome must
be distinguished from vascular claudication, which
can manifest with similar complaints in a similar
subset of patients. Vascular claudication differs from
neurogenic claudication in several ways. Neurogenic
claudication occurs with little or no exercise and, in
some cases, with just standing. In contrast, vascular
claudication typically requires some exertion on the
part of the patient to stress the blood supply to the
musculature of the lower extremities. One of the key
differences between the conditions is that standing
and resting fail to relieve leg pain in neurogenic
claudicators, whereas cessation of activity, regardless
of posture or position, relieves the pain in the
vascular group. Furthermore, the character of the
pain may be described differently, with vascular
claudication manifesting as a dull ache in a calf
muscle, for example, whereas neurogenic claudica-
tors may describe more of a radicular pain radiating
from the back or buttocks down the leg and into the
calf or foot.
Other clinical findings further help to distinguish
these two entities. Due to the poor circulation in the
lower extremities associated with vascular claudica-
tion, the feet are cool to the touch and pedal pulses
are weak or absent. Other findings include smooth
skin and a paucity of hair on the lower legs. Venous
stasis and atrophic skin may also be associated with
vascular claudication. Noninvasive testing includes
measurement of the ankle–brachial index, a ratio of
blood pressure in the upper extremity compared to
the lower extremity. In most cases, patients will be
worked up with a radiographic imaging study of the
lumbar spine. Other tests for nerve root compression
(neurogenic claudication) include electromyography
and nerve conduction velocity studies.
The etiology of the pain syndrome in neurogenic
claudication is unclear. Three primary explanations
are currently proposed as the cause of the pain. One
528 CAUDA EQUINA SYNDROME AND NEUROGENIC CLAUDICATION
posterior spinal column arcade, whose major blood
supply enters the thoracolumbar canal via the artery
magna of Adamkiewicz through a single foramen
that varies in different individuals and is most com-
monly between the T10 and usually on the left side.
Disorders of the cauda equina are classified as
developmental, postinfectious, posttraumatic, and
tumorous. Developmental delay closure of the neural
tube results in paraplegia due to failure of the cauda
equina to innervate the lumbosacral segments of the
body. In less extreme cases, the spinal cord terminus
and the cauda equina are tethered down by a short,
stubby filum terminale leading to chronic neurologi-
cal sequelae as the child grows into adulthood.
Postinfectious (bacterial, viral, or chemical) adhe-
sions may result in clumping of the nerve rootlets and
major progressive motor and sensory deficits, includ-
ing lower sacral nerve root dysfunction with bowel
and bladder paresis. A clumping of the rootlets in
this fashion is clinically referred to as arachnoiditis.
Other leading causes of arachnoiditis occur after
major vertebral trauma or a not uncommon sequelae
of multiple surgeries performed on the degenerative
lumbar spine. Tumors are relatively rare (o2 per
100,000 people per year), with the most common
being schwannoma. Tumors of the nonneural tissue
account for the other common lesion found in this
location, the myxopapillary ependymoma of the
filum terminale. Meningiomas, which grow from
the arachnoid cells and are usually attached to the
dura matter, are the least common tumors in this
location. Metastatic drop deposits from central
nervous system tumors higher up in the neuraxis
can grow within the cauda equina rootlets and rarely
cancerous tumors may metastasize to the cauda
equina from outside of the central nervous system.
—Michael H. Lavyne
See also–Arachnoiditis; Cauda Equina Syndrome
and Neurogenic Claudication; Leptomeninges:
Arachnoid and Pia; Spinal Cord Anatomy; Spinal
Roots
Cauda Equina Syndrome and
Neurogenic Claudication
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN HUMANS, the spinal cord ends at the level of L1–
L2, at which point the spinal cord divides into the
nerve roots of the lumbosacral spine. These nerve
rootlets are abundant in number and fan out in such
a way as to appear grossly as a horse’s tail, hence the
Latin name cauda equina. Compression of the
lumbosacral nerve roots from disorders such as
lumbar stenosis, herniated disk material, tumors,
and trauma can lead to neurogenic claudication,
cauda equina syndrome, or both. The signs and
symptoms of these two entities are related.
Patients with neurogenic claudication primarily
complain of pain radiating down the legs as well as
weakness, numbness, and tingling in the lower
extremities. Since pain is such a dominant compo-
nent of neurogenic claudication, this syndrome must
be distinguished from vascular claudication, which
can manifest with similar complaints in a similar
subset of patients. Vascular claudication differs from
neurogenic claudication in several ways. Neurogenic
claudication occurs with little or no exercise and, in
some cases, with just standing. In contrast, vascular
claudication typically requires some exertion on the
part of the patient to stress the blood supply to the
musculature of the lower extremities. One of the key
differences between the conditions is that standing
and resting fail to relieve leg pain in neurogenic
claudicators, whereas cessation of activity, regardless
of posture or position, relieves the pain in the
vascular group. Furthermore, the character of the
pain may be described differently, with vascular
claudication manifesting as a dull ache in a calf
muscle, for example, whereas neurogenic claudica-
tors may describe more of a radicular pain radiating
from the back or buttocks down the leg and into the
calf or foot.
Other clinical findings further help to distinguish
these two entities. Due to the poor circulation in the
lower extremities associated with vascular claudica-
tion, the feet are cool to the touch and pedal pulses
are weak or absent. Other findings include smooth
skin and a paucity of hair on the lower legs. Venous
stasis and atrophic skin may also be associated with
vascular claudication. Noninvasive testing includes
measurement of the ankle–brachial index, a ratio of
blood pressure in the upper extremity compared to
the lower extremity. In most cases, patients will be
worked up with a radiographic imaging study of the
lumbar spine. Other tests for nerve root compression
(neurogenic claudication) include electromyography
and nerve conduction velocity studies.
The etiology of the pain syndrome in neurogenic
claudication is unclear. Three primary explanations
are currently proposed as the cause of the pain. One

theory attributes the pain to the direct compressive
forces on the nerves, particularly in the lateral
recesses and foramina of the lumbar spinal canal,
where the nerves exit. Another possibility is that the
blood supply to the nerve root is compromised as a
result of the compression, leading to nerve pain
similar to the muscular pain of vascular claudication.
The final theory attributes the pain to a lack of nerve
root nutrition resulting from stenosis-induced stag-
nation of cerebrospinal fluid.
Cauda equina syndrome is also caused by com-
pression of the lumbar nerve roots, but it is less
related to lumbar stenosis than neurogenic claudica-
tion. Patients with cauda equina syndrome usually
complain of numbness in the buttocks (saddle
anesthesia), urinary and bowel sphincter dysfunc-
tion, severe bilateral sciatic pain, and significant
bilateral weakness, especially below the knees.
Sensory deficits may be present and tend to be
asymmetric. The legs may be numb and this sensory
change is usually asymmetric. The bowel and bladder
dysfunction results from compression of the sacral
nerve roots that innervate the perineum. Conse-
quently, erectile dysfunction, although uncommon,
has been described. Cauda equina syndrome is a
medical emergency, and the nerve roots must be
decompressed as soon as possible to obtain the best
outcome. Pain and numbness are usually the initial
constellation of complaints, but symptoms can
progress rapidly to include the bowel and bladder.
Some patients may not regain bowel or bladder
control despite aggressive surgical management.
Broad-based disk herniations or large free disk
fragments tend to be the cause of cauda equina
syndrome. A combination of disk herniation exacer-
bated by lumbar stenosis may also be present.
In both diseases, magnetic resonance imaging
(MRI) helps identify the source of the nerve
compression. In the case of neurogenic claudication,
the most common finding is multilevel lumbar
stenosis. In the case of cauda equina syndrome,
lumbar stenosis, a herniated lumbar disk, or both
may underlie the findings. Furthermore, tumors of
the conus medullaris, such as meningiomas and
ependymomas, can also manifest with symptoms of
the cauda equina syndrome. To eliminate artifact on
MRI, patients who have undergone prior lumbar
spine surgery and had metal hardware implanted
may be imaged best with computed tomography–
myelography.
Patients with neurogenic claudication as a result of
lumbar stenosis tend to fare well with lumbar
CAUDATE NUCLEUS 529
laminectomy. Many long-term follow-up studies
have been performed on cohorts of patients treated
with lumbar laminectomy and the results are
encouraging. Approximately 70% of patients report
that their symptoms improve after surgery. Patients
who demonstrate spondylolisthesis (i.e., slipping of
one vertebral body onto another) may also benefit
from a fusion procedure during laminectomy.
Several studies have reported favorable outcomes
from the surgical treatment of the cauda equina
syndrome as well. Full recovery of motor and
sphincter function can require more than 1 year.
Persistent bowel and bladder dysfunction is a
devastating complication and indicates the need
for emergent decompression. The early identification
of patients with this syndrome cannot be over-
emphasized; consequently, emergency room and
primary care physicians must be aware of this
entity.
—Mark S. Gerber and Volker K. H. Sonntag
See also–Cauda Equina; Radiculopathy,
Lumbosacral; Stenosis, Lumbar
Further Reading
Clark, K. (1969). Significance of the small lumbar spinal canal:
Cauda equina compression syndromes due to spondylosis. 2:
Clinical and surgical significance. J. Neurosurg. 31, 495–498.
Ehni, G. (1969). Significance of the small lumbar spinal canal:
Cauda equina compression syndromes due to spondylosis. 1:
Introduction. J. Neurosurg. 31, 490–494.
Shapiro, S. (1993). Cauda equina syndrome secondary to lumbar
disc herniation. Neurosurgery 32, 743–747.
Wilson, C. B. (1969). Significance of the small lumbar spinal canal:
Cauda equina compression syndromes due to spondylosis. 3:
Intermittent claudication. J. Neurosurg. 31, 499–596.
Caudate Nucleus
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAUDATE is a large bilateral group of neurons
forming one of the nuclei of the deep basal ganglia
group. In conjunction with the putamen, located
laterally and below the caudate, both neuronal
groups are sometimes referred to as the striated
body or corpus striatum. The caudate lies contiguous
to the ventricular system containing cerebrospinal
fluid. The large caudate head indents medially into
the anterior horns of the lateral ventricles. The

theory attributes the pain to the direct compressive
forces on the nerves, particularly in the lateral
recesses and foramina of the lumbar spinal canal,
where the nerves exit. Another possibility is that the
blood supply to the nerve root is compromised as a
result of the compression, leading to nerve pain
similar to the muscular pain of vascular claudication.
The final theory attributes the pain to a lack of nerve
root nutrition resulting from stenosis-induced stag-
nation of cerebrospinal fluid.
Cauda equina syndrome is also caused by com-
pression of the lumbar nerve roots, but it is less
related to lumbar stenosis than neurogenic claudica-
tion. Patients with cauda equina syndrome usually
complain of numbness in the buttocks (saddle
anesthesia), urinary and bowel sphincter dysfunc-
tion, severe bilateral sciatic pain, and significant
bilateral weakness, especially below the knees.
Sensory deficits may be present and tend to be
asymmetric. The legs may be numb and this sensory
change is usually asymmetric. The bowel and bladder
dysfunction results from compression of the sacral
nerve roots that innervate the perineum. Conse-
quently, erectile dysfunction, although uncommon,
has been described. Cauda equina syndrome is a
medical emergency, and the nerve roots must be
decompressed as soon as possible to obtain the best
outcome. Pain and numbness are usually the initial
constellation of complaints, but symptoms can
progress rapidly to include the bowel and bladder.
Some patients may not regain bowel or bladder
control despite aggressive surgical management.
Broad-based disk herniations or large free disk
fragments tend to be the cause of cauda equina
syndrome. A combination of disk herniation exacer-
bated by lumbar stenosis may also be present.
In both diseases, magnetic resonance imaging
(MRI) helps identify the source of the nerve
compression. In the case of neurogenic claudication,
the most common finding is multilevel lumbar
stenosis. In the case of cauda equina syndrome,
lumbar stenosis, a herniated lumbar disk, or both
may underlie the findings. Furthermore, tumors of
the conus medullaris, such as meningiomas and
ependymomas, can also manifest with symptoms of
the cauda equina syndrome. To eliminate artifact on
MRI, patients who have undergone prior lumbar
spine surgery and had metal hardware implanted
may be imaged best with computed tomography–
myelography.
Patients with neurogenic claudication as a result of
lumbar stenosis tend to fare well with lumbar
CAUDATE NUCLEUS 529
laminectomy. Many long-term follow-up studies
have been performed on cohorts of patients treated
with lumbar laminectomy and the results are
encouraging. Approximately 70% of patients report
that their symptoms improve after surgery. Patients
who demonstrate spondylolisthesis (i.e., slipping of
one vertebral body onto another) may also benefit
from a fusion procedure during laminectomy.
Several studies have reported favorable outcomes
from the surgical treatment of the cauda equina
syndrome as well. Full recovery of motor and
sphincter function can require more than 1 year.
Persistent bowel and bladder dysfunction is a
devastating complication and indicates the need
for emergent decompression. The early identification
of patients with this syndrome cannot be over-
emphasized; consequently, emergency room and
primary care physicians must be aware of this
entity.
—Mark S. Gerber and Volker K. H. Sonntag
See also–Cauda Equina; Radiculopathy,
Lumbosacral; Stenosis, Lumbar
Further Reading
Clark, K. (1969). Significance of the small lumbar spinal canal:
Cauda equina compression syndromes due to spondylosis. 2:
Clinical and surgical significance. J. Neurosurg. 31, 495–498.
Ehni, G. (1969). Significance of the small lumbar spinal canal:
Cauda equina compression syndromes due to spondylosis. 1:
Introduction. J. Neurosurg. 31, 490–494.
Shapiro, S. (1993). Cauda equina syndrome secondary to lumbar
disc herniation. Neurosurgery 32, 743–747.
Wilson, C. B. (1969). Significance of the small lumbar spinal canal:
Cauda equina compression syndromes due to spondylosis. 3:
Intermittent claudication. J. Neurosurg. 31, 499–596.
Caudate Nucleus
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAUDATE is a large bilateral group of neurons
forming one of the nuclei of the deep basal ganglia
group. In conjunction with the putamen, located
laterally and below the caudate, both neuronal
groups are sometimes referred to as the striated
body or corpus striatum. The caudate lies contiguous
to the ventricular system containing cerebrospinal
fluid. The large caudate head indents medially into
the anterior horns of the lateral ventricles. The
530 CAUDATE NUCLEUS
protrusion makes the caudate head clearly evident on
brain imaging scans from computed tomography
(CT) or magnetic resonance imaging. The body of
the caudate extends backwards, parallel to the lateral
ventricles forming its inferolateral wall. The tail of
the caudate curves laterally and forward, terminating
adjacent to the amygdaloid nuclei, ahead of the
temporal horn of the lateral ventricles. The lower
anterior region of the caudate is fused with a portion
of the putamen, and this area is called the septal
acumbens.
The basal ganglia receive their arterial supply from
the lenticular-striate vessels that arise early from the
middle cerebral arteries and perforate upward into
the brain substance to reach those structures. The
head of the caudate is supplied by a similar
perforating vessel, the recurrent artery of Hübner,
which arises instead from the anterior cerebral artery.
The basal ganglia nuclei are particularly susceptible
to two types of strokes: hypertensive intracerebral
hemorrhages and small ischemic strokes referred to
as lacunes, so named because their oblong shape
resembles small lakes.
NEURONAL ORGANIZATION AND
MAIN NEUROTRANSMITTERS
Neurons forming the caudate and putamen are
distributed in two main groups; approximately
80% are medium-sized spiny neurons localized at
the matrix, and 20% form patches called striato-
somes. A significant number of both neuronal groups
produce the inhibitory neurotransmitter g-aminobu-
tyric acid (GABA). Some caudate neurons also
produce substance P and opioid peptides, and other
large excitatory neurons contain acetylcholine.
The majority of matrix neurons have D2 dopa-
mine receptors on their surface, whereas the striato-
some neurons have D1 dopamine receptors. The D2
receptors are several times more sensitive to dopa-
mine than are the D1 receptors. Whereas dopamine
acts on D2 receptors to produce a net inhibitory
influence on GABA release, dopamine is excitatory to
D1 receptors.
EXCITATORY CONNECTIONS
TO THE CAUDATE
The striate structures receive widespread excitatory
connections arising from smaller pyramidal neurons
at the third and fifth cortical layers and from
thalamic parafascicular and intralaminar neurons
involved in attentional arousal. Cortical neuronal
connections to the caudate use glutamate as the
excitatory neurotransmitter. The head of the caudate
receives specific connections from the dorsolateral
and orbitofrontal prefrontal cortex. The body of the
caudate and putamen also receive connections from
the parietal cortical association areas where sensory–
visual–spatial processing takes place. The inferolat-
eral limbic amygdala sends fibers to the lower medial
caudate and to the low posterior putamen. The
temporal limbic amygdala processes memory and
emotionally relevant information.
INHIBITORY BRAINSTEM CONNECTIONS TO
THE CAUDATE
The brainstem substantia nigra compacta neurons
project approximately two-thirds of their fibers to
the head of the caudate nucleus and use dopamine as
the inhibitory neurotransmitter modulating the
caudate output. The posterior midline (dorsomedian)
brainstem raphe neurons project fibers to the lower
posterior portions of the caudate as well as to
substantia nigra neurons at the midbrain. The raphe
neurons produce the neurotransmitter serotonin
(Fig. 1). Stimulation of the posterior midline raphe
produces long-lasting inhibition of caudate neurons.
Therefore, although the preponderant functional
nature of the caudate nucleus is an inhibitory
restraint on the globus pallidus, the substantia nigra
and the midline raphe exert a net facilatory effect.
CAUDATE OUTFLOW CONNECTIONS AND
MOTOR FEEDBACK LOOPS
At least two outflow pathways form parallel circuit
loops for functional motor feedback control. One is
referred to as the direct motor loop or the
striatonigral pathway. It connects the excitatory
cortical neurons to the caudate–putaminal striato-
somes that express D1 dopamine receptors and
transmit GABA, substance P, and opioid dynorphin.
In turn, they inhibit the medial globus pallidus
(GPm) and the reticular substantia nigra (SNr)
located at the midbrain. The inhibited SNr neurons
decrease inhibition on the ventrolateral (VL) nuclei
of the thalamus (main cerebral sensory input
structure). The uninhibited thalamic nuclei then
increase excitatory glutamic transmission back to
the cerebral cortex. According to Young and Penny,
this loop is used to sustain or enhance ongoing motor
patterns.

Figure 1
Coronal view of the brain illustrating the main excitatory ( þ ) and
inhibitory (
) connections acting on the caudate nucleus. The
cortical neurons exert their excitatory action through the
neurotransmitter glutamate. Some thalamic excitatory neurons
may also use glutamate, but other unidentified neurotransmitters
could also be involved. The main inhibitory-modulating
neurotransmitters acting on the caudate are dopamine, which
arises preponderantly from the midbrain substantia nigra, and
serotonin, arising from dorsal brainstem midline raphe neurons.
The caudate neuronal outflow connections form part of at least
two parallel complex motor feedback loops, briefly discussed in
the text but not shown here [from Rees, G. (1999). Attentional
suppression in human extrastriate cortex. Trends Cog. Sci. 3, 46].
The second motor pathway is referred to as the
indirect loop or the striatopallidal pathway. Excita-
tory cortical neurons connect to caudate–putaminal
matrix neurons that express D2 dopamine receptors
and transmit GABA and the opioid peptide enke-
phalin. They in turn inhibit the lateral globus
pallidus neurons, which then stop inhibiting the
subthalamic nucleus. This structure can then excite
the GPm and the SNr. In turn, both GPm and SNr
strongly inhibit the VL thalamic nucleus, which then
decreases excitatory input back to the cortex
CAUDATE NUCLEUS 531
neurons. Most likely, this circuit loop is used to
suppress unwanted motor patterns.
These simplified feedback loop models help
explain how selective damage to different structures
within those circuits produce opposite clinical
symptoms such as bradykinetic slowness in Parkin-
son’s disease and hyperkinetic chorea in Hunting-
ton’s disease.
METABOLIC PROPERTIES AND
DISEASE SUSCEPTIBILITIES
Neuronal activity at the basal ganglia relies heavily
on oxidative metabolic reactions. Electron transfers
take place within neuronal mitochondria by means
of oxidative cytochrome enzyme chains. Basal gang-
lia neurons are quite susceptible to acute carbon
monoxide, methanol (wood alcohol) or cyanide
poisoning, and chronic organic methylated mercury,
manganese, copper, or iron toxicity.
These neurons are also vulnerable to inborn errors
such as in Wilson’s disease, in which a genetic defect
at chromosome 13 leads to low serum copper
ceruloplasmin and ATPase–ATP7b cellular transport,
causing excessive accumulation of copper in the
basal ganglia, eyes, and liver. Huntington’s chorea, a
dominant genetic disease with excessive repeats
(435) of the trinucleotide cytosine–adenine–gua-
nine, shows progressively severe atrophy of the
caudate nuclei. It has been postulated that excessive
caudate neuronal sensitivity to the neurotoxic effect
of the excitatory neurotransmitter glutamate may be
the cause of the profound focal atrophy.
COGNITIVE DEFICITS OF BILATERAL
CAUDATE ATROPHY
Neuropsychological tests performed on patients with
disorders that preferentially affect the caudate nuclei,
such as Huntington’s disease, have shown similar
deficits to those produced by frontal lobe lesions.
Even in early stages, these individuals are unable to
shift attention to new concepts as task requirement
changes (i.e., shift attentional set). They also exhibit
semantic fluency limitations, poor personal spatial
orientation on map planning, and impaired learning
of rotary-pursuit procedural tasks.
Strong correlations link cognitive test scores with
caudate size atrophy measured by CT and with
reduction of caudate glucose metabolic rate as
measured by positron emission tomography. These
findings further support the notion that the caudate
532 CAVERNOUS MALFORMATIONS
nuclei play a critical role in performing adaptive
cognitive tasks.
HISTORICAL SURGICAL LESIONS
OF THE CAUDATE
Unilateral extirpation of the caudate nucleus head by
Russell Myers in 1939 was the first successful basal
ganglia operation to relieve contralateral hemi-
Parkinson’s. The use of a stereotactic apparatus for
precise deep brain localizations began in the 1950s.
By 1970, the new levodopa treatment became
dominant and surgical approaches waned. In 1987,
Madrazo et al. reported that Parkinson’s patients
improved notably after having their own extirpated
adrenal gland tissue reimplanted surgically into an
open pocket incision at the caudate. This experi-
mental approach triggered renewed worldwide inter-
est in neurosurgical approaches to alleviate
movement disorders.
—Enrique L. Labadie
See also–Basal Ganglia; Basal Ganglia, Diseases
of; Brain Anatomy; Huntington’s Disease;
Neurotransmitters, Overview; Parkinson’s
Disease; Wilson’s Disease
Further Reading
Carpenter, M. B. (1991). Core Text of Neuroanatomy, 4th ed.
Williams & Wilkins, Baltimore. [See Chapters 1 and 9.]
Dubois, B., and Pillon, B. (1998). Cognitive and behavioural
aspects of movement disorders. In Parkinson’s Disease and
Movement Disorders (J. Jankovic and E. Tolosa, Eds.), 3rd ed.,
pp. 837–855. Williams & Wilkins, Baltimore.
Lange, K. W., Sahakian, B. J., Quinn, N. P., et al. (1995).
Comparison of executive and visuospatial memory functions in
Huntington’s disease and dementia of Alzheimer’s type J.
Neural. Neurosurg. Psychiatr. 58, 598–606.
Lawrence, A. D., Hodges, J. R., Rosser, A. E., et al. (1998).
Evidence for specific cognitive deficits in preclinical Hunting-
ton’s disease. Brain 121, 1329–1341.
Parent, A., and Hazrati, L. N. (1995). Functional anatomy of the
basal-ganglia: 1. The cortico-basal-ganglia-thalamo-cortical-
loop. Brain Res. Rev. 20, 91–127.
Parent, A., and Hazrati, L. N. (1995). The functional anatomy of
the basal ganglia: 2. The role of subthalamic nucleus and
external pallidum in basal ganglia circuitry. Brain Res. Rev. 20,
128–154.
Sprengehneyer, R., Lange, H., and Homberg, V. (1995). The
pattern of attentional deficits in Huntington’s disease. Brain
118, 145–152.
Young, A. B., and Penney, J. B. (1998). Biochemical and functional
organization of the basal ganglia. In Parkinson’s Disease and
Movement Disorders (J. Jankovic and E. Tolosa, Eds.), 3rd ed.,
pp. 1–13, 341–355. Williams & Wilkins, Baltimore.
Cavernous Malformations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CAVERNOUS MALFORMATIONS account for 5–10%
of all central nervous system (CNS) vascular mal-
formations. In surgical series they are the second
most common vascular malformation responsible for
hemorrhage, outnumbered only by arteriovenous
malformations (AVMs). They occur throughout the
CNS in approximate relationship to the volume of
the various compartments: 70–80% supratentorially,
10–20% in the posterior fossa, and 5–10% in the
spine.
Advances in neuroimaging and molecular genetics
have improved our understanding of cavernous
malformations, whereas the adoption of new surgical
techniques and the development of frameless stereo-
tactic systems have changed our approach to their
management. This entry examines the epidemiology,
natural history, and indications for surgical treat-
ment of these lesions.
PATHOLOGY
Macroscopically, cavernous malformations are well-
defined, dark red or purple, mulberry-like masses
that range in diameter from a few millimeters to
several centimeters. Hemosiderin from recurrent
episodes of focal hemorrhage and thrombosis accu-
mulates by diapedesis in macrophages and glia
around the lesions, producing a characteristic brown
or dark yellow stain that surrounds the mass (Fig. 1).
Histologically, cavernous malformations are com-
posed of markedly dilated vascular channels (ca-
verns) with thin walls devoid of elastin and smooth
muscle and lined by a single layer of vascular
endothelium (Fig. 2). The channels are separated by
dense fibrous tissue with little or no intervening
neural parenchyma except perhaps at the periphery.
These dilated capillary channels contain blood and/
or thrombi of various ages and degrees of organiza-
tion. Small focal areas of calcification are common
and may be visualized on computerized tomography
(CT).
EPIDEMIOLOGY
Once considered relatively rare, cavernous malfor-
mations are recognized with increasing frequency. In
postmortem studies, cavernous malformations affect
532 CAVERNOUS MALFORMATIONS
nuclei play a critical role in performing adaptive
cognitive tasks.
HISTORICAL SURGICAL LESIONS
OF THE CAUDATE
Unilateral extirpation of the caudate nucleus head by
Russell Myers in 1939 was the first successful basal
ganglia operation to relieve contralateral hemi-
Parkinson’s. The use of a stereotactic apparatus for
precise deep brain localizations began in the 1950s.
By 1970, the new levodopa treatment became
dominant and surgical approaches waned. In 1987,
Madrazo et al. reported that Parkinson’s patients
improved notably after having their own extirpated
adrenal gland tissue reimplanted surgically into an
open pocket incision at the caudate. This experi-
mental approach triggered renewed worldwide inter-
est in neurosurgical approaches to alleviate
movement disorders.
—Enrique L. Labadie
See also–Basal Ganglia; Basal Ganglia, Diseases
of; Brain Anatomy; Huntington’s Disease;
Neurotransmitters, Overview; Parkinson’s
Disease; Wilson’s Disease
Further Reading
Carpenter, M. B. (1991). Core Text of Neuroanatomy, 4th ed.
Williams & Wilkins, Baltimore. [See Chapters 1 and 9.]
Dubois, B., and Pillon, B. (1998). Cognitive and behavioural
aspects of movement disorders. In Parkinson’s Disease and
Movement Disorders (J. Jankovic and E. Tolosa, Eds.), 3rd ed.,
pp. 837–855. Williams & Wilkins, Baltimore.
Lange, K. W., Sahakian, B. J., Quinn, N. P., et al. (1995).
Comparison of executive and visuospatial memory functions in
Huntington’s disease and dementia of Alzheimer’s type J.
Neural. Neurosurg. Psychiatr. 58, 598–606.
Lawrence, A. D., Hodges, J. R., Rosser, A. E., et al. (1998).
Evidence for specific cognitive deficits in preclinical Hunting-
ton’s disease. Brain 121, 1329–1341.
Parent, A., and Hazrati, L. N. (1995). Functional anatomy of the
basal-ganglia: 1. The cortico-basal-ganglia-thalamo-cortical-
loop. Brain Res. Rev. 20, 91–127.
Parent, A., and Hazrati, L. N. (1995). The functional anatomy of
the basal ganglia: 2. The role of subthalamic nucleus and
external pallidum in basal ganglia circuitry. Brain Res. Rev. 20,
128–154.
Sprengehneyer, R., Lange, H., and Homberg, V. (1995). The
pattern of attentional deficits in Huntington’s disease. Brain
118, 145–152.
Young, A. B., and Penney, J. B. (1998). Biochemical and functional
organization of the basal ganglia. In Parkinson’s Disease and
Movement Disorders (J. Jankovic and E. Tolosa, Eds.), 3rd ed.,
pp. 1–13, 341–355. Williams & Wilkins, Baltimore.
Cavernous Malformations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CAVERNOUS MALFORMATIONS account for 5–10%
of all central nervous system (CNS) vascular mal-
formations. In surgical series they are the second
most common vascular malformation responsible for
hemorrhage, outnumbered only by arteriovenous
malformations (AVMs). They occur throughout the
CNS in approximate relationship to the volume of
the various compartments: 70–80% supratentorially,
10–20% in the posterior fossa, and 5–10% in the
spine.
Advances in neuroimaging and molecular genetics
have improved our understanding of cavernous
malformations, whereas the adoption of new surgical
techniques and the development of frameless stereo-
tactic systems have changed our approach to their
management. This entry examines the epidemiology,
natural history, and indications for surgical treat-
ment of these lesions.
PATHOLOGY
Macroscopically, cavernous malformations are well-
defined, dark red or purple, mulberry-like masses
that range in diameter from a few millimeters to
several centimeters. Hemosiderin from recurrent
episodes of focal hemorrhage and thrombosis accu-
mulates by diapedesis in macrophages and glia
around the lesions, producing a characteristic brown
or dark yellow stain that surrounds the mass (Fig. 1).
Histologically, cavernous malformations are com-
posed of markedly dilated vascular channels (ca-
verns) with thin walls devoid of elastin and smooth
muscle and lined by a single layer of vascular
endothelium (Fig. 2). The channels are separated by
dense fibrous tissue with little or no intervening
neural parenchyma except perhaps at the periphery.
These dilated capillary channels contain blood and/
or thrombi of various ages and degrees of organiza-
tion. Small focal areas of calcification are common
and may be visualized on computerized tomography
(CT).
EPIDEMIOLOGY
Once considered relatively rare, cavernous malfor-
mations are recognized with increasing frequency. In
postmortem studies, cavernous malformations affect

Figure 1
Photograph of a gross pathological specimen demonstrating a
cluster of closely packed blood vessels in the subcortical white
matter, surrounded by a ring of hemosiderin staining. The dark
discoloration is caused by formalin fixation (original magnification
 1).
0.3–0.5% of the population. An extensive review of
more than 20,000 magnetic resonance imaging
(MRI) examinations by two groups found a remark-
ably similar frequency—0.4–0.5%. Obviously, only a
small fraction of these lesions reach medical atten-
tion while the majority remain asymptomatic.
Cavernous malformations occur in two forms:
sporadic and familial. The sporadic form occurs de
novo, and affected individuals typically have a single
lesion. The familial form is characterized by multiple
lesions and an autosomal dominant mode of
inheritance. Multiple lesions and a strong family
history of seizures are pathognomonic for the
familial form of cavernous malformations.
The first suggestion that cavernous malformations
might be a hereditary disorder appeared in the
German medical literature in 1928. Sporadic reports
of the familial occurrence of cerebral cavernous
malformations (CCMs) followed, but studies were
hampered by the lack of a reliable diagnostic tool for
identifying affected individuals.
By the mid-1980s, the MRI characteristics of
CCMs were well established, making it possible to
accurately diagnose and screen patients for the
familial form of this disease. In 1994, collaborators
at the Center for Medical Genetics in Marshfield,
Wisconsin, and at the Barrow Neurological Institute
in Phoenix, Arizona, linked the gene for familial
CCMs, designated CCM1, to the long arm of
chromosome 7 (7q11–q22) in a large Hispanic
CAVERNOUS MALFORMATIONS 533
family. Subsequent work by these investigators and
others confirmed this observation.
In these studies, however, were reports of a
number of families (specifically non-Hispanic fam-
ilies) with either weak or no clear linkage to the
CCM1 locus on chromosome 7q. In 1998, investi-
gators at Yale reported results of a linkage analysis
study in 20 Caucasian families that demonstrated
evidence for two new loci, CCM2 and CCM3.
CCM2 was also on chromosome 7, but on its short
arm (7p15–p13), and CCM3 was on the long arm of
chromosome 3 at q25.2–q27. Analysis indicated that
in the CCM population, 40% of families linked to
CCM1, 20% linked to CCM2, and 40% linked to
CCM3. A recent study from France analyzed 36 non-
Hispanic European CCM families using STRP
markers from the CCM1–CCM3 loci. Analysis of
these non-Hispanic families showed that 65% linked
to CCM1.
The most exciting development in the genetics of
cavernous malformations is the recent discovery by
two independent groups of investigators that muta-
tions in the KRIT1 gene are responsible for CCM1.
The function of the KRIT1-encoded protein is the
focus of ongoing research. Initially, KRIT1 was
isolated as a binding protein associated with Krev-
1/rap1a. Krev-1/rap1a is a member of the Ras family
of GTPases with tumor-suppressing activity for the
Ras oncogenes. Based on this information, a working
Figure 2
Photomicrograph of a cavernous malformation reveals a network
of thin-walled, dilated vascular channels (caverns) with no
intervening brain parenchyma. The capillary-like vessels are lined
by a single layer of vascular endothelium. Chronic organized
hemorrhage fills the lumen of several vessels in the upper left
corner (hematoxylin–eosin, original magnification  250).
534 CAVERNOUS MALFORMATIONS

model for the CCM1 mutations is that cavernous

malformations are benign vascular tumors that
develop due to an alteration in an important growth
control pathway(s) involving the regulation of Krev-
1/rap1a by the KRIT1 protein. In support of this
hypothesis, the Krev-1/rap1a pathway is known to be
altered in tuberous sclerosis type 2 (TSC2), an
autosomal dominant condition characterized by
benign neurocutaneous tumors. The TSC2 gene
product, tuberin, functions as a tumor-suppressor
protein by acting as a GTPase-activating protein for
Krev-1/rap1a. Somatic inactivation or loss of hetero-
zygosity of the wild-type tuberin allele in TSC2-
associated tumors leads to unregulated growth.
The focal nature of cavernous malformations
suggests that they also develop due to loss of the
wild-type KRIT1 allele in the developing cerebral
vasculature. A two-hit model, with a central tumor-
suppressor function of KRIT1, would be similar to
the mechanism of tuberin inactivation in TSC2-
associated tumors. Alternatively, the etiology of
vascular lesions may relate to a mechanical or
environmental trigger in the cerebral vasculature,
Figure 3
coupled with the underlying genetic defect in KRIT1.
Axial T2-weighted magnetic resonance image demonstrating the
Whatever the exact mechanism, the data indicate a classic appearance of a cavernous malformation. The core of the
role for the KRIT1 and Krev-1/rap1a pathway in the lesion has a reticulated ‘‘salt-and-pepper’’ pattern and is
pathogenesis of cavernous malformations and poten- surrounded by a ring of low signal intensity (arrows). This halo of
tially in that of other cerebrovascular disorders. lost signal is a result of metallic artifact created by iron in the
hemosiderin that characteristically surrounds these lesions. Note
the absence of mass effect and edema.
DIAGNOSIS
In patients with cavernous malformations, CT will be CLINICAL PRESENTATION
positive if there has been recent hemorrhage within
the lesion or if the lesion contains areas of calcifica- Evidence of prior hemorrhage is a constant feature of
tion. As the hemorrhage becomes organized, the cavernous malformations. The breakdown of blood
lesions become isodense with the surrounding brain. products results in the gradual deposition of hemo-
Angiography is almost always negative; occasionally, siderin in the cerebral tissue surrounding the
it shows faint venous pooling or an associated cavernous malformation. The iron present in hemo-
venous malformation. The presence of early draining siderin is a well-known epileptogenic material, and
veins or other angiographic abnormalities should iron has been used experimentally in laboratory
bring the diagnosis of cavernous malformation into models of epilepsy. Not unexpectedly, seizures are
question. the most common initial manifestation of patients
MRI is the method of choice for visualizing with supratentorial cavernous malformations, ac-
cavernous malformations. MRI is significantly more counting for 60–80% of the symptoms. Lesions often
sensitive than CT as a screening test. In addition, the receive clinical attention when hemorrhage leads to
signal characteristics of cavernous malformations on the new onset or exacerbation of seizure activity
MRI are sufficiently unique to be diagnostic in the (Fig. 4). Focal neurological deficits related to mass
majority of cases. Cavernous malformations are best effect are rarely associated with supratentorial
appreciated on heavily T2-weighted spin–echo lesions unless the lesions are located in the basal
images. The classic appearance is that of a mixed ganglia or thalamus.
signal ‘‘variegated’’ core, surrounded by a ring of In contrast, the sudden onset of focal neurological
low-intensity signal (Fig. 3). deficits is the most frequent presentation of patients

Figure 4
Intermediate-weighted, axial spin-echo magnetic resonance image
in a patient with an acute exacerbation of temporal lobe seizure
activity. Note the focal area of high signal intensity (arrow)
compatible with subacute hemorrhage in the region of the left
hippocampus. A ring of low signal intensity surrounds this lesion,
consistent with heavy hemosiderin deposition from previous
episodes of hemorrhage. Surgical pathology confirmed the
diagnosis of cavernous malformation.
with brainstem cavernous malformations. In the
brainstem, even relatively small hemorrhages may
be poorly tolerated when lesions are adjacent to
nuclear structures (Fig. 5). Symptoms tend to im-
prove gradually and often resolve completely as the
hemorrhage is organized and absorbed. Recurrent
episodes of hemorrhage can produce permanent
deficits or, more rarely, death.
MANAGEMENT
The decision of whether to recommend surgical
resection or observation for any particular cavernous
malformation should be based on a careful analysis
of the potential risks and benefits of the planned
CAVERNOUS MALFORMATIONS 535
procedure. The risks of surgery primarily depend on
the location of the lesion as well as on the patient’s
age and medical condition, whereas benefits are
directly related to changes in the natural history
produced by treatment.
Incidental Lesions
Incidental cavernous malformations most often are
found when MRI is performed to evaluate patients
with a history of headache or other nonlocalizing
neurological symptoms. The available data suggest
that the risk of symptomatic hemorrhage from these
incidental lesions is less than 1% per year. Surgical
risks may be higher for patients with incidental
cavernous malformations. In the absence of recent
hemorrhage, lesions tend to be firmly adherent to the
surrounding normal brain parenchyma and thus
more difficult to resect. Furthermore, because in-
cidental cavernous malformations are usually small,
they may be difficult to localize. Together, these
factors argue strongly against the resection of
incidental cavernous malformations. Patients re-
ferred for evaluation with such lesions should be
reassured that the risk of symptomatic hemorrhage is
small and that the initial episode of hemorrhage
seldom produces permanent deficits.
Symptomatic Lesions
Evidence of focal hemorrhage and hemosiderin
deposition is one of the hallmarks of cavernous
Figure 5
Sagittal T1-weighted magnetic resonance image in a patient
presenting with a history of decreased facial sensation and double
vision. A small, approximately 1-cm lesion is apparent in the floor
of the fourth ventricle (arrow). Surgical pathology confirmed the
diagnosis of cavernous malformation.
536 CAVERNOUS MALFORMATIONS
malformations. Symptoms occur when these hemor-
rhages cause sufficient irritation in the surrounding
brain to produce seizure activity or when the lesions
reach sufficient size to compress adjacent neurologi-
cal structures. Indications for surgery after sympto-
matic hemorrhage vary with the location of the
lesion, symptoms, and type of hemorrhage. In
prospective studies, the risk of recurrent sympto-
matic hemorrhage ranges from 1 to 5% per year.
Hemorrhage rates are particularly high in patients
who present after bleeding episodes that violate the
lesion capsule, producing a ‘‘gross’’ extralesional
hemorrhage into the surrounding brain (Fig. 6). In
this select group of patients, symptomatic hemor-
rhage rates of 20–30% per year have been reported.
In the brainstem, recurrent hemorrhage from such
lesions can lead to permanent deficits and death.
Surgical resection should be considered for all
patients with this pattern of hemorrhage.
Figure 6
Coronal T1-weighted magnetic resonance image in a 10-year-old
boy presenting with sudden onset of mild weakness and decreased
sensation in the left upper extremity. His history was positive for
an episode of seizure activity at 4 years of age with a negative
computed tomographic study. The large area of subacute blood
(arrow) extends outside the capsule of the lesion, producing a
so-called ‘‘gross’’ hemorrhage.
For supratentorial lesions located in the subcor-
tical white matter, the threshold for resection is
considerably lower than for lesions located in the
basal ganglia or brainstem. Patients with supraten-
torial lesions most often present with the new onset
or exacerbation of seizure activity. In such patients,
MRI usually reveals evidence of a focal area of acute
or subacute hemorrhage within the lesion as well as
the more typical features of cavernous malforma-
tions. In patients with a single isolated lesion and
new onset of seizures, surgery may eliminate the need
for lifelong medication. We prefer simple lesionec-
tomy in this group, even for temporal lobe cavernous
malformations. In our experience, simple lesionec-
tomy eliminates the need for medication in 80–90%
of patients with the new onset of seizures. Seizure
surgery with hippocampectomy, invasive monitoring,
and resection of a wider tissue focus is reserved for
patients with poorly controlled seizures.
In patients with the familial form of the disease or
multiple lesions, a more conservative approach is
indicated. In this group, surgical resection is reserved
for patients with poorly controlled seizures in whom
the seizure focus has been clearly localized to one
lesion by the preoperative evaluation. Seizure
activity is controlled, with or without medication,
in only 50–60% of the patients in this group. Long-
term control may be limited because of the fact that
other lesions may become epileptogenic, including
new lesions in the same or adjacent areas. The
development of new de novo lesions in the familial
form of this disease is well documented, with an
incidence in the range of 6% per year. Presentation
with focal neurological deficits is unusual for
patients with supratentorial cavernous malforma-
tions, unless the lesion lies within the basal ganglia
or thalamus. The surgical management of these deep
lesions is similar to that of brainstem cavernous
malformations.
The role of surgery in the management of
cavernous malformations located in the brainstem
is rapidly evolving. Once considered inoperable, the
successful resection of brainstem cavernous malfor-
mations is reported with increasing frequency.
Surgery is usually limited to symptomatic lesions
that abut a pial or ependymal surface. Determination
of whether the lesion reaches a pial or ependymal
surface should be based on review of high-resolution,
T1-weighted MRIs, which are the most anatomically
accurate of the imaging sequences and are the least
susceptible to artifact produced by hemosiderin.
Almost all authorities recommend observing lesions

that lie deep to the surface of the brainstem and that
would require dissection through normal tissue.
As previously noted, the risk of symptomatic
hemorrhage is related to a lesion’s history. The risk is
extremely low for incidental cavernous malforma-
tions and higher for those with previous sympto-
matic bleeding episodes. Hemorrhage from
cavernous malformations does not carry the dire
consequences associated with bleeding from AVMs
and aneurysms. Permanent deficits are unusual
without a history of previous symptomatic hemor-
rhages, and death as the result of a single bleeding
episode is extremely rare. Therefore, the prevention
of recurrent hemorrhage after a single episode of
symptomatic bleeding should not be considered an
absolute indication for surgical resection. The
symptoms related to an episode of hemorrhage
typically resolve within several weeks to months.
Patients often recover completely by the time they
are referred for neurosurgical evaluation.
At the authors’ institution, surgery is considered
for patients with brainstem cavernous malformations
who have two or more documented episodes of
symptomatic hemorrhage or evidence of gross
hemorrhage from a lesion that reaches a pial or
ependymal surface.
SURGICAL TECHNIQUE
The goal of surgery is complete resection of the
lesion. Partial resection of cavernous malformations
appears to be associated with an increased risk of
hemorrhage and relatively rapid recurrence of
symptoms. This finding correlates well with the
observation that once hemorrhage has violated the
capsule of the lesion, the risk of recurrent sympto-
matic bleeding may be as high as 25% per year.
Accurate localization is key for the safe resection of
deep subcortical and brainstem vascular malforma-
tions. Advances in imaging and computer technology
have led to the development of frameless stereotactic
navigation systems that allow precise intraoperative
localization.
The approach to most supratentorial lesions is
relatively straightforward. With stereotactic gui-
dance, small tailor-made craniotomies can be used
for resection. Lesions that lie below the cortical
surface can usually be approached though an
adjacent fissure or sulcus, minimizing the need for
cortical trauma. As discussed previously, surgery for
cavernous malformations of the brainstem and basal
ganglia is limited to lesions that abut a pial or
CAVERNOUS MALFORMATIONS 537
ependymal surface. Skull-base approaches reduce the
need for retraction and are important for minimizing
morbidity and morality rates.
After the lesion has been localized, it is dissected
using standard microsurgical technique. As the lesion
is mobilized, it is partially resected and coagulated
with bipolar cauterization. Because cavernous mal-
formations are low-flow lesions, the surgeon can
maintain the dissection plane immediately along the
edge of the lesion with little risk of hemorrhage. Care
should be taken to avoid damage to any large venous
channels associated with these lesions. In our
experience, almost all cavernous malformations are
associated with some type of venous anomaly.
We perform surgery as soon after hemorrhage as
possible. Resection is considerably easier in the acute
or subacute stage before the hematoma has become
organized and replaced by a dense, reactive, gliotic
capsule.
SURGICAL OUTCOMES
Supratentorial Lesions
We previously reviewed our surgical experience with
116 consecutive patients with supratentorial caver-
nous malformations during a 10-year period. The
indications for surgery were seizures in 72% and
focal neurological deficits in 28%. Headaches, a
common complaint, were present in 30% of patients.
There were no deaths, and the overall morbidity rate
was 8.6% for the series: temporary deficits in 8
patients (6.9%) and permanent deficits in 2 (1.7%).
Brainstem Lesions
We recently reviewed our surgical results with
brainstem cavernous malformations. Between 1985
and 1997, 86 consecutive patients underwent surgi-
cal resection. The indications for surgery were
symptomatic hemorrhage in 96.5%, with a mean of
1.9 episodes per patient (range, 1–6 episodes). All
patients had lesions that abutted a pial or ependymal
surface. Of the 86 patients, 85 underwent gross total
resection. Early in our experience, 1 patient with a
cervicomedullary lesion underwent subtotal resection
and developed a symptomatic recurrence 2 years
after the initial surgery. The recurrent lesion was
resected completely in a second procedure with a
good outcome.
The procedure-related mortality rate was 4%.
Postoperatively, increased or new deficits occurred in
58% of the patients (50 of 86). Fortunately, most
538 CAVERNOUS SINUS DISORDERS
patients improved over time. At follow-up at an
average of 34 months after surgery, only 10 patients
(12%) had persistent deficits related to the proce-
dure. When long-term outcomes were compared to
patients’ preoperative status, neurological function
was better or the same in 87% of the patients, worse
in 9% of the patients, while 4% of the patients had
died. The rate of morbidity and mortality was
greatest for brainstem lesions involving the floor of
the fourth ventricle and least for those above the
pontomedullary junction.
CONCLUSIONS
Cavernous malformations are relatively common
lesions affecting 0.3–0.5% of the population. Only
a small percentage of these lesions become sympto-
matic and require surgical intervention. Indications
for surgery include seizures and focal neurological
deficits. Surgery should be avoided in patients with
asymptomatic incidental lesions and in patients with
a history of remote symptoms and no evidence of
recent hemorrhage on MRI. In the brainstem,
surgery should be considered only for symptomatic
lesions that abut a pial or ependymal surface.
Mounting evidence suggests that the origin of
these lesions is neoplastic and that they should be
reclassified as benign vascular tumors that occur in
both sporadic and familial forms.
—Joseph M. Zabramski and Robert F. Spetzler
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Central Nervous System
Malformations; Cerebrovascular Malformations
(Angiomas); Venous Malformation
Further Reading
Awad, I. A., and Barrow, D. L. (Eds.) (1993). Cavernous
Malformations. American Association of Neurological Sur-
geons, Park Ridge, IL.
Johnson, E. W., Marchuk, D. A., and Zabramski, J. M. (2001).
Genetics of cerebral cavernous malformations. In Youman’s
Neurological Surgery (H. W. Winn, Ed.), 5th ed. Saunders,
Philadelphia.
Laberge-le Couteulx, S., Jung, H. H., Labauge, P., et al. (1999).
Truncating mutations in CCM1, encoding KRIT1, cause
hereditary cavernous angiomas. Nat. Genet. 23, 189–193.
Porter, R. W., Detwiler, P. W., Spetzler, R. F., et al. (1999).
Cavernous malformations of the brainstem: Experience with
100 patients. J. Neurosurg. 90, 50–58.
Rigamonti, D., Drayer, B. P., Johnson, P. C., et al. (1998). Familial
cerebral cavernous malformations. N. Engl. J. Med. 319, 343–
347.
Russell, D. S., and Rubenstein, L. J. (1989). Pathology of Tumors
of the Nervous System, 5th ed., pp. 730–736. Williams &
Wilkins, Baltimore.
Sahoo, T., Johnson, E. W., Thomas, J. W., et al. (1999). Mutations
in the gene encoding KRIT1, a Krev-1/rap1a binding protein,
cause cerebral cavernous malformations (CCM1). Hum. Mol.
Genet. 8, 2325–2333.
Serebriiskii, I., Estojak, J., Sonoda, G., et al. (1997). Association of
Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing
protein encoded by a gene mapping to 7q21–22. Oncogene 15,
1043–1049.
Zabramski, J. M., and Han, P. P. (2001). Epidemiology and natural
history of cavernous malformations. In Youman’s Neurological
Surgery (H. W. Winn, Ed.), 5th ed. Saunders, Philadelphia.
Zabramski, J. M., Henn, J. S., and Coons, S. (1999). Pathology of
cerebral vascular malformations. Neurosurg. Clin. North Am.
10, 395–410.
Cavernous Sinus Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAVERNOUS SINUS comprises multiple trabecu-
lated venous channels that contain important struc-
tures of the afferent (sensory) and efferent (motor)
nervous system. The cavernous sinus receives venous
blood from the superior and inferior ophthalmic veins
and drains posteriorly through the superior and
inferior petrosal sinuses. The cavernous sinus regions
encompass portions of the ocular motor cranial
nerves (third, fourth, and sixth nerves), the trigeminal
nerve (first and second divisions), the internal carotid
artery, and the ocular sympathetic nerves. Parts of the
third, fourth, and fifth cranial nerves run within the
lateral wall of the cavernous sinus, and the sixth
nerve runs through the middle of the cavernous sinus.
CLINICAL FINDINGS
Symptoms of cavernous sinus disorders include
double vision, drooping eyelid, and facial pain or
numbness. Signs of cavernous sinus disease include
any limitation of ocular movement in the distribution
of the third, fourth, or sixth cranial nerves; facial
pain or numbness (typically in the V1 distribution);
partial or complete ptosis; dilated pupil (third nerve
involvement); or Horner’s syndrome (ipsilateral
miosis or ptosis) (Fig. 1). If the lesion extends from
the cavernous sinus to involve the intracranial or
intraorbital optic nerve, ipsilateral visual loss may
occur. Patients with combined ocular sympathetic
(Horner’s syndrome) and parasympathetic (third
538 CAVERNOUS SINUS DISORDERS
patients improved over time. At follow-up at an
average of 34 months after surgery, only 10 patients
(12%) had persistent deficits related to the proce-
dure. When long-term outcomes were compared to
patients’ preoperative status, neurological function
was better or the same in 87% of the patients, worse
in 9% of the patients, while 4% of the patients had
died. The rate of morbidity and mortality was
greatest for brainstem lesions involving the floor of
the fourth ventricle and least for those above the
pontomedullary junction.
CONCLUSIONS
Cavernous malformations are relatively common
lesions affecting 0.3–0.5% of the population. Only
a small percentage of these lesions become sympto-
matic and require surgical intervention. Indications
for surgery include seizures and focal neurological
deficits. Surgery should be avoided in patients with
asymptomatic incidental lesions and in patients with
a history of remote symptoms and no evidence of
recent hemorrhage on MRI. In the brainstem,
surgery should be considered only for symptomatic
lesions that abut a pial or ependymal surface.
Mounting evidence suggests that the origin of
these lesions is neoplastic and that they should be
reclassified as benign vascular tumors that occur in
both sporadic and familial forms.
—Joseph M. Zabramski and Robert F. Spetzler
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Central Nervous System
Malformations; Cerebrovascular Malformations
(Angiomas); Venous Malformation
Further Reading
Awad, I. A., and Barrow, D. L. (Eds.) (1993). Cavernous
Malformations. American Association of Neurological Sur-
geons, Park Ridge, IL.
Johnson, E. W., Marchuk, D. A., and Zabramski, J. M. (2001).
Genetics of cerebral cavernous malformations. In Youman’s
Neurological Surgery (H. W. Winn, Ed.), 5th ed. Saunders,
Philadelphia.
Laberge-le Couteulx, S., Jung, H. H., Labauge, P., et al. (1999).
Truncating mutations in CCM1, encoding KRIT1, cause
hereditary cavernous angiomas. Nat. Genet. 23, 189–193.
Porter, R. W., Detwiler, P. W., Spetzler, R. F., et al. (1999).
Cavernous malformations of the brainstem: Experience with
100 patients. J. Neurosurg. 90, 50–58.
Rigamonti, D., Drayer, B. P., Johnson, P. C., et al. (1998). Familial
cerebral cavernous malformations. N. Engl. J. Med. 319, 343–
347.
Russell, D. S., and Rubenstein, L. J. (1989). Pathology of Tumors
of the Nervous System, 5th ed., pp. 730–736. Williams &
Wilkins, Baltimore.
Sahoo, T., Johnson, E. W., Thomas, J. W., et al. (1999). Mutations
in the gene encoding KRIT1, a Krev-1/rap1a binding protein,
cause cerebral cavernous malformations (CCM1). Hum. Mol.
Genet. 8, 2325–2333.
Serebriiskii, I., Estojak, J., Sonoda, G., et al. (1997). Association of
Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing
protein encoded by a gene mapping to 7q21–22. Oncogene 15,
1043–1049.
Zabramski, J. M., and Han, P. P. (2001). Epidemiology and natural
history of cavernous malformations. In Youman’s Neurological
Surgery (H. W. Winn, Ed.), 5th ed. Saunders, Philadelphia.
Zabramski, J. M., Henn, J. S., and Coons, S. (1999). Pathology of
cerebral vascular malformations. Neurosurg. Clin. North Am.
10, 395–410.
Cavernous Sinus Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CAVERNOUS SINUS comprises multiple trabecu-
lated venous channels that contain important struc-
tures of the afferent (sensory) and efferent (motor)
nervous system. The cavernous sinus receives venous
blood from the superior and inferior ophthalmic veins
and drains posteriorly through the superior and
inferior petrosal sinuses. The cavernous sinus regions
encompass portions of the ocular motor cranial
nerves (third, fourth, and sixth nerves), the trigeminal
nerve (first and second divisions), the internal carotid
artery, and the ocular sympathetic nerves. Parts of the
third, fourth, and fifth cranial nerves run within the
lateral wall of the cavernous sinus, and the sixth
nerve runs through the middle of the cavernous sinus.
CLINICAL FINDINGS
Symptoms of cavernous sinus disorders include
double vision, drooping eyelid, and facial pain or
numbness. Signs of cavernous sinus disease include
any limitation of ocular movement in the distribution
of the third, fourth, or sixth cranial nerves; facial
pain or numbness (typically in the V1 distribution);
partial or complete ptosis; dilated pupil (third nerve
involvement); or Horner’s syndrome (ipsilateral
miosis or ptosis) (Fig. 1). If the lesion extends from
the cavernous sinus to involve the intracranial or
intraorbital optic nerve, ipsilateral visual loss may
occur. Patients with combined ocular sympathetic
(Horner’s syndrome) and parasympathetic (third
 CAVERNOUS SINUS DISORDERS 539

nerve palsy) denervation may have a midsized,

Figure 1
Occular motility photographs (arrowheads indicate direction of
gaze) demonstrate complete ptosis of the right upper lid (middle).
On attempted right gaze (left side) the right eye does not abduct,
elevate, or depress. On attempted left gaze (right side), the right
eye does not adduct, elevate, or depress when compared to the
normal left eye. (Top, middle) The right eye does not elevate. The
right pupil is larger than the left. These findings are consistent with
right third, fourth, and sixth nerve palsy from a right cavernous
sinus lesion.
poorly reactive pupil. Table 1 lists the causes and
characteristic features of cavernous sinus lesions.
The evaluation of a patient with signs or symp-
toms localizing to the cavernous sinus should include
neuroimaging, usually magnetic resonance imaging
(MRI) (Fig. 2). In the absence of a mass lesion,
inflammatory and infectious etiologies should be
evaluated with tests including serology for syphilis,
chest radiography and angiotensin converting en-
zyme for sarcoidosis, blood work for giant cell
arteritis in the elderly, and skin testing for tubercu-
losis. Patients with diabetes should have rapid
evaluation for mucormycosis, including otolaryngo-
logic consultation. Cerebral arteriography may be
necessary to search for intracavernous aneurysm or
carotid cavernous fistula. MRI and MR angiography
usually demonstrate a characteristic flow void in
aneurysm (Fig. 3). Patients with a rapidly progressive
cavernous sinus mass should undergo evaluation for
metastitic cancer. Patients with cavernous sinus
thrombosis should be evaluated for infectious
sources with blood cultures.

Table 1 CAUSES AND CHARACTERISTIC FEATURES OF CAVERNOUS SINUS LESIONS

Etiology Other signs or features Comment

Carotid cavernous fistula Orbital bruit, proptosis, chemosis, Enlarged superior ophthalmic vein
injection, arterialized vessels on neuroimaging
Cavernous sinus thrombosis Proptosis, chemosis, injection. May follow infections of the upper
Systemic symptoms (e.g., fever, face, mouth, orbit or sinuses;
malaise, altered level of may be septic or aseptic
consciousness)
Cavernous sinus aneurysm Signs of carotid cavernous fistula if
ruptures
Infiltration (e.g., sarcoid,
leukemia)
Persistent primitive trigeminal Congenital vessel connecting Rare; may compress cavernous
artery carotid artery and basilar artery sinus
Neoplasms (e.g., meningioma, Neuroimaging characteristics vary
hemangioma, lymphoma, based on tumor type
metastasis, perineural spread of
skin cancers, pituitary apoplexy,
craniopharyngiomas,
nasopharyngeal tumors,
schwannomas)
Mucormycosis Rapidly progressive, acute onset, Consider in diabetics (especially
debilitated or with ketoacidosis)
immunocompromised patient
Trauma (including surgery) Associated skull fracture in Perineural or intraneural
nonsurgical trauma hemorrhage
Tolosa–Hunt syndrome Painful ophthalmoplegia, steriod A diagnosis of exclusion
responsive
540 CAVERNOUS SINUS DISORDERS

Patients may present with painful ophthalmople-

gia due to idiopathic granulomatous inflammation of
the cavernous sinus. This has been termed Tolosa–
Hunt syndrome. Pain usually improves rapidly and
dramatically with steroid therapy. This finding is not
pathognomonic of Tolosa–Hunt syndrome, however,
and cavernous sinus syndromes from neoplasm,
other types of inflammation, and aneurysm can
sometimes be steroid responsive. The neuroimaging
characteristics of Tolosa–Hunt syndrome may be
indistinguishable from cavernous sinus meningioma,
lymphoma, or metastatic carcinoma or sarcoidosis.
Thus, an extensive evaluation for underlying meta-
static disease, inflammatory processes such as sarcoi-
dosis, Wegener’s granulomatosis, and other
infiltrative lesions should be performed in all cases.
Figure 2 Tolosa–Hunt syndrome should be considered a
Bilateral enhancing mass lesions (in this case due to amyloidosis) in diagnosis exclusion.
the cavernous sinus in an axial T1-weighted postcontrast magnetic
Cavernous sinus thrombosis usually presents in an
resonance image (arrowheads).
individual with systemic symptoms such as fever,
nausea, vomiting, or altered level of consciousness.
Cavernous sinus meningioma is a challenging Patients may develop severe eye pain and headache.
therapeutic problem. The resectability of the tumor Orbital signs including chemosis, proptosis, injection,
depends in large part on the involvement of the and ophthalmoplegia may be present. Findings may
internal carotid artery. Rapidly progressive visual be unilateral or bilateral. Stenosis or thrombosis of
loss or ophthalmoplegia may be indications for more the intracavernous internal carotid artery may result
aggressive treatment. Close observation and serial
neuroimaging are required.
Carotid cavernous fistulas (CCFs) may present
with an orbital bruit, ophthalmoplegia, proptosis,
chemosis, and arterialized blood vessels. CCFs may
have low flow and begin spontaneously in older
patients due to hypertensive atherosclerotic disease
in small branches of the carotid artery. Increased
venous pressure reverses the flow in the cavernous
sinus and results in signs of orbital congestion,
including a dilated superior ophthalmic vein. Lower
flow CCFs may close spontaneously, may thrombose
after angiography or with therapeutic intermittent
carotid artery compression, or may require endovas-
cular embolization therapy. Post-traumatic, direct
CCFs are usually more symptomatic than sponta-
neous low-flow CCFs and more often require closure
by endovascular embolization.
Intracavernous carotid aneurysms may present
with ophthalmoplegia or pain. MRI and standard
cerebral angiography are usually required for diag-
nosis. Many intracavernous aneurysms do not
require therapy, but aneurysms beyond the cavernous Figure 3
sinus usually do. Post-traumatic aneurysms that Axial T2-weighted magnetic resonance imaging study shows a
enlarge over time or show progressive clinical signs dark flow void in the cavernous sinus on the right (arrowhead) due
require endovascular or surgical treatment. to an intracavernous carotid artery aneurysm.

in other neurological signs. Cavernous sinus throm-
bosis may be septic or aseptic. Infectious causes
usually require aggressive antibiotic treatment. Asep-
tic thrombosis may require anticoagulation.
—Andrew G. Lee
See also–Aneurysms; Carotid Artery; Cerebral
Blood Vessels: Veins and Venous Sinuses;
Eyelids; Facial Pain; Headache, Sinus
Further Reading
Ersahin, Y., Ozdamar, N., Demirtas, E., et al. (1999). Meningioma
of the cavernous sinus in a child. Child’s Nervous Syst. 15, 8–10.
Friedlander, R. M., Ojemann, R. G., and Thornton, A. F. (1999).
Management of meningiomas of the cavernous sinus: Conserva-
tive surgery and adjuvant therapy. Clin. Neurosurg. 45, 279–282.
Jafar, J. J., and Huang, P. P. (1998). Surgical treatment of carotid
cavernous aneurysms. Neurosurg. Clin. North Am. 9, 755–763.
Kida, Y., Kobayashi, T., and Mori, Y. (1999). Radiosurgery of
angiographically occult vascular malformations. Neurosurg.
Clin. North Am. 10, 291–303.
Kim, J. K., Seo, J. J., Kim, Y. H., et al. (1996). Traumatic bilateral
carotid-cavernous fistulas treated with detachable balloon. A
case report. Acta Radiol. 37, 46–48.
Newman, S. A. (1999). The cavernous sinus. Neurosurg. Clin.
North Am. 10, 731–757.
O’Sullivan, M. G., van Loveren, H. R., and Tew, J. M., Jr. (1997).
The surgical resectability of meningiomas of the cavernous
sinus. Neurosurgery 40, 238–247.
Phillips, P. H. (1999). Carotid-cavernous fistulas. Neurosurg. Clin.
North Am. 10, 653–665.
Rosseau, G. (1999). Benign tumors of the cavernous sinus. Clin.
Neurosurg. 45, 260–262.
Cell Adhesion Molecules
(CAMs)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CELL ADHESION MOLECULES (CAMs) are a group of
membrane glycoprotein and carbohydrate molecules
that mediate the adhesion of cells to cells or cells to
the extracellular matrix (ECM). These molecules have
essential functions for tissue integrity and intercellular
communication. All CAMs have cytoplasmic, trans-
membrane, and extracellular domains. The cytoplas-
mic domains often anchor to cytoskeletal filaments,
whereas the extracellular domains bind to either the
same (homophilic binding) or different (heterophilic
binding) types of CAMs expressed on other cells or
the ECM. Depending on their sequence homology and
individual structure, CAMs are classified into four
CELL ADHESION MOLECULES 541
Figure 1
Schematic illustration of four major families of cell adhesion
molecules. (A) Integrin heterodimers bind to extracellular matrix
(ECM). (B) Cadherins cause adhesion via homophilic binding to
other cadherins in a calcium-dependent manner. (C) Ig-CAMs
mediate heterophilic interactions with integrins. (D) Selectins bind
to carbohydrate ligands on cells.
major families: integrins, the immunoglobulin-like
CAMs (Ig-CAMs), cadherins, and selectins (Fig. 1).
Integrins are a large family of membrane glyco-
proteins consisting of heterodimers between a and b
subunits. Most integrins bind to ECM components,
such as fibronectin and laminins, whereas others bind
to counter-receptors on other cells. In addition to
their primary function in cell adhesion, integrins also
play important roles in communication between cells
and between cells and the ECM. Importantly,
integrins exist in ‘‘active’’ or ‘‘inactive’’ states.
Activation of the integrin receptor sends ‘‘outside-
in’’ signals that can affect various intracellular
changes. However, an activated cell can also send
‘‘inside-out’’ signals to modify the binding of the
membrane integrins with their ligands.
A large number of CAMs belong to Ig-CAMs
because they all have one or more copies of Ig-like
structures in their extracellular domain. Many of the
Ig-CAMs are predominantly expressed in nerve
tissues. Such neural Ig-CAMs include neural cell
adhesion molecules (NCAMs), L1, telencephalin,
and contactins. These CAMs may have important
functions in many aspects of neurobiology. For
example, NCAM-1 mediates homophilic binding
and may induce the outgrowth of neuritis; telence-
phalin may be involved in signaling specific subsets of
growing axons to make proper synaptic connections.
In addition, gene mutations of the L1-CAM have been
implicated in neurological syndromes such as X-
linked hydrocephalus and dysgenesis of the corpus
callosum. Some Ig-CAMs are mainly found on
vascular endothelial cells and are involved in leuko-
cyte trafficking to inflammatory sites. These include
intercellular adhesion molecule-1 (ICAM-1), vascular
adhesion molecule-1 (VCAM-1), and platelet-en-
dothelial cell adhesion molecule-1. Agents such as

in other neurological signs. Cavernous sinus throm-
bosis may be septic or aseptic. Infectious causes
usually require aggressive antibiotic treatment. Asep-
tic thrombosis may require anticoagulation.
—Andrew G. Lee
See also–Aneurysms; Carotid Artery; Cerebral
Blood Vessels: Veins and Venous Sinuses;
Eyelids; Facial Pain; Headache, Sinus
Further Reading
Ersahin, Y., Ozdamar, N., Demirtas, E., et al. (1999). Meningioma
of the cavernous sinus in a child. Child’s Nervous Syst. 15, 8–10.
Friedlander, R. M., Ojemann, R. G., and Thornton, A. F. (1999).
Management of meningiomas of the cavernous sinus: Conserva-
tive surgery and adjuvant therapy. Clin. Neurosurg. 45, 279–282.
Jafar, J. J., and Huang, P. P. (1998). Surgical treatment of carotid
cavernous aneurysms. Neurosurg. Clin. North Am. 9, 755–763.
Kida, Y., Kobayashi, T., and Mori, Y. (1999). Radiosurgery of
angiographically occult vascular malformations. Neurosurg.
Clin. North Am. 10, 291–303.
Kim, J. K., Seo, J. J., Kim, Y. H., et al. (1996). Traumatic bilateral
carotid-cavernous fistulas treated with detachable balloon. A
case report. Acta Radiol. 37, 46–48.
Newman, S. A. (1999). The cavernous sinus. Neurosurg. Clin.
North Am. 10, 731–757.
O’Sullivan, M. G., van Loveren, H. R., and Tew, J. M., Jr. (1997).
The surgical resectability of meningiomas of the cavernous
sinus. Neurosurgery 40, 238–247.
Phillips, P. H. (1999). Carotid-cavernous fistulas. Neurosurg. Clin.
North Am. 10, 653–665.
Rosseau, G. (1999). Benign tumors of the cavernous sinus. Clin.
Neurosurg. 45, 260–262.
Cell Adhesion Molecules
(CAMs)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CELL ADHESION MOLECULES (CAMs) are a group of
membrane glycoprotein and carbohydrate molecules
that mediate the adhesion of cells to cells or cells to
the extracellular matrix (ECM). These molecules have
essential functions for tissue integrity and intercellular
communication. All CAMs have cytoplasmic, trans-
membrane, and extracellular domains. The cytoplas-
mic domains often anchor to cytoskeletal filaments,
whereas the extracellular domains bind to either the
same (homophilic binding) or different (heterophilic
binding) types of CAMs expressed on other cells or
the ECM. Depending on their sequence homology and
individual structure, CAMs are classified into four
CELL ADHESION MOLECULES 541
Figure 1
Schematic illustration of four major families of cell adhesion
molecules. (A) Integrin heterodimers bind to extracellular matrix
(ECM). (B) Cadherins cause adhesion via homophilic binding to
other cadherins in a calcium-dependent manner. (C) Ig-CAMs
mediate heterophilic interactions with integrins. (D) Selectins bind
to carbohydrate ligands on cells.
major families: integrins, the immunoglobulin-like
CAMs (Ig-CAMs), cadherins, and selectins (Fig. 1).
Integrins are a large family of membrane glyco-
proteins consisting of heterodimers between a and b
subunits. Most integrins bind to ECM components,
such as fibronectin and laminins, whereas others bind
to counter-receptors on other cells. In addition to
their primary function in cell adhesion, integrins also
play important roles in communication between cells
and between cells and the ECM. Importantly,
integrins exist in ‘‘active’’ or ‘‘inactive’’ states.
Activation of the integrin receptor sends ‘‘outside-
in’’ signals that can affect various intracellular
changes. However, an activated cell can also send
‘‘inside-out’’ signals to modify the binding of the
membrane integrins with their ligands.
A large number of CAMs belong to Ig-CAMs
because they all have one or more copies of Ig-like
structures in their extracellular domain. Many of the
Ig-CAMs are predominantly expressed in nerve
tissues. Such neural Ig-CAMs include neural cell
adhesion molecules (NCAMs), L1, telencephalin,
and contactins. These CAMs may have important
functions in many aspects of neurobiology. For
example, NCAM-1 mediates homophilic binding
and may induce the outgrowth of neuritis; telence-
phalin may be involved in signaling specific subsets of
growing axons to make proper synaptic connections.
In addition, gene mutations of the L1-CAM have been
implicated in neurological syndromes such as X-
linked hydrocephalus and dysgenesis of the corpus
callosum. Some Ig-CAMs are mainly found on
vascular endothelial cells and are involved in leuko-
cyte trafficking to inflammatory sites. These include
intercellular adhesion molecule-1 (ICAM-1), vascular
adhesion molecule-1 (VCAM-1), and platelet-en-
dothelial cell adhesion molecule-1. Agents such as
542 CELL DEATH
inflammatory mediators and bacterial endotoxins can
stimulate the endothelium for coordinate expression
of these vascular adhesion receptors, which in turn
interact with the counter-receptors on leukocytes
(integrin b2 for ICAM-1 and b1 for VCAM-1) and
mediate leukocyte focal adhesion and emigration.
Cadherins form zipper-like structures between
adjacent cells via homophilic binding to other
cadherins in a calcium-dependent manner. Classic
cadherins, such as the N-, P-, and E-cadherins, localize
in adherence junctions to form an adhesion belt and
build a connection with the actin-containing cytoske-
leton. Cadherins are involved in not only cell-to-cell
adhesion but also morphogenesis and histogenesis. In
the developing nervous system, cadherins are impli-
cated in multiple functions in building neuronal
structures. For example, N-cadherin plays roles in
neurulation, regionalization of neuroectoderm, neu-
ronal migration, and axon growth and fasciculation.
Selectins are cell surface lectins that have evolved to
mediate the adhesion of leukocytes to endothelial cells
and platelets under flow. Three selectins have been
identified: L-selectin (leukocyte selectin), P-selectin
(platelet selectin), and E-selectin (endothelial selectin).
Selectins bind to carbohydrate ligands sialyl Lewis X
(‘‘sticky sugar’’) and result in relatively weak binding.
In collaboration with other CAM families, selectins
play important roles in leukocyte trafficking to the
sites of inflammation. For example, the rolling of
leukocytes along the endothelium is mediated by
selectins, whereas the firm adhesion and transendothe-
lial migration of leukocytes require the interaction
between the integrin family and Ig-CAMs such as
ICAM-1 and VCAM-1. Inflammatory episodes in the
central nerve system are associated with the patho-
geneses of a variety of neurological diseases, including
ischemic brain injury and autoimmune neuropathies.
In fact, blocking leukocyte recruitment with mono-
clonal antibodies against specific types of CAMs, such
as L-selectin, leukocyte integrins, and ICAM-1, can
reduce inflammatory and ischemic brain injury in
many experimental models of neurological disorders.
—Nanping Wang
Further Reading
Frenette, P., and Wagner, D. (1996). Adhesion molecules. N. Engl.
J. Med. 334, 1526–1529.
Giancotti, F., and Ruoslahti, E. (1999). Integrin signaling. Science
285, 1031–1032.
Jones, L. S. (1996). Integrins: Possible functions in the adult CNS.
Trends Neurosci. 19, 68–72.
Rutishauser, U. (1993). Adhesion molecules of the nervous system.
Curr. Opin. Neurobiol. 3, 709–715.
Cell Death
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CELL DEATH is the cardinal event in many neurolo-
gical diseases, including trauma, stroke, and degen-
erative syndromes. Conversely, cell death is also a
normal and necessary part of nervous system
development. During development, newly formed
neurons migrate and establish connections with their
target cells. At the same time, they acquire a
dependence on neurotrophic factors provided by
the target cells. Those neurons that establish wrong
connections, or migrate to an inappropriate place,
fail to receive appropriate neurotrophic signals and
consequently die. This process has been termed
programmed cell death because the cell death occurs
in an orderly, controlled fashion, with the dying cells
playing an active role in their own demise. In
contrast, the term necrosis refers to uncontrolled,
passive cell death such as occurs in brain trauma and
severe ischemia. It has recently become appreciated,
however, that programmed cell death may also
contribute to cell death after mild ischemia and in
certain neurodegenerative diseases.
CHARACTERISTICS OF PROGRAMMED CELL
DEATH AND NECROSIS
Three forms of programmed cell death are recognized
during development. Type I or apoptotic cell death is
characterized by blebbing of the plasma membrane,
chromatin condensation, nuclear fragmentation, and
cell dissolution into small fragments containing
organelles. These fragments, termed apoptotic bodies,
are engulfed by neighboring cells to prevent lysis and
release of cell contents to the tissue. Type II or
autophagic cell death is characterized by the presence
of large intracellular vesicles that contain lysosomal
components and degrade cellular contents. The
plasma membrane and nucleus remain intact, and
these cells are eventually phagocytized by neighbor-
ing cells. Type III programmed cell death, also termed
nonlysosomal vesiculated cell death, differs from type
II mainly in the nature of the vesicles, which are
presumed to come from mitochondria and endoplas-
mic reticulum rather than lysosomes. An important
feature shared by all types of programmed cell death
is that the intracellular contents of dying cells are kept
out of the extracellular space, thereby preventing
542 CELL DEATH
inflammatory mediators and bacterial endotoxins can
stimulate the endothelium for coordinate expression
of these vascular adhesion receptors, which in turn
interact with the counter-receptors on leukocytes
(integrin b2 for ICAM-1 and b1 for VCAM-1) and
mediate leukocyte focal adhesion and emigration.
Cadherins form zipper-like structures between
adjacent cells via homophilic binding to other
cadherins in a calcium-dependent manner. Classic
cadherins, such as the N-, P-, and E-cadherins, localize
in adherence junctions to form an adhesion belt and
build a connection with the actin-containing cytoske-
leton. Cadherins are involved in not only cell-to-cell
adhesion but also morphogenesis and histogenesis. In
the developing nervous system, cadherins are impli-
cated in multiple functions in building neuronal
structures. For example, N-cadherin plays roles in
neurulation, regionalization of neuroectoderm, neu-
ronal migration, and axon growth and fasciculation.
Selectins are cell surface lectins that have evolved to
mediate the adhesion of leukocytes to endothelial cells
and platelets under flow. Three selectins have been
identified: L-selectin (leukocyte selectin), P-selectin
(platelet selectin), and E-selectin (endothelial selectin).
Selectins bind to carbohydrate ligands sialyl Lewis X
(‘‘sticky sugar’’) and result in relatively weak binding.
In collaboration with other CAM families, selectins
play important roles in leukocyte trafficking to the
sites of inflammation. For example, the rolling of
leukocytes along the endothelium is mediated by
selectins, whereas the firm adhesion and transendothe-
lial migration of leukocytes require the interaction
between the integrin family and Ig-CAMs such as
ICAM-1 and VCAM-1. Inflammatory episodes in the
central nerve system are associated with the patho-
geneses of a variety of neurological diseases, including
ischemic brain injury and autoimmune neuropathies.
In fact, blocking leukocyte recruitment with mono-
clonal antibodies against specific types of CAMs, such
as L-selectin, leukocyte integrins, and ICAM-1, can
reduce inflammatory and ischemic brain injury in
many experimental models of neurological disorders.
—Nanping Wang
Further Reading
Frenette, P., and Wagner, D. (1996). Adhesion molecules. N. Engl.
J. Med. 334, 1526–1529.
Giancotti, F., and Ruoslahti, E. (1999). Integrin signaling. Science
285, 1031–1032.
Jones, L. S. (1996). Integrins: Possible functions in the adult CNS.
Trends Neurosci. 19, 68–72.
Rutishauser, U. (1993). Adhesion molecules of the nervous system.
Curr. Opin. Neurobiol. 3, 709–715.
Cell Death
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CELL DEATH is the cardinal event in many neurolo-
gical diseases, including trauma, stroke, and degen-
erative syndromes. Conversely, cell death is also a
normal and necessary part of nervous system
development. During development, newly formed
neurons migrate and establish connections with their
target cells. At the same time, they acquire a
dependence on neurotrophic factors provided by
the target cells. Those neurons that establish wrong
connections, or migrate to an inappropriate place,
fail to receive appropriate neurotrophic signals and
consequently die. This process has been termed
programmed cell death because the cell death occurs
in an orderly, controlled fashion, with the dying cells
playing an active role in their own demise. In
contrast, the term necrosis refers to uncontrolled,
passive cell death such as occurs in brain trauma and
severe ischemia. It has recently become appreciated,
however, that programmed cell death may also
contribute to cell death after mild ischemia and in
certain neurodegenerative diseases.
CHARACTERISTICS OF PROGRAMMED CELL
DEATH AND NECROSIS
Three forms of programmed cell death are recognized
during development. Type I or apoptotic cell death is
characterized by blebbing of the plasma membrane,
chromatin condensation, nuclear fragmentation, and
cell dissolution into small fragments containing
organelles. These fragments, termed apoptotic bodies,
are engulfed by neighboring cells to prevent lysis and
release of cell contents to the tissue. Type II or
autophagic cell death is characterized by the presence
of large intracellular vesicles that contain lysosomal
components and degrade cellular contents. The
plasma membrane and nucleus remain intact, and
these cells are eventually phagocytized by neighbor-
ing cells. Type III programmed cell death, also termed
nonlysosomal vesiculated cell death, differs from type
II mainly in the nature of the vesicles, which are
presumed to come from mitochondria and endoplas-
mic reticulum rather than lysosomes. An important
feature shared by all types of programmed cell death
is that the intracellular contents of dying cells are kept
out of the extracellular space, thereby preventing

inflammation. This contrasts with necrotic cell death,
in which disruption of the cytoplasmic membrane
spills intracellular contents into the surrounding
tissues in an uncontrolled fashion. The morphological
and biochemical changes that characterize necrosis all
stem from energy failure, namely dissipation of
normal membrane ion gradients, cell swelling, and
rapid cell lysis.
The most common form of programmed cell death
is type I or apoptosis. The molecular mechanisms
involved in this process are well defined, as outlined
later. Much less is known about the processes involved
in type II and type III programmed cell death.
THE APOPTOTIC PATHWAYS
Apoptosis (from Greek ‘‘to drop off’’) can be divided
into two phases: activation and execution. Activation
can occur by several pathways, many of them specific
for particular cell types, but the execution pathway is
common to all cells that display the apoptotic
morphology. The core of the execution pathway is
a proteolytic cascade composed of a group of
cysteine proteases named caspases. Fourteen distinct
mammalian caspases are recognized; of these,
caspases 3, 6, and 7 are considered the executioner
caspases. These proteases are normally present as
inactive zymogens known as procaspases. When
activated, they cleave a large number of protein
substrates to accomplish the organized cell death that
characterizes apoptosis, in some cases activating and
some cases inactivating the target molecule. Their
substrates include structural proteins that contribute
to the morphological changes of apotosis, such as
actin and lamin, as well as signal transduction
proteins, such as MEKK1 and Akt kinase. One key
substrate is intranucleosomal DNase (CAD/CPAN/
DFF40), which when activated by caspase cleavage
causes fragmentation of DNA into nucleosomal
multimeres, a hallmark feature of apoptosis. Addi-
tionally, caspase cleavage of DNA repair enzymes
such as PARP1 ensures that the DNA fragmentation
cannot be repaired.
One way that the caspases cascade can be triggered
is by activation of particular receptors on the plasma
membrane known as death receptors. Examples of
these are tumor necrosis factor receptor-1 (TNFR-1)
and Fas. The death receptors contain a ‘‘death
domain’’ that allows them to interact with adapter
proteins, which in turn recruit activator caspases
such as caspase-8 (Fig. 1). Once activated, caspase-8
is released from the complex and activates execu-
CELL DEATH 543
tioner caspases, which then digest protein targets to
execute the apoptotic program. Since activation of
the pathway comes from outside the cell, this
pathway is termed the extrinsic pathway.
Several death-inducing signals, such as UV radia-
tion, heat shock, chemotherapeutic drugs, and
trophic factor withdrawal, converge in an intrinsic
pathway that activate caspases by releasing pro-
apoptotic molecules from the mitochondria. Cyto-
chrome c is one of these molecules, and it induces the
oligomerization of an adapter protein called Apaf-1
(apoptosis activating factor-1). Apaf-1 has a region
named caspase activating recruitment domain that
binds procaspase-9, forming a complex known as
apoptosome. Bringing together the procaspase-9
molecules induces their activation. Active caspase-9
is then released from the apoptosomes and activates
executioner caspases. A molecular connection be-
tween the extrinsic and intrinsic activation pathways
is provided by the protein Bid. Bid is cleaved by
caspase-8 in the extrinsic pathway, and the truncated
Bid translocates to the mitochondria, where it
induces cytochrome c release and hence activation
of the intrinsic pathway.
As might be expected, numerous regulatory
systems control these activation pathways to ensure
that apoptosis is not triggered inappropriately. The
Bcl-2 family of proteins was among the first
regulatory systems to be identified. The Bcl-2 family
is divided into two subfamilies: an anti-apoptotic
subfamily, headed by Bcl-2, and a pro-apoptotic
subfamily, represented by Bax. Most of the members
of the family reside in the outer membrane of the
mitochondria and presumably regulate the release of
pro-apoptotic molecules, although their actual me-
chanism is unknown. Other proteins, such as the
inhibitors of apoptosis proteins (IAPs), control the
activation of caspases. Another molecule, Smac/
Diablo, is released from mitochondria along with
cytochrome c to ensure the progression of apoptosis
once the intrinsic pathway is activated. Smac/Diablo
binds to IAPs, releases the caspases so they can reach
their targets, and promotes IAP degradation.
NECROTIC AND PROGRAMMED CELL DEATH
IN NEUROLOGICAL DISEASES
Necrotic cell death is typical of acute disorders,
occurring over minutes to hours, that produce energy
failure. Trauma and ischemia are the primary causes
of necrosis in the nervous system. Although long
considered a purely passive process, it is now
544 CELL DEATH

Intrinsic Pathway
Extrinsic Pathway

Intracellular
Ligand (FasL) death signal

Death Receptor
(Fas) mitochondria ?
Bcl2 Family
?
DD

D
D
D
D

Cyt c Smac/Diablo
DD

Adapter Cyt C release

(FADD)
DED DED
DED
Activator Caspase Activation
(casp-8)
d apoptosome
tBi
Activator caspases activation

Active Caspase
(casp-8) IAP Smac/diablo

Activated Procaspases 3, 6, 7
Caspases 3, 6, 7
Procaspases 3, 6, 7
Activated
Caspases 3, 6, 7

APOPTOSIS
Figure 1
The extrinsic and intrinsic pathways to apoptosis. The extrinsic pathway is initiated by receptors at the cell surface, exemplified here by the
Fas receptor. Ligand binding activates the death domain (DD) of this receptor, which then permits interaction with adapter proteins. The
adapter proteins in turn recruit activator caspases such as caspase-8. Once activated, caspase-8 is released from the complex and activates
executioner caspases, which then digest protein targets to execute the apoptotic program. The intrinsic pathway is initiated by the release of
pro-apoptotic molecules from the mitochondria, such as cytochrome c. Cytochrome c induces the oligomerization of an adapter protein
called Apaf-1 (apoptosis activating factor-1), which in turn binds procaspase-9 to form a complex known as the apoptosome. Active caspase-
9 is then released from the apoptosome and activates executioner caspases. Numerous checkpoints are present in these apoptosis cascades.
One of these is the Bcl-2 family of proteins present on the mitochondrial membrane, some of which promote and some of which inhibit
apoptosis. A second is the Smac/Diablo molecule, which promotes the degradation of inhibitor of apoptosis proteins (IAPs). A connection
between the extrinsic and intrinsic activation pathways is provided by the protein Bid. Bid is cleaved by caspase-8 in the extrinsic pathway,
and the truncated Bid translocates to the mitochondria, where it induces cytochrome c release and hence activation of the intrinsic pathway.
(See color plate section.)

apparent that at least one active process significantly
contributes to necrotic cell death. DNA damage
triggers activation of poly(ADP-ribose) polymerase
(PARP). PARP consumes NAD þ in the process of
forming long ADP-ribose polymers on histones and
other proteins in the neighborhood of DNA strand
breaks. These polymers appear to serve a signaling or
scaffolding function for DNA repair enzymes. When
DNA damage is extensive, as occurs in ischemia
reperfusion and other conditions that produce
oxygen free radicals, PARP consumption of NAD þ
can be sufficient enough to significantly exacerbate
energy failure. Accordingly, PARP inhibitors can
markedly reduce necrotic cell death in a variety of
experimental systems.
There is indirect evidence for apoptotic neuronal
death in several chronic neurological diseases,
including amyotrophic lateral sclerosis, Huntington’s
disease, Parkinson’s disease, Alzheimer’s disease, and
HIV-1 dementia. This evidence comes primarily from
animal and cell culture models of these diseases, in
which caspase inhibitors and genetic manipulation of
caspases or caspase regulatory proteins have been
shown in several settings to delay or attenuate cell
death. Direct morphological evidence for apoptotic
cell death is lacking; however, this may simply reflect

the fact that only a very small number of neurons are
dying at any one time in these chronic diseases. It has
also been suggested that mature neurons may not
express a classic apoptotic phenotype or may under-
go a nonapoptotic form of cell death in neurodegen-
erative disease.
There is also evidence suggesting a role for
apoptosis in mild cerebral ischemia, especially in
the immature brain. As in neurodegenerative dis-
eases, classic apoptotic morphology is rarely, if ever,
detectable. However, numerous studies have demon-
strated internucleosomal DNA fragmentation after
cerebral ischemia as well as increased expression of
the pro-apoptotic protein Bax in neurons destined to
die. Most important, both infusion of caspases
inhibitors and genetic upregulation of the anti-
apoptotic regulator Bcl-2 decrease infarct size in
rodent models of transient cerebral ischemia. These
findings reinforce the concept that programmed cell
death may take nonclassic forms in postmitotic cells
such as neurons, and they suggest that therapeutic
interventions in programmed cell death pathways
may prove effective in stroke and in other neurolo-
gical diseases.
—Raymond A. Swanson and Susana Castro-Obregón
See also–Alzheimer’s Disease; Amyotrophic
Lateral Sclerosis (ALS); Brain Tumors, Biology of;
HIV Infection, Neurological Complications of;
Huntington’s Disease; Ischemic Cell Death,
Mechanisms; Neurotrophins; Parkinson’s
Disease; Vertebrate Nervous System,
Development of
Further Reading
Clarke, P. G. (1990). Developmental cell death: Morphological
diversity and multiple mechanisms. Anat. Embryol. 181, 195–
213.
Earnshaw, W. C., Martins, L. M., and Kaufmann, S. H. (1999).
Mammalian caspases: Structure, activation, substrates,
and functions during apoptosis. Annu. Rev. Biochem. 68,
383–424.
Graham, S. H., and Chen, J. (2001). Programmed cell death in
cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 99–109.
Nijhawan, D., Honarpour, N., and Wang, X. (2000). Apoptosis in
neural development and disease. Annu. Rev. Neurosci. 23, 73–87.
Central Herniation
see Herniation
CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW 545
Central Nervous System
Infections, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE GROSS and microscopic neuropathology of
central nervous system (CNS) infections depends on
a number of different variables, including the
infectious organism, the mechanism by which the
infectious agent gains access to the CNS, environ-
mental influences, and systemic characteristics of the
patient. This entry reviews these general principles
and characteristics of CNS infections and illustrates
them with selective examples. Specific neuropatho-
logical details of CNS infections are well covered in
standard textbooks and review articles.
LOCALIZATION
Epidural and Subdural Spaces
Epidural and subdural infections, also known as
empyemas when accompanied by a purulent exudate,
develop following penetrating injuries, such as
trauma or surgical procedures, or occur as direct
extensions from infections of the adjacent bony
structures. Because of the relatively large epidural
space surrounding the spinal cord, abscesses in these
locations generally concentrate in the epidural space.
In contrast, the epidural spaces surrounding the brain
are small or nonexistent, so dural abscesses in this
location tend to involve the subdural space. Bacteria,
including acid-fast bacilli, are the usual infectious
organisms. The brain or spinal cord are damaged as a
result of compression from the overlying empyema,
venous infarction when the dural sinuses are throm-
bosed, or meningitis due to extension of the dural
abscess into the underlying subarachnoid space.
Subarachnoid Space
Meningitis is a generic term for infection and
inflammation of the subarachnoid space. Grossly, the
subarachnoid spaces are cloudy (Fig. 1) and may have
a slightly gritty sensation on light palpation. Micro-
scopically, the leptomeninges contain inflammatory
cells and the causative organism may be identified on
routine histology or with special stains. Bacterial
meningitis usually is associated with a purulent
exudate that fills the subarachnoid space and obscures
the underlying brain or spinal cord. In contrast,
inflammation is sparse with a viral meningitis and

the fact that only a very small number of neurons are
dying at any one time in these chronic diseases. It has
also been suggested that mature neurons may not
express a classic apoptotic phenotype or may under-
go a nonapoptotic form of cell death in neurodegen-
erative disease.
There is also evidence suggesting a role for
apoptosis in mild cerebral ischemia, especially in
the immature brain. As in neurodegenerative dis-
eases, classic apoptotic morphology is rarely, if ever,
detectable. However, numerous studies have demon-
strated internucleosomal DNA fragmentation after
cerebral ischemia as well as increased expression of
the pro-apoptotic protein Bax in neurons destined to
die. Most important, both infusion of caspases
inhibitors and genetic upregulation of the anti-
apoptotic regulator Bcl-2 decrease infarct size in
rodent models of transient cerebral ischemia. These
findings reinforce the concept that programmed cell
death may take nonclassic forms in postmitotic cells
such as neurons, and they suggest that therapeutic
interventions in programmed cell death pathways
may prove effective in stroke and in other neurolo-
gical diseases.
—Raymond A. Swanson and Susana Castro-Obregón
See also–Alzheimer’s Disease; Amyotrophic
Lateral Sclerosis (ALS); Brain Tumors, Biology of;
HIV Infection, Neurological Complications of;
Huntington’s Disease; Ischemic Cell Death,
Mechanisms; Neurotrophins; Parkinson’s
Disease; Vertebrate Nervous System,
Development of
Further Reading
Clarke, P. G. (1990). Developmental cell death: Morphological
diversity and multiple mechanisms. Anat. Embryol. 181, 195–
213.
Earnshaw, W. C., Martins, L. M., and Kaufmann, S. H. (1999).
Mammalian caspases: Structure, activation, substrates,
and functions during apoptosis. Annu. Rev. Biochem. 68,
383–424.
Graham, S. H., and Chen, J. (2001). Programmed cell death in
cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 99–109.
Nijhawan, D., Honarpour, N., and Wang, X. (2000). Apoptosis in
neural development and disease. Annu. Rev. Neurosci. 23, 73–87.
Central Herniation
see Herniation
CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW 545
Central Nervous System
Infections, Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE GROSS and microscopic neuropathology of
central nervous system (CNS) infections depends on
a number of different variables, including the
infectious organism, the mechanism by which the
infectious agent gains access to the CNS, environ-
mental influences, and systemic characteristics of the
patient. This entry reviews these general principles
and characteristics of CNS infections and illustrates
them with selective examples. Specific neuropatho-
logical details of CNS infections are well covered in
standard textbooks and review articles.
LOCALIZATION
Epidural and Subdural Spaces
Epidural and subdural infections, also known as
empyemas when accompanied by a purulent exudate,
develop following penetrating injuries, such as
trauma or surgical procedures, or occur as direct
extensions from infections of the adjacent bony
structures. Because of the relatively large epidural
space surrounding the spinal cord, abscesses in these
locations generally concentrate in the epidural space.
In contrast, the epidural spaces surrounding the brain
are small or nonexistent, so dural abscesses in this
location tend to involve the subdural space. Bacteria,
including acid-fast bacilli, are the usual infectious
organisms. The brain or spinal cord are damaged as a
result of compression from the overlying empyema,
venous infarction when the dural sinuses are throm-
bosed, or meningitis due to extension of the dural
abscess into the underlying subarachnoid space.
Subarachnoid Space
Meningitis is a generic term for infection and
inflammation of the subarachnoid space. Grossly, the
subarachnoid spaces are cloudy (Fig. 1) and may have
a slightly gritty sensation on light palpation. Micro-
scopically, the leptomeninges contain inflammatory
cells and the causative organism may be identified on
routine histology or with special stains. Bacterial
meningitis usually is associated with a purulent
exudate that fills the subarachnoid space and obscures
the underlying brain or spinal cord. In contrast,
inflammation is sparse with a viral meningitis and
546 CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW
Figure 1
Bacterial meningitis with thick tan–gray purulent exudate in
subarachnoid space that obscures the underlying brain. (A) Adult
with streptococcal meningitis over lateral surface of the cerebral
hemisphere. (B) Infant with Escherichia coli meningitis over
inferior surfaces of cerebral and cerebellar hemispheres and
brainstem. (See color plate section.)
only mild thickening of the meninges is observed.
Bacterial meningitis in adults tends to concentrate
over the top and sides of the brain (Fig. 1A), whereas
tubercular or fungal infections, and bacterial menin-
gitis in infants (Fig. 1B), typically involve the base of
the brain. Brain damage occurs from cerebral edema,
extension of the infection into the brain, or hemor-
rhage or infarction due to the development of
vasculitis within the meningeal infection.
Brain and Spinal Cord
Cerebritis (or myelitis) develops with bacterial and
fungal infections and may be secondary to meningi-
tis, penetrating injury, or hematogeneous dissemina-
tion from systemic infection. Small collections of
acute inflammatory cells indicate the start of a
bacterial abscess (Fig. 2A). Repair occurs with
peripheral infiltration of macrophages, new blood
vessels, and fibrosis (granulation tissue), and a
fibrous capsule eventually walls off the abscess
(Fig. 2B). Abscess repair and capsule formation is
time dependent and typically follows a stereotypic
pattern of organization. Cerebral toxoplasmosis is a
major exception to the general rule that brain
abscesses heal by fibrous encapsulation. With tox-
oplasmosis, inflamed, necrotic brain is walled off by
a thin rim of macrophages, with the eventual
formation of a cystic cavity resembling an old infarct
rather than a fibrous capsule. Encephalitis is the term
for viral and rickettsial infections of brain; organiza-
tion and healing occur by microglial activation,
neuronal loss, and reactive astrocytosis (Fig. 3).
Neurons and Glia
Selective necrosis of neurons or glia is characteristic
of viral infections because there are specific interac-
tions between viral proteins and cell surface recep-
tors on the host cells. An example of this is the
interaction between the poliovirus and the acetylcho-
line receptor of anterior horn cells in the spinal cord.
Productive viral infection can produce intranuclear
inclusions as seen with cytomegalovirus (Fig. 3A),
herpes simplex virus infection, or SV40 papovavirus
infection of oligodendroglia in progressive multifocal
leukoencephalopathy (PML). Cytoplasmic viral in-
clusions are characteristic of rabies virus infection
(Fig. 3B). Following viral infection of neurons,
microglia and monocytes surround and phagocytose
the dying neuron, a process given the graphic
description of neuronophagia (Fig. 3C). Viral infec-
tion of oligodendroglia causes demyelination. This
develops in PML and, less commonly, varicella-
zoster virus.
Cerebral Ventricles
Ependymitis and choroid plexitis may accompany
meningitis or cerebritis or directly arise from
hematogeneous dissemination to the choroid plexus.
 CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW 547

SYSTEMIC AND ENVIRONMENTAL FACTORS

AFFECTING THE NEUROPATHOLOGY OF
CNS INFECTIONS
The likelihood for brain infection increases when
there is preexisting infection in other parts of the
body, particularly the lungs and the heart valves, or

Figure 2
(A) Acute inflammation with early microabscess formation. (B)
Abscess with fibrous capsule (Masson trichrome). (See color plate
section.)

In the latter condition, secondary cerebrospinal fluid

(CSF) dissemination spreads infection to the brain
and spinal cord. This mode of spread may be
particularly important in bacterial infections of
children and in parasitic diseases of Chagas’ disease
and toxoplasmosis. Certain infections exhibit a
predilection for the ependyma or subventricular
areas, including congenital syphilis and cytomegalo-
virus encephalitis.

INFLAMMATION
Each group of infectious agents elicits certain types
of inflammatory responses in the CNS (Figs. 2A and
4). This is outlined in Table 1, which provides
general guidelines for analyses of CSF cytology and
brain biopsies. However, many exceptions exist to
these general rules and are dependent on specific Figure 3
(A) Intranuclear inclusion of cytomegalovirus; cytoplasm is
characteristics of certain organisms. For example,
immunoreactive for cytomegalovirus antigen. (B) Intracytoplasmic
acute inflammation accompanies herpes simplex inclusion (Negri body) (arrows) of rabies virus. (C) Microglial
virus and the initial inflammatory response to the proliferation and neuronophagia in rabies encephalitis. (See color
coxsackievirus or poliomyelitis. plate section.)
548 CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW

SECONDARY CONSEQUENCES OF
CNS INFECTION
Vasculitis with subsequent cerebral infarction or
hemorrhage or aneurysmal formation can occur in
the setting of meningitis or when there is actual
infection of the blood vessel. This latter condition is
characteristic of certain fungal infections (candida,
aspergillus, and mucormycosis) and the resultant
neuropathology is a combination of fungal cerebritis
and cerebral ischemia and hemorrhage (Figs. 5A and
5B). The encapsulation of Cryptococcus neoformans
produces a gelatinous exudate that expands the
meningeal and perivascular spaces and produces a
typical gross neuropathological appearance. The
larvae of Taenia solium (cysticercosis) typically
spread to the brain, where they encyst and remain
viable for years without eliciting inflammation and
capsule formation until their death (Fig. 5C).
The brain’s reaction to infection and its mode of
repair are dependent on the inflammatory reaction
and characteristics of the infectious organism. Acute
purulent inflammation is accompanied by brain
edema, and a secondary vasculitis can cause brain
hemorrhage and infarction. If severe, meningitis can
leave residual fibrosis with obstruction of the normal
Figure 4 CSF flow and development of obstructive hydro-
(A) Microglial nodules and multinucleated giant cells in a patient cephalus (Fig. 5D). Microglial activation, typically
with HIV encephalitis. (B) Creutzfeld–Jakob disease displays seen with viral infections, is accompanied by
parenchymal vacuolation but inflammation is absent.
secondary neuronal injury due to release of neuro-
toxic substances, such as cytokines and free radicals.
This mechanism of brain damage is typified by HIV,
in which brain atrophy and neuronal injury and
when the immune system is suppressed. In the latter
condition, primary CNS infection may be unusually
severe and widely distributed, or latent infections can
Table 1 INFLAMMATION IN CNS INFECTIONS
reactivate and spread to the CNS. Such opportunistic
infections include cryptococcus, aspergillus, and Inflammatory
candida fungal infections; cerebral toxoplasmosis; Infection response Cell type
cytomegalovirus; and PML. In addition, immune
Bacteria Acute inflammation Polymorphonuclear
suppression reduces the inflammatory response in leukocytes
parallel with the severity of the systemic immune Acid-fast Granulomatous Lymphocytes,
suppression. Chronic medical conditions may pre- bacilli inflammation histiocytes, giant cells
dispose to certain infections, as seen with diabetes Spirochetes Subacute Lymphocytes, plasma
and infection with mucormycosis. Environmental inflammation cells
factors that influence the presence of infectious Fungi Chronic inflammation Lymphocytes, giant cells
organisms in the local community will influence Parasites Chronic inflammation Lymphocytes,
their potential to infect the CNS. A recent, dramatic eosinophils
example in certain areas of the world is the Rickettsia Chronic inflammation Lymphocytes, microglial
nodules
introduction of spongiform encephalopathy in cows
Viruses Chronic inflammation Lymphocytes, microglial
(bovine spongiform encephalopathy) with secondary
nodules
spread to humans as new variant Creutzfeld–Jacob
Prions None
disease.
 CENTRAL NERVOUS SYSTEM INFECTIONS, OVERVIEW
Figure 5
(A) Aspergillus fungus infiltrating brain tissue and artery. (B) Hemorrhage and necrosis of basal ganglia and cerebral white matter due to
aspergillus infection. (C) Encapsulated abscess due to cysticercosis larva. (D) Section of medulla with meningeal fibrosis and obstruction of
the foramena of Luscha. (See color plate section for A and B.)
death may be due to the inflammatory response
rather than to direct viral infection of neurons.
—Carol K. Petito
See also–Central Nervous System
Malformations; Central Nervous System,
Overview; Central Nervous System Tumors,
Epidemiology; Immune System, Overview;
Lymphatic Drainage of the Central Nervous
System; Measles Virus, Central Nervous System
Complications of; Neuroimmunology, Overview
Acknowledgments
The helpful critiques of Dr. Micheline McCarthy are gratefully
appreciated. This entry was supported in part by the National
Institutes of Health Grant RO1-NS39177.
Further Reading
Brown, P., Wolff, A., and Gajdusek, D. C. (1990). A simple and
effective method for inactivating virus infectivity in formalin-
549
fixed tissue samples from patients with Creutzfeldt–Jakob
disease. Neurology 40, 887–890.
DeArmond, S. J., and Prusiner, S. B. (1995). Etiology
and pathogenesis of prion diseases. Am. J. Pathol. 146,
785–811.
Falangola, M. F., Reichle, B. S., and Petito, C. K. (1994).
Histopathology of cerebral toxoplasmosis in HIV infection: A
comparison between patients with early AIDS and late AIDS.
Hum. Pathol. 25, 1091–1097.
Flaris, N. A., and Hickey, W. F. (1992). Development and
characterization of an experimental model of brain abscess in
the rat. Am. J. Pathol. 141, 1299–1307.
Gonzalez-Scarano, F., and Tyler, K. L. (1987). Molecular
pathogenesis of neurotropic viral infections. Ann. Neurol. 22,
565–574.
Nelson, J. S., Parisi, J. E., and Schochet, S. S., Jr. (Eds.)
(1993). Principles and Practice of Neuropathology. Mosby,
St. Louis.
Pruitt, A. A. (1998). Infections of the nervous system. Neurol.
Clinics 16, 419–447.
Rajnik, M., and Ottolini, M. G. (2000). Serious infections of the
central nervous system: Encephalitis, meningitis, and brain
abscess. Adolescent Med. 11, 401–425.
 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
Gilman, S. (1996). Manter and Gatzs’ Essentials of Clinical
Neuroanatomy and Neurophysiology, 9th ed. Davis, Philadel-
phia.
Haines, D. E. (2000). Neuroanatomy: An Atlas of Structions,
Sections and Systems, 5th ed. Lippincott Williams & Wilkins,
Baltimore.
Haines, D. E. (2002). Fundamental Neuroscience, 2nd ed.
Churchill Livingstone, New York.
Kandel, E. R., Schwartz, J. H., and Jessell, T. M. (2000). Principles
of Neural Science, 4th ed. McGraw-Hill, New York.
Leblanc, A. (1995). The Cranial Nerves: Anatomy, Imaging,
Vascularisation, 2nd ed. Springer-Verlag, Berlin.
Central Nervous System
Tumors, Epidemiology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IT WAS ESTIMATED that in 2000, 16,500 individuals
in the United States would be diagnosed with a
malignant primary nervous system tumor and 13,000
of these would die from the disease. When benign as
well as malignant brain tumors are included, the
incidence is more than twice that for malignant brain
tumors alone. Only about half of patients with
malignant brain tumors are still alive 1 year after
diagnosis. Epidemiology studies the distribution of
primary tumors of the brain, cranial meninges, and
cranial nerves (hereafter called brain tumors) in
human populations to obtain clues as to the causes of
these tumors. This entry summarizes key descriptive
epidemiological findings related to the patterns of
brain tumor occurrence and also reports suggestive
etiological findings from analytical epidemiological
studies.
Although the incidence of brain tumors, particu-
larly the more lethal subtypes, increased in recent
decades, it appears that trends in childhood brain
tumors and adult tumors increased due to the
introduction of diagnostic improvements, including
computed tomography (CT) scans in the mid-1970s
and magnetic resonance imaging (MRI) in the mid-
1980s. This issue and the recent explosion of
epidemiological and molecular genetic studies of
brain tumors have focused attention on this impor-
tant human cancer that until only a few decades ago
was relatively little studied. Despite this surge of
interest, the etiology of the majority of nervous
system tumors remains unknown. Inherited syn-
dromes that predispose affected individuals to brain
tumor development and/or the presence of nervous
557
system tumors in other family members appear to be
present in fewer than 5% of brain tumor patients.
Some environmental agents, in particular ionizing
radiation, are clearly implicated in the etiology of
brain tumors but also appear to account for few cases.
Numerous other physical, chemical, and infectious
agents that have long been suspected risk factors have
not been established as etiologically relevant.
This entry focuses on tumors of the brain, cranial
nerves, and cranial meninges, which account for
95% of all central nervous system (CNS) tumors.
These tumors are unique because of their location
within the bony structure of the cranium. Symptoms
depend on location of the tumor. Furthermore,
histologically benign tumors can result in similar
symptomatology and outcome as malignant tumors
because growth of both normal and tumor tissue is
confined to the cranial space. For this reason, some
cancer registries voluntarily include both benign and
malignant intracranial tumors. For simplicity, this
group of tumors will be called brain tumors or, when
benign tumors are excluded, brain cancer. The term
central nervous system tumors (or cancer) indicates
that tumors of the spinal cord and spinal meninges
are included along with brain tumors, and the term
nervous system tumors indicates that tumors of the
peripheral nerves are included as well.
DESCRIPTIVE EPIDEMIOLOGY
Variation in Inclusion Criteria
The descriptive epidemiology of CNS tumors has
been difficult to study because of the wide variation
in specific tumors included in published frequency
rates. Quantitatively, the most important variation is
estimated to be approximately 50% and relates to
the inclusion or exclusion of benign tumors. This
critical difference has often been ignored in compar-
isons across geographic areas. Benign tumors are
included from descriptive data for Los Angeles
County discussed in this entry. It should be noted
that pineal and pituitary tumors, included in some
standard definitions of brain and CNS tumors, are
not included. As will become clear from later
discussion of analytical (i.e., etiological) studies, more
is known about the etiology of benign histological
types such as meningiomas than about the etiology of
neuroepithelial tumors, which are more common
than meningiomas and usually malignant.
Another variation relates to whether or not
clinically diagnosed tumors are included. The
558 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY

microscopic confirmation rate of brain and nervous
system cancers varies widely (from 0 to 100%)
across geographic areas, registries, and specific
population groups covered by a registry. In general,
for relatively inaccessible cancer sites, a higher rate
of microscopic confirmation increases the likelihood
that a neoplasm actually existed and that it was
correctly classified. On the other hand, in some
registries a very high rate of microscopic confirma-
tion (e.g., 100%) of brain tumors may indicate that
clinically or radiologically diagnosed tumors may
have been missed. With the advent of radiosurgery,
which does not allow for pathological examination
of tumor tissue, this is an increasing limitation.
Pathological Classification
Because brain tumors are morphologically and
cytogenetically diverse, most studies attempt to
define homogeneous subgroups for the purpose of
epidemiological analyses. Histological groups of
tumors that occur within the CNS and their
corresponding International Classification of Dis-
eases for Oncology (ICD-O) codes are listed in Table
1. Rorke et al. proposed a modification of this
scheme for classification of pediatric brain tumors. In
both children and adults, neuroepithelial tumors
(more commonly called gliomas) are the most
common major histological type; these are predomi-
nantly malignant tumors that arise in the glial cells
that comprise the supporting structure for the brain.
In Los Angeles, neuroepithelial tumors account for
59% of primary tumors of the brain and cranial
meninges among men and 42% among women.
More than 80% of neuroepithelial tumors are
astrocytic gliomas (i.e., astrocytomas and glioblasto-
ma multiforme). Astrocytic tumors that are grades 1
and 2 are generally classified as astrocytomas, those
that are grade 3 are classified as anaplastic astro-
cytomas, and those that are grade 4 are classified as
glioblastomas. The possibility that this practice is not
followed consistently is suggested by the considerable
geographic variation in the relative proportions of
astrocytic tumors that are classified as glioblastomas.
This variation is seen, for example, among the
various U.S. registries in the SEER program.
The other two most common major histological
types are predominantly benign. Meningiomas arise
in the cranial meninges and account for 20% of all
primary brain tumors in men and 36% in women.
Nerve sheath tumors, called neuromas, neurilemmo-
mas, or schwannomas, arise in the Schwann cells of
the nerve sheath. Approximately 8% of brain tumors
in both men and women are nerve sheath tumors. It
is interesting that approximately 90% arise in the
eighth cranial nerve; these are called acoustic
neuromas.
Improved diagnostic technology is currently avail-
able in many general hospitals in the United States

Table 1 ANATOMICAL AND PATHOLOGICAL CLASSIFICATION OF TUMORS OF THE CENTRAL NERVOUS SYSTEM

Subsite ICD-Oa code, 1976 ICD-O code, 1991

Brain 191.0–191.9 C 71.1–C 71.9
Cranial nerve 192.0 C-72.2–C72.5
Cerebral meninges 192.1 C-70.0
Spinal cord 192.2 C-72.0
Spinal meninges 192.3 C-70.1

Histological type ICD-O code

Neuroepithelial tumors 9380–9481 —
Astrocytoma 9384, 9400–21 —
Glioblastoma multiforme 9440–42 —
Ependymoma 9391–94 —
Primitive 9470–73 —
Neuroectodermal Tumor (PNET)
Oligodendroglioma 9450–60 —
Other neuroepithelial tumors 9380–83, 9390, 9422–30, 9443, 9472–81 —
Meningioma 9530–39 —
Nerve sheath tumors 9540–60 —
Other 9120–61 —
Unspecified 8000–02 —
No microscopic confirmation 9990 —
a
ICD-O, International Classification of Disease for Oncology.
 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
and other industrialized countries, and the differen-
tial diagnosis of intracranial masses is often made by
physicians who are not specialists in neurological
disease. The heterogeneous nature of many CNS
tumors makes the assignment of histological class
difficult. Accuracy of clinical diagnosis of primary
brain tumors will continue to vary by geographical
region and hospital, even though CT and MRI are
now available in many regions of the United States,
due to variation in how the equipment is used and
the degree of training of individuals who interpret
the films.
Distribution by Age and Changes in Age
Incidence Curves over Time
The average annual age-specific incidence of brain
tumors is shown in Fig. 1. In both males and females,
rates decline after a peak in childhood (younger than
age 10), increase after age 25, and level off after age
75. Comparisons of data from different areas of the
United States have shown that the shape of the age–
incidence curve after age 60 is highly dependent on
the autopsy rate and completeness of diagnosis in the
elderly. These comparisons suggest that brain tumor
incidence continues to increase with age throughout
life but that there is, or at least there was, often a
significant underascertainment of cases in the oldest
age groups. Therefore, historical comparisons of
Figure 1
Age-specific incidence (per 100,000) of tumors of the brain, cranial nerves, and cranial meninges (benign and malignant combined) in males
and females, Los Angeles County, 1972–1998, whites (excluding Spanish-surnamed). Total cases ¼ 6777 males and 6947 females.
559
brain tumor rates from different registries are
hampered by the changes in the widespread avail-
ability of neural specialists across geographic areas
and over time; such comparisons might be more
meaningful if restricted to age groups younger than
age 65. The dramatic increase in brain tumor
incidence rates in the elderly in recent decades
indicates that this underascertainment has become
less pronounced.
Distribution by Gender, Race,
and Geography
Figure 1 shows that for all types of brain tumors
combined, rates are higher in males than in females.
Table 2 shows the age-adjusted annual incidence
rates for the major histological groups of primary
brain tumors by sex and ethnic group in Los Angeles
County from 1972 to 1997. Surname, maiden name,
and information on ethnicity available from medical
records are all used to determine Hispanic ethnicity.
For all histological types and races combined, the
rate is higher in men than in women. For most ethnic
groups, male rates for all histological types combined
are higher than female rates. However, the male:fe-
male sex ratio (SR) varies considerably by histologi-
cal type. In each ethnic group, neuroepithelial tumor
rates are higher in males than in females (SR for all
races combined ¼ 1.5), and meningioma rates are
560 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY

Table 2 AVERAGE ANNUAL AGE-ADJUSTEDa INCIDENCE RATES (PER 100,000) BY MAJOR HISTOLOGICAL TYPE OF PRIMARY BRAIN
TUMOR BY SEX AND ETHNIC GROUP, LOS ANGELES COUNTY, 1972–1998

Neuroepithelial Meningioma Nerve sheath All histologies No.

Males Black 4.2 2.1 0.4 7.9 825

Spanish surnamedb 4.6 1.3 0.4 7.7 1542
Other whites 6.9 1.7 1.0 11.2 6777
Chinese 2.8 0.7 0.3 4.6 99
Japanese 2.0 0.7 0.8 4.5 75
Filipino 2.6 1.7 0.7 5.8 103
Korean 2.6 0.6 0.1 3.7 49
Other races 2.1 1.3 0.7 4.7 144
All races 5.7 1.6 0.8 9.5 9614

Females Black 2.9 3.1 0.4 7.2 885

Spanish surnamedb 3.6 2.4 0.5 7.4 1528
Other whites 4.7 3.0 1.0 9.7 6947
Chinese 1.8 1.5 0.4 4.2 90
Japanese 1.2 1.4 0.6 3.9 79
Filipino 2.0 2.0 0.6 5.1 114
Korean 1.9 1.1 0.3 4.7 63
Other races 1.5 2.2 0.8 4.8 178
All races 3.9 2.8 0.8 8.5 9884
a
Age-adjusted by the direct method to the 1970 U.S. population.
b
Maiden name and medical chart information on ethnicity used in addition to surname.

higher in women (SR ¼ 0.6). The SR in children
younger than age 15 is 1.2 for all tumor types
combined. In contrast, primitive neuroectodermal
tumors (PNETs; formerly called medulloblastoma),
which occur almost exclusively in children, have an
SR of approximately 2, but no male excess is seen
among U.S. black children.
SRs for specific histological types also vary by
anatomical subsite and by age group. One of the
most interesting examples of this relates to menin-
giomas. Among non-Spanish-surnamed whites in Los
Angeles County, spinal meningiomas are 3.5 times
more common in women than in men (SR ¼ 0.3),
whereas cerebral meningiomas are only 1.5 times
more common in women (SR ¼ 0.7). Similar patterns
are seen for meningiomas in Norway. Also, the
female:male ratio for spinal meningiomas increases
with age, whereas for cerebral meningiomas the
female excess is greatest during the reproductive
years and declines after age 55. The sex differential
for spinal meningiomas suggests the etiological
relevance of some factor related to aging in women.
We hypothesized that this factor may be vertebral
osteoporosis, and a series of three epidemiological
studies designed to test this hypothesis provide some,
although limited, support.
Rates of neuroepithelial tumors are lower among
black males and females than among whites, but the
reverse is true for meningiomas (Table 2). In general,
rates among whites in Canada, the United States,
Europe, the United Kingdom, and Australia are
relatively similar, although rates are lower in certain
Eastern European countries and former Soviet
republics (Russia, Belarus, and Krygystan). Rates
are lowest in Asian populations in Japan, India, and
among the Chinese in Singapore. Rates are also
lower in Puerto Rico, Costa Rica, and Brazil. Among
each racial group, rates are usually higher in migrant
populations than in native populations that remain in
their country of origin. These differences between
migrant and native populations suggest that some
change in lifestyle may be occurring in migrant
populations that places them at higher risk for brain
tumors, although an increase in diagnostic efficiency
may be an alternate explanation for these differences.
Social Class
Age-adjusted data for all primary tumors of the brain
and cranial meninges by social class (as determined
by census tract of residence) for Los Angeles County
non-Spanish-surnamed whites show a clear trend of
increasing incidence with increasing social class. For
males, this trend is evident for neuroepithelial tumors
and nerve sheath tumors. For females, this trend is
clearly evident only for nerve sheath tumors. The
exception to this is meningiomas, which show the
 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
inverse relationship among both males and females.
A similar trend of increasing overall brain cancer
rates with increasing social class (as determined by
occupation) was reported for men in Washington
state and New Zealand. Because this trend occurs
more strikingly among males than among females, it
seems unlikely that it might relate to factors such as
diagnostic efficiency or exposure to diagnostic radio-
graphy of the head (e.g., dental x-rays), both of
which might be expected to be greater among those
in higher social classes.
Survival
Recent relative 5-year survival rates for brain and
nervous system cancer are approximately 25% (24%
for whites and 32% for blacks among U.S. cases
diagnosed from 1981 to 1986) compared to less than
20% 20 years ago. Survival rates for all tumors vary
considerably by location, behavior, histological type,
and age.
Summary of Descriptive Epidemiology
Perhaps the most important finding from this review
of the descriptive epidemiology of brain tumors is
that the pattern of occurrence and survival both vary
considerably by histological type, age, and tumor
location. For neuroepithelial tumors, the sex ratio is
greater than 1; incidence declines after an early peak
at less than 10 years of age and rises again after age
25; rates are higher in whites than nonwhites and are
lowest in Asians; and incidence increases with
increasing social class, particularly in males. For
meningiomas, the sex ratio is less than 1, the female
excess is greatest from ages 25 to 54, and rates in
U.S. populations are commonly higher in blacks than
in whites.
SUGGESTED CAUSES OF HUMAN
BRAIN TUMORS
Ionizing Radiation
The occurrence of excess brain tumors after high-
dose exposure to ionizing radiation is well estab-
lished. A follow-up of an Israeli cohort that received
scalp irradiation as a treatment for ringworm
showed that the relative risk is greatest for nerve
sheath tumors of the head and neck (RR ¼ 33.1),
intermediate for meningiomas (RR ¼ 9.5), and low-
est for neuroepithelial tumors (RR ¼ 2.6). Children
with leukemia who received radiation treatment to
the CNS have an increased risk of developing a
561
primary brain tumor. Case-control studies of menin-
giomas and nerve sheath tumors in adults have found
elevated risks associated with exposure to full-mouth
dental x-rays decades ago when doses were relatively
high as well as with prior radiation treatment to the
head. The association with low-dose exposure is
more controversial. Prenatal exposure to diagnostic
radiography has been related to excess pediatric
brain tumors in several studies since this association
was first reported in 1958, including a study of
Swedish twins that found that abdominal x-rays of
the mother during pregnancy were associated with
increased CNS tumor incidence. The findings ap-
peared not to be confounded by mother’s age,
obstetrical complications, or other factors.
Nonionizing Radiation
Much controversy in the past 15 years has sur-
rounded the suggestion that exposure to nonionizing
electromagnetic radiation such as power frequency
(50–60 Hz) magnetic fields might contribute to the
development of CNS tumors. These fields have not
been shown experimentally to be either genotoxic or
carcinogenic, but there is some suggestion that they
may act as a tumor promoter. Epidemiological
evidence is inconsistent both in studies of residential
exposures and pediatric CNS tumors and in studies
of CNS cancer in relation to high levels of job
exposure. Two recent studies showed no evidence of
a link between residential exposure and brain tumors
in children, and a review article concluded that
overall there is little evidence of an association. A
comparative analysis of studies of electric utility
workers suggests a small increase in brain tumor risk
but notes that findings vary across studies, as do
exposure measurements.
Studies of the effect of radiofrequency (RF)
exposure in humans have included microwave
exposures, the use of radar equipment (occupational
and handheld), and direct occupational exposures
such as would occur for those working with RF
heaters, sealers and plastic welders, some medical
workers, amateur radio operators, and telecommu-
nication workers. In general, relative risks are small,
not statistically significant, and inconsistent across
studies. An association between cellular telephone
usage and the development of brain tumors has been
suggested in the legal arena. The rapid increase in the
use of cellular telephones combined with their direct
exposure to selected regions of the brain have
stimulated epidemiological research that to date has
reported no associations.
562 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
Occupational Exposures
Numerous epidemiological studies have investigated
the variation in brain tumor occurrence as it relates
to employment, but repeated studies in various
geographic areas have been completed for only a
few groups of workers, including those employed in
agricultural or health professions and rubber, petro-
chemical, and electrical workers. A recent meta-
analysis of 33 studies of brain cancer and farming
found an increased risk of 1.25 among farmers in the
central United States. For the most part, however,
various studies of each occupational group have
provided conflicting results and no specific chemical
or other exposure has been implicated. Even when,
prompted by experimental findings, a particular
chemical exposure is investigated, results are often
inconclusive, but a recent review of studies of
workers exposed to vinyl chloride concluded that
this exposure has not caused brain tumors.
Similarly, several studies have investigated possible
associations between occupational exposures of
parents and the development of brain tumors in
their children. Multiple studies have suggested an
increase in pediatric brain tumor risk among children
with a parent employed in paint-related, aircraft,
electricity-related, agricultural, metal, and construc-
tion industries, although these studies have failed to
conclusively implicate any particular exposure.
Pesticides
Several epidemiological studies have investigated
home and occupational use of pesticides, insecticides,
or herbicides as possible etiological factors for brain
tumors. A twofold increased risk of brain cancer was
found in a study of licensed pesticide applicators and
occupational exposure to pesticides. Some case-
control studies have linked household use or pest
exterminations to the development of childhood
brain tumors, but few associations were seen in a
recent study of pesticide exposure during gestation
and childhood brain tumors. Associations of CNS
tumors with either household or occupational
exposures to pesticides are not well established and
require confirmation.
Nitroso Compounds
Although various chemical, physical, and biological
agents can cause nervous system tumors in experi-
mental animals, N-nitroso compounds (NOCs),
particularly the nitrosoureas, are by far the most
effective and the most studied. These carcinogens
show marked nervous system selectivity in some
species, including various primates, and tumors can
be produced by relatively low levels of NOC
precursors in the animals’ food and drinking water.
If exposure is transplacental, only one-fiftieth (1/50)
of the dose of ethylnitrosourea (ENU) required in
adult animals is sufficient to cause 100% tumor
induction. However, no tumors develop if ascorbate
(vitamin C) is also added to the pregnant dam’s diet.
Because there is no reason to believe that humans are
less susceptible to these compounds, it is likely that
NOCs cause cancer in humans as well. Although
NOC exposures in some occupational settings (e.g.,
machine shops and tire and rubber factories) can be
substantial, most people have low-level, but virtually
continuous, exposure to NOCs throughout life.
However, because NOCs are the most potent of
carcinogens in animals (and likely in humans as
well), only small doses are needed to cause cancer.
Epidemiological studies of pediatric and adult
brain tumor patients have provided limited support
for the hypothesis that NOC exposures are related to
the development of CNS tumors. The finding that use
of vitamin supplements and/or high intake of fresh
fruit or vegetables protect against brain tumor
development might also be interpreted as supportive
of the N-nitroso hypothesis, although this effect may
be due to another mechanism. The experimental
model and its potential relevance to humans are
sufficiently compelling to encourage further investi-
gation of this hypothesis despite the fact that it is
difficult to test epidemiologically. Future studies must
include more complete dietary histories to differenti-
ate between findings supportive of the NOC/brain
tumor hypothesis and those suggestive of other
mechanisms for dietary effects.
Other Dietary Factors
The majority of dietary investigations of CNS tumor
patients have only collected data on dietary sources
of NOC exposures rather than complete dietary
histories. Nonetheless, these studies have attempted
to evaluate the association between certain dietary
micronutrients and brain tumor risk; adequate
evaluation of micronutrient intake will require
investigation of complete dietary histories. Use of
vitamin supplements, particularly vitamins C and E
and multivitamins, has been found to reduce brain
tumor risk in adults in some studies but not others. In
children, risk may be reduced by their personal
 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
vitamin use, by their mother’s vitamin use during
pregnancy, or by her intake of fruit, fruit juice, and
vegetables.
Although the finding of reduced risk of brain
tumors in children and adults associated with
increased intake of vitamin supplements, fruits, and
vegetables may be related to the N-nitroso hypoth-
esis by the inhibition of endogenous formation of
nitrosureas, it is important to consider other poten-
tial mechanisms of effect. In this respect, it is
interesting that a study of childhood brain tumors
reported higher relative risks associated with chil-
dren’s consumption of cured meats when they did not
take multivitamins than when they did take multi-
vitamins.
Recent studies have investigated the possible
associations of brain tumors with other dietary
micronutrients. In particular, a case-control study
of childhood PNET found significant protective
trends with increasing levels of dietary vitamins A
and C, betacarotene, and folate by the mother during
pregnancy. In a related study of childhood astro-
cytoma, reduced risks were evident for dietary
vitamins A and C, but these trends were not
significant. There was no relationship of childhood
astrocytoma to dietary betacarotene or folate.
Although these preliminary results suggest exciting
prospects for the possible prevention of childhood
brain tumors, interpretation is difficult because both
studies were primarily focused on the evaluation of
dietary NOCs. Thus, evaluation of other micronu-
trients was limited to the micronutrient composition
of NOC-related food items. A recent Israeli study in
which complete dietary histories for the relevant
pregnancies were obtained did not confirm the
associations suggested by earlier studies; instead, it
found that brain tumor risk in offspring was
increased among mothers who had higher intakes
of vegetable fat and potassium. These conflicting
results highlight the need to incorporate complete
dietary evaluations in future epidemiological studies
of various populations.
Recent studies have also suggested an association
of brain cancer with household drinking water levels
of nitrate, chlorine, or trihalomethanes. Caution is
urged in the interpretation of such studies, however,
because of assumptions made in exposure assessment.
Prior Head Trauma, Infection, or Other
Medical Conditions
The epidemiological evidence associating head trau-
ma and brain tumors is strongest for meningiomas.
563
Numerous case reports present convincing circum-
stantial evidence, and case-control studies have
found an excess risk of meningiomas in women with
histories of head trauma treated medically, in men
who boxed as a sport, and in men with histories of
serious head injuries. Limited experimental evidence
suggests that trauma may act as a cocarcinogen in the
induction of neuroepithelial tumors as well as
meningiomas. Childhood brain tumors, which are
predominantly neuroepithelial tumors, have some-
times been associated with birth trauma (prolonged
labor, forceps delivery, and cesarean section). Be-
cause trauma is often regarded by laypersons as
related to tumor development, an attempt must be
made to limit reporting of trauma to injuries of a
certain minimum severity (such as those requiring
medical attention or hospitalization) and thereby
limit recall bias.
The observation that more than 90% of all nerve
sheath tumors arise in the eighth cranial (acoustic)
nerve suggests an exposure unique to this nerve. A
case-control study of acoustic neuromas in Los
Angeles County residents supports the hypothesis
that acoustic trauma may relate to the development
of these tumors. A dose–response analysis showed an
increase in risk related to the number of years of job
exposure to extremely loud noise (P for tren-
d ¼ 0.02), with an OR of 13.2 (CI ¼ 2.01, 86.98)
for exposure of 20 or more years accumulated up to
10 years before diagnosis. Although noise exposure
can cause hearing loss, other symptoms led to tumor
diagnosis in these patients. These findings may
support the general hypothesis that mechanical
trauma may contribute to tumorigenesis.
Astrocytomas, but not other histological types of
brain tumors, were previously associated with
positive antibody titers to Toxoplasma gondii, but
a recent study failed to confirm this association.
There are numerous reports in the literature of the
isolation of viruses or virus-like particles from
human cerebral tumors or tumor cell lines, but
whether these findings have etiological implications
is uncertain. Recent reviews of the conflicting
literature conclude that excess brain tumors have
not been found among those who received polio
vaccine contaminated with SV40 or those whose
mothers had influenza or various other infections
while they were in utero.
Excesses of brain tumors reported in various
cohorts of epileptics most likely occur because
seizures are a common early brain tumor symptom.
Studies have found no increase in risk related to
564 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
in utero or childhood exposure to barbiturates after a
history of epilepsy was considered.
Brain tumors have been associated with various
other chronic diseases, but none of these associations
has been investigated in more than one or two
studies, with the exception of a consistent finding
across studies from several countries of a deficit of
allergic conditions, particularly among patients with
neuroepithelial tumors. Neuroepithelial tumors, but
not meningiomas, occur much less frequently in
diabetics, who have a lower frequency of all cancers
at autopsy. Serum cholesterol has been positively
related to brain cancer in some, but not all, studies,
but because no studies have evaluated dietary intake,
the possibility that an existing brain tumor might
cause a spurious increase in serum cholesterol has
not been excluded.
Clinicians should be aware that an association
between meningiomas and breast cancer and, re-
cently, colon cancer has been observed so that they
will not assume that CNS lesions that are discovered
after breast or colon cancer diagnosis and treatment
are necessarily metastatic. Tissues from meningiomas
have been shown to contain hormone receptors, but
it is unclear whether this finding has etiological
implications.
Predisposing Genetic Syndromes and
Familial Occurrence
Some CNS tumors have a relatively clear genetic
character, particularly those occurring in association
with neurofibromatosis and other phakomatoses,
which often display an autosomal dominant pattern
of inheritance with varying degrees of penetrance.
Occurrence of multiple primary brain tumors, of
either similar or different histological types, is
associated with the phakomatoses but is also
observed in the absence of such syndromes.
Data from registries of families with multiple
members diagnosed with primary brain tumors are
difficult to evaluate because they are not population
based. The few population-based studies of familial
aggregation of CNS tumors have been the most
informative. Population-based studies of children
with CNS tumors, particularly those with medullo-
blastoma and glioblastoma, have consistently found
that these children are more likely than control
children to have relatives with nervous system
tumors, but this familial occurrence, although
statistically significant, is observed for fewer than
2% of children with CNS tumors. It needs to be kept
in mind that population-based studies that have
investigated associations of brain tumors with
recognized predisposing genetic syndromes and/or
with familial aggregations indicate that the propor-
tion of brain tumors attributable to inheritance is less
than 5%.
Other Suggested Risk Factors
A number of other factors have been suggested to be
related to brain tumor risk, including barbiturates
and other drugs, alcohol, tobacco smoke, and
reproductive and hormonal factors. These possible
associations have not been studied often or very
thoroughly, and for some factors (e.g., alcohol and
tobacco) conflicting results have been obtained. The
best one can do in attempting to evaluate their
etiological relevance is to keep them in mind and
hope that these possible associations will be investi-
gated in the future.
PATHOGENESIS OF NERVOUS
SYSTEM TUMORS
Various physical, infectious, and chemical agents
appear to relate to the development of cancer
because they increase cell proliferation; for example,
this may explain why acoustic trauma can lead to the
development of acoustic neuromas. Replication may
perpetuate a DNA mutation before it can be
corrected in the cell in which it arises. Apparently,
various genetic pathways can be involved in the
pathogenesis of CNS tumors, and this may be true
even for tumors of the same phenotype. Although
many of the inherited syndromes that predispose to
CNS tumors were described decades ago, the
chromosomal locus of the affected gene has not been
identified for most. In the past decade, hundreds of
investigators have described molecular events that
they have observed in tumor tissue from patients
with various types of CNS tumors.
Molecular Genetic Characteristics
Studies of the molecular biology and cytogenetics of
CNS tumors suggest that specific types of tumors
(e.g., subsets of glioblastoma) have characteristic
genetic abnormalities. Such characterization contri-
butes importantly to our understanding of the
pathogenesis of CNS tumors, although the etiologi-
cal, prognostic, and other implications of specific
characteristics remain to be defined. It is anticipated
that molecular markers may aid in reducing the
known misclassification in the diagnosis of some
tumor subtypes.
 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
Possible Interactions of Genetic and
Environmental Factors
For a number of reasons, epidemiological studies of
the hypothesis that nitrosamide exposures relate to
brain tumors are very difficult. Thus, it is appealing to
be able to rely on some biomarker of exposure.
Unfortunately, finding a biomarker of N-nitroso
exposure for use in brain tumor patients or their
mothers, when the relevant exposures occurred years
earlier, has not proved easy. N-nitrosoureas have been
shown to form chemical adducts in vivo, but the
extent of damage induced by these adducts in various
tissues does not seem to correlate well with tumor-
igenicity. What seems more promising is to identify a
genetic polymorphism (one that could easily be
assayed in epidemiological studies) for an enzyme or
other system that regulates N-nitroso metabolism or
detoxification or the repair of the molecular damage
caused by nitroso compounds. Many of the problems
confronted by epidemiological studies of brain tumors
and nitrosamides also apply to studies of other
suspected brain carcinogens, such as several investi-
gated in occupational studies. Although in a number
of industries an apparent excess of brain tumors
among workers has long been noted, it has proved
difficult to implicate specific exposures. Simultaneous
evaluation of exposures to specific chemicals and of
individual susceptibility to insult from those chemi-
cals may be the direction of the future.
CONCLUSION
We simply have no idea what causes most nervous
system tumors. Certain inherited syndromes can
predispose individuals to the development of brain
and other nervous system tumors. However, only a
few percent of patients with nervous system tumors
have one of these rare phakomatoses or a family
member with a nervous system tumor. Studies of
such patients and their families have described
genetic events that are correlates of nervous system
tumor pathogenesis, but the etiological implications
of these findings are unclear.
Ionizing radiation, the only well-established en-
vironmental risk factor for nervous system tumors,
can cause all three major histological types of brain
tumors (neuroepithelial tumors, meningiomas, and
nerve sheath tumors), but only a few percent of
incident CNS tumors are likely to relate to such
exposure and the association appears weakest for
gliomas. Nonetheless, minimizing population expo-
sure to x-rays of the head is the best prospect for
565
prevention of all three types of tumors. Beyond this,
the etiology of neuroepithelial tumors remains
largely unknown. More is known about the etiology
of meningiomas and nerve sheath tumors. Ionizing
radiation and trauma appear to be important risk
factors for both.
Are there additional etiological clues to be gleaned
from the descriptive epidemiology of brain tumors?
The increased incidence and mortality rates in recent
decades were initially thought by some to suggest the
effect of an environmental exposure, but on further
consideration it appears to be largely an artifact of
improved diagnosis. Compared to cancer rates at
other sites, brain tumor rates show relatively little
international variation. This suggests that either the
relevant environmental exposures are ubiquitous or
endogenous factors are important. The gender
differences in distribution by histological type of
brain tumor, namely the male predominance of
neuroepithelial tumors and the female predominance
of meningioma, have long been noted, and although
evidence suggesting the importance of hormonal
factors is weak, any compelling hypothesis related
to this difference would be worth investigating. Most
brain tumors in children are neuroepithelial tumors,
and some types, such as PNET, occur predominantly
in children younger than age 5. The observation that
PNET rates, unlike rates of other pediatric brain
tumors, which are similar in the two genders, are up
to two times higher in boys than in girls also remains
unexplained. For neuroepithelial tumors as a major
group, as well as for specific glioma subtypes, it
seems possible that some of the crucial etiological
questions have not yet been posed. In our continued
investigation of suspected brain carcinogens, we need
to identify and focus on histology-specific associa-
tions and use improved methods of exposure assess-
ment. In addition, we need to simultaneously
consider host factors, particularly detectable poly-
morphisms, that influence susceptibility.
—Susan Preston-Martin
See also–Brain Tumors, Biology; Brain Tumors,
Clinical Manifestations and Treatment; Brain
Tumors, Genetics; Central Nervous System,
Overview; Childhood Brain Tumors;
Epidemiology, Overview; Glial Tumors; Nerve
Sheath Tumors; Neuroepidemiology, Overview
of Incidence and Prevalence Rates; Pituitary
Tumors; Primary Central Nervous System
Lymphoma and Germ Cell Tumors; Spinal Cord
Tumors, Biology of
566 CEREBELLAR DISORDERS
Further Reading
Davis, F., and Preston-Martin, S. (1998). Epidemiology—Incidence
and survival in central nervous system neoplasia. In Russell and
Rubinstein’s Pathology of Tumors of the Nervous System (D. D.
Bigner, Ed.), 6th ed., Vol. 1, pp. 5–45. Arnold, London.
Inskip, P. D., Tarone, R. E., Hatch, E. E., et al. (2001). Cellular-
telephone use and brain tumors. N. Engl. J. Med. 344, 79–86.
Kheifets, L., Sussman, S., and Preston-Martin, S. (1999). Child-
hood brain tumors and residential electromagnetic fields
(EMF). Rev. Environ. Contam. Toxicol. 159, 111–129.
Kleihues, P., and Cavenee, W. K. (Eds.) (2000). Pathology and
Genetics of Tumours of the Nervous System. IARC, Lyon,
France.
Legler, J. M., Gloeckler Ries, L. A., Smith, M. A., et al. (1999).
Brain and other central nervous system cancers: Recent
trends in incidence and mortality. J. Natl. Cancer Inst. 91,
1382–1390.
Preston-Martin, S., and Mack, W. (1996). Neoplasms of the
nervous system. In Cancer Epidemiology and Prevention (D.
Schottenfeld and J. F. Fraumeni, Jr., Eds.), 2nd ed. Oxford Univ.
Press, New York.
Preston-Martin, S., Pike, M. C., Ross, R. K., et al. (1990).
Increased cell division as a cause of human cancer. Cancer Res.
50, 7413–7419.
Schlehofer, B., Blettner, M., Preston-Martin, S., et al. (1999). The
role of medical history in brain tumor development: Results
from the international adult brain tumor study. Int. J. Cancer.
82, 155–160.
Smith, M. A., Freidlin, B., Ries, L. A., et al. (1998). Trends in
reported incidence of primary malignant brain tumors in
children in the United States. J. Natl. Cancer Inst. 90,
1249–1251.
Cerebellar Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CEREBELLUM is a brain structure located behind
the cerebral hemispheres and overlying the brain-
stem. It consists of two large hemispheres, an
anterior lobe, and a midline portion called the
vermis. The vermis functions in the control of
balance and eye movements, the anterior lobe is
particularly important to gait function, and the
lateral parts, or hemispheres, are involved in motor
planning and fine coordination of muscles.
Syndromes with pure cerebellar signs are rare
because the cerebellum is connected to numerous
other structures. Cerebellar disorders often affect
more than one of the functionally different subdivi-
sions of the cerebellum and are particularly likely to
involve the brainstem regions of the nearby medulla
and pons due to pressure or obliteration of blood
vessels that supply contiguous brain areas. Pressure
effects are common in the posterior region of the
brain because expansion is anatomically limited by
the skull and the stiff structure, called the tentorium,
that separates the cerebellum from the cerebral
hemispheres.
Based on anatomical divisions, cerebellar disorders
can be divided into three classic syndromes. Although
these syndromes are prototypic, many patients will
have overlap of one with the other and may also
show signs of brain damage outside the cerebellar
system if other regions have been simultaneously
damaged. The three divisions are variably named but
relate to predominant involvement of the vermis,
anterior lobe, or hemispheres.
Lesions of the lower vermis, also called the
vestibulocerebellum or archicerebellum, cause the
so-called flocculonodular syndrome. Brain tumors or
hemorrhage from a stroke or leaking blood vessel
provoke postural instability or ataxia so that the
head and trunk sway during sitting, standing, and
walking. Patients frequently fall backwards or to the
side when sitting and cannot support themselves. The
classic example is the brain tumor known as a
medulloblastoma, which occurs most often in the
midline of the cerebellum in children between 5 and
10 years of age. In these children, cerebellar
symptoms are first limited to unsteadiness of gait
and stance, and in most cases there is little or no
incoordination of the extremities when the patient is
lying in bed. Severe postural sway is present when
they try to sit, and even with their eyes open they
cannot maintain a steady posture. Slurred speech is
frequently present.
Damage to the anterior lobe causes the paleocer-
ebellar syndrome, a specific problem of unsteady
stance and gait without abnormal sitting. This
syndrome of the anterior lobe is mainly observed in
chronic alcoholics, although it can be seen in other
medical conditions. Unlike patients with the vermis
syndrome, patients use their eyes to help stabilize
themselves and fall more when their eyes are shut.
Dysarthria and dysmetric saccades are frequently
associated cerebellar signs, but they have relatively
preserved fine coordinated movements of the upper
limbs.
Damage to the cerebellar hemispheres or their
connecting pathways causes the neocerebellar
syndrome with poor coordination of the extremi-
ties, termed limb ataxia. This damage can occur
bilaterally or unilaterally; when the syndrome is
unilateral, the damage to the cerebellar hemisphere
is on the same side as that which shows the clinical
550 CENTRAL NERVOUS SYSTEM, MALFORMATIONS
Central Nervous System,
Malformations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
MALFORMATIONS of the brain and spinal cord may
be genetically determined or may be acquired. Most
dysgeneses that occur early in gestation have a
genetic basis, whereas those beginning late in
gestation more likely result from destructive lesions
such as infarcts that may interfere with development
of particular structures. The distinction between
atrophy (shrinkage of a previously well-formed
Table 1 PROPOSED MOLECULAR GENETIC CLASSIFICATIONS OF MALFORMATIONS OF EARLY CNS DEVELOPMENTa
Disorders of the primitive streak and node
Overexpression of genes
Underexpression of genes
Disorders of ventralization of the neural tube
Overexpression of the ventrodorsal gradient
Duplication of spinal central canal
Duplication of ventral horns of spinal cord
Diplomyelia (and diastematomyelia?)
Duplication of entire neuraxis
Ventralizing induction of somite
Segmental amyoplasia
Underexpression of ventrodorsal gradient
Fusion of ventral horns of spinal cord
Sacral (thoracolumbosacral) agenesis
Arinencephaly
Holoprosencephaly
Disorders of dorsalization of the neural tube
Overexpression of dorsoventral gradient
Duplication of dorsal horns of spinal cord
Duplication of dorsal brainstem structures
Underexpression of dorsalization of the neural tube
Fusion of dorsal horns of spinal cord
Septo optic dysplasia(?)
Rhombencephalosynapses (absence of vermis with fusion of
cerebellar hemispheres)
Disorders of the rostrocaudal gradient and/or segmentation
Decreased domains of homeoboxes
Agenesis of mesencephalon and metencephalon
Global cerebellar aplasia or hypoplasia
Aplasia of basal telencephalic nuclei
Increased domains of homeoboxes or ectopic expression
Chiari II malformation
Aberrations in cellular lineage by genetic mutation
Nonneoplastic
Striated muscle in the Central Nervous System
Dysplastic ganglicytoma of cerebellum (Lhermitte–Duclos)
Tuberous sclerosis
Hemimegalencephaly (also see disorders of symmetry)
a
From Sarnat and Flores-Sarnat (2001).
structure) and hypoplasia (deficient development of
a structure than never achieves normal size) is not
always clear in degenerative processes or acquired
lesions of fetal life, in which an insult is imposed on a
structure that is not yet fully formed. Examples
include ischemic lesions in fetal brain associated with
congenital cytomegalovirus infections, fetal degen-
erative diseases such as pontocerebellar hypoplasia,
and polymicrogyria in zones of relative ischemia
surrounding porencephalic cysts due to middle
cerebral artery occlusion in fetal life. White matter
infarcts in the cerebrum may destroy radial glial
fibers and prevent normal migration of neuroblasts
and glioblasts from the subventricular zone or
germinal matrix.
Neoplastic
Myomedulloblastoma
Dysembryoplastic neuroepithelial tumors
Ganglioglioma and other mixed neural tumors
Disorders of secretory molecules and genes that mediate migration
Neuroblast migration
Initial course
Filamin1 (perinventricular nodular heterotopia)
Middle course
DOUBLECORTIN (DCX; subcortical laminar
heterotopia)
LIS1 (type I lisencephaly; Miller–Dieker syndrome)
FUKUTIN(type II lissencephaly; Fukuyama muscular
dystrophy)
EMPTY SPIRACLES (EMX2; schizencephaly)
Astrotacin
Late course
REELIN (pachygyria)
DISABLES1(DAB1)
L1-NCAM(X-linked hydrocephalus with pachygyria and
aqueductal stenosis)
Gliblast migration
Focal migratory disturbances secondary to acquired lesions of
fetal brain
Disorders of secretory molecules and genes that attract or repel
axonal growth cones
Netrin downregulation
Keratan sulfate and other glycosaminoglycan and proteoglycan
downregulations
S-100b protein downregulation or upregulation(?)
Disorders of symmetry
Hemimegalencephaly (also see aberrations of cellular lineages)
Isolated hemimegalencephaly
Syndromic hemimegalencephaly
Epidermal nevus
Proteus
Klippel–Trenaunay–Weber
Hemihyperplasia of the cerebellum
 CENTRAL NERVOUS SYSTEM, MALFORMATIONS 551

Regardless of cause, malformations are tradition-
ally classified as disturbances in developmental
processes. Although this type of classification retains
a validity for understanding the type of develop-
mental process most disturbed, such as cellular
proliferation or neuroblast migration, current under-
standing of developmental genes and their role in the
ontogenesis of the nervous system provides a
complementary molecular genetic classification of
early neurogenesis that recognizes the genetic regula-
tion of development. Thus, it is an etiological scheme
of classification rather than descriptive or morpho-
logical. An example of an attempt to use these new
data to organize thinking about developmental
malformations of the brain is proposed in Table 1,
which provides a scheme that will undoubtedly
undergo considerable revision in the future as more
data become available.
Because the nervous system develops in precise
temporal and spatial sequences, it is often possible to
assign a precise timing of a malformation or at least
to determine the time when the insult was first
expressed. In most cases, an insult—whether from
overexpression or underexpression of a developmen-
tal gene or from an ongoing acquired process such as
a congenital viral infection or repeated episodes of
ischemia—affects nervous system development over
an extended period and thereby involves processes
occurring at various stages of development. Devel-
opmental genes, such as organizer genes early in
ontogenesis and regulator genes later, may serve a
series of different functions, thereby involving

Table 2 MALFORMATIONS: GENE LOCATIONS OF KNOWN MUTATIONSa

Malformation Inheritance Locus Gene for transcription

Cerebrohepatorenallb AR Xq22–q23 DCX

Hemimegalencephaly AR Xq28 L1-CAM
Holoprosencephalyc AD; AR 7q36-qter SHH
AR; sporadic 13q32 ZIC2
AR; sporadic 2q21 SIX3
R; sporadic Q22 7PTC
Kallmann’s syndrome XR Xp22.3 KALI; EMX2
Lissencephaly type I (Miller–Dieker syndrome) AR 17p13.3 LIS1
Midbrain agenesis AR; sporadic 7q36 EN2
Periventricular heterotopia XD Xq28 FILAMINI
Rett syndrome XD Xq28 MECP2
Sacral agenesisd AD 7q36.1-qter SHH
AD Lq41–q42.1 HLXB9
Schizencephaly AR 10q26.1 EMX2
Septooptic pituitary dyspl AR; sporadic 3p21.1–p21.2 HEX1
Subcortical laminar heterotopia (band heterotopia; double cortex) XD Xq22.3–q23 DCX
Tuberous sclerosis AD 9q34.3 TSC1
AD 16p13.3 TSC2
X-linked hydrocephalus (X-linked aqueductal stenosis and pachygyria) XR Xq28 L1-CAM
a
Modified from sarnat (2000) abbreviations used: AD, autosomal dominant; AR, autosomal recessive; XD, X-linked dominant; XR, X-
linked recessive; CAM, cell adhesion molecule; DCX, Doublecortin; EN, Engrailed; PTC, Patched; SHH, Sonic hedgehog.
b
The DCX mutation is primary in subcortical laminar heterotopia but is also described in cerebrohepatorenal (Zellweger’s) syndrome,
although probably only as a secondary defect in this lysosomal disorder with defective neuroblast migration to and in the cerebral cortex.
DCX is also a secondary defect in Kallmann syndrome’s (olfactory agenesis and hypogonadotropic hypogonadism, with olfactory bulb
neurons and hypothalamic secretory neurons having the same embroyological origin).
c
Holoprosencephaly is associated with many chromosomal defects in addition to those listed here but the gene products associated with
the others have not been identified.
d
Sacral agenesis (AD form) maps to the same locus at 7q36 as one form of holoprosencephaly and is associated with defective SHH
expression, the same genetic defect expressed at opposite ends of the neural tube. Sacral agenesis and holoprosencephaly also occur with a
high incidence in infants born to mothers with diabetes mellitus. Agenesis of more than two vertebral bodies is generally associated with
dysplasia of the spinal cord in that region during fetal development, fusion of ventral horns and deformed central canal with heterotopic
ependyma, consistent with defective neural induction.
552 CENTRAL NERVOUS SYSTEM, OVERVIEW
various processes. Defective expression of SHH, for
example, may result in holoprosencephaly because of
its early effects on midline ventralization in the
prosencephalon, but it may affect granule cell
proliferation in the cerebellum as well; the timing
of these two events is different.
The traditional descriptions of major malforma-
tions of the human nervous system are classified as
anatomical and physiological processes of central
nervous system development, but the new perspec-
tive of molecular genetic programming will forever
be an integral part of our understanding of these
disorders of development. Just as no two adults, even
monozygotic twins, are identical, no two fetuses and
no two cerebral malformations are identical. Indivi-
dual biological variations occur in abnormal and
normal development, and allowance must be made
for small differences while recognizing the principal
patterns that denote pathogenesis.
The number of cerebral malformations in Table 2
will undoubtedly increase. Not included in this table
are many other malformations for which the genetic
bases are still provisional, incompletely proved,
speculative, or based on animal models that resemble
human dysgeneses but lack molecular genetic con-
firmation in humans.
—Harvey B. Sarnat
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Cavernous
Malformations; Central Nervous System
Infections, Overview; Central Nervous System,
Overview; Central Nervous System Tumors,
Epidemiology; Cerebrovascular Malformations
(Angiomas); Nervous System, Neuroembryology
of; Rett Syndrome; Tuberous Sclerosis Complex
(TSC); Venous Malformation; Vertebrate
Nervous System, Development of
Further Reading
Faina, G. T., Cardini, F. A., D’Incerti, L., et al. (1997). Familial
schizencephaly associated with EMX2 mutation. Neurology 48,
1403–1406.
Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., et al. (1998).
Mutations in Filamin 1 prevent migration of cerebral cortical
neurons in human periventricular heterotopia. Neuron 21,
1315–1325.
Gleeson, J. G., Minnerath, S. R., Fox, J. W., et al. (1999).
Characterization of mutations in the gene Doublecortin in
patients with double cortex syndrome. Ann. Neurol. 45, 146–
153.
Jones, A. C., Shyamsundar, M. M., Thomas, M. W., et al. (1999).
Comprehensive mutation analysis of TSC1 and TSC2 and
phenotypic correlations in families 150 with tuberous sclerosis.
Am. J. Hum. Genet. 64, 1305–1315.
Lo Nigro, C., Chong, S. S., Smith, A. C. M., et al. (1997). Point
mutations and an intragenic deletion in LIS1, the lissencephaly
causative gene in isolated lissencephaly sequence and Miller–
Dieker syndrome. Hum. Mol. Genet. 6, 157–164.
Lynch, S. A., Bond, P. M., Copp, A. J., et al. (1995). A gene for
autosomal dominant sacral agenesis maps to the holoprosence-
phaly region at 7q36. Nat. Genet. 11, 93–95.
O’Rourke, N. A., Dailey, M. E., Smith, S. J., et al. (1992). Diverse
migratory pathways in the developing cerebral cortex. Science
258, 299–302.
Sarnat, H. B. (2000). Central nervous system malformations:
Locations of known human mutations. Eur. J. Paediatr. Neurol.
4, 289–290.
Sarnat, H. B., and Flores-Sarnat, L. (2001). A new classification of
malformations of the nervous system. Integration of morpho-
logical and molecular genetic criteria. Eur. J. Paediatr. Neurol.
5, 57–64.
Snow, D. M., Steindler, D. A., and Silver, J. (1990). Molecular
and cellular characterization of the glial roof plate of
the spinal cord and optic tectum: A possible role for a
proteoglycan in the development of an axon barrier. Dev. Biol.
138, 359–376.
Tanabe, Y., and Jessell, T. M. (1996). Diversity and pattern in the
developing spinal cord. Science 274, 1115–1123.
Central Nervous System,
Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CENTRAL NERVOUS SYSTEM (brain and spinal
cord) in a very real sense makes us what we are. It
receives and interprets a wide range of inputs from
our environment and experiences and allows us to
respond in an appropriate and meaningful way. It
interprets what we see, hear, taste, feel, and experi-
ence both subjectively and objectively. It is the seat of
our enjoyments, disappointments, and pleasures and,
through complex circuits, gives us a personality. The
central nervous system consists of the spinal cord,
brainstem (medulla, pons, and midbrain), cerebellum,
thalamus, and cerebral hemisphere.
NEUROGENESIS
The central nervous system arises from a plate of
neuroectoderm on the posterior aspect of the
developing embryo. The edges of this plate fold
toward the midline and join to form the neural tube.
The spinal cord and brain arise from caudal and
rostral portions of this tube, respectively. The cavity
of the neural tube becomes the central canal and
ventricles of the adult.
552 CENTRAL NERVOUS SYSTEM, OVERVIEW
various processes. Defective expression of SHH, for
example, may result in holoprosencephaly because of
its early effects on midline ventralization in the
prosencephalon, but it may affect granule cell
proliferation in the cerebellum as well; the timing
of these two events is different.
The traditional descriptions of major malforma-
tions of the human nervous system are classified as
anatomical and physiological processes of central
nervous system development, but the new perspec-
tive of molecular genetic programming will forever
be an integral part of our understanding of these
disorders of development. Just as no two adults, even
monozygotic twins, are identical, no two fetuses and
no two cerebral malformations are identical. Indivi-
dual biological variations occur in abnormal and
normal development, and allowance must be made
for small differences while recognizing the principal
patterns that denote pathogenesis.
The number of cerebral malformations in Table 2
will undoubtedly increase. Not included in this table
are many other malformations for which the genetic
bases are still provisional, incompletely proved,
speculative, or based on animal models that resemble
human dysgeneses but lack molecular genetic con-
firmation in humans.
—Harvey B. Sarnat
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Cavernous
Malformations; Central Nervous System
Infections, Overview; Central Nervous System,
Overview; Central Nervous System Tumors,
Epidemiology; Cerebrovascular Malformations
(Angiomas); Nervous System, Neuroembryology
of; Rett Syndrome; Tuberous Sclerosis Complex
(TSC); Venous Malformation; Vertebrate
Nervous System, Development of
Further Reading
Faina, G. T., Cardini, F. A., D’Incerti, L., et al. (1997). Familial
schizencephaly associated with EMX2 mutation. Neurology 48,
1403–1406.
Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., et al. (1998).
Mutations in Filamin 1 prevent migration of cerebral cortical
neurons in human periventricular heterotopia. Neuron 21,
1315–1325.
Gleeson, J. G., Minnerath, S. R., Fox, J. W., et al. (1999).
Characterization of mutations in the gene Doublecortin in
patients with double cortex syndrome. Ann. Neurol. 45, 146–
153.
Jones, A. C., Shyamsundar, M. M., Thomas, M. W., et al. (1999).
Comprehensive mutation analysis of TSC1 and TSC2 and
phenotypic correlations in families 150 with tuberous sclerosis.
Am. J. Hum. Genet. 64, 1305–1315.
Lo Nigro, C., Chong, S. S., Smith, A. C. M., et al. (1997). Point
mutations and an intragenic deletion in LIS1, the lissencephaly
causative gene in isolated lissencephaly sequence and Miller–
Dieker syndrome. Hum. Mol. Genet. 6, 157–164.
Lynch, S. A., Bond, P. M., Copp, A. J., et al. (1995). A gene for
autosomal dominant sacral agenesis maps to the holoprosence-
phaly region at 7q36. Nat. Genet. 11, 93–95.
O’Rourke, N. A., Dailey, M. E., Smith, S. J., et al. (1992). Diverse
migratory pathways in the developing cerebral cortex. Science
258, 299–302.
Sarnat, H. B. (2000). Central nervous system malformations:
Locations of known human mutations. Eur. J. Paediatr. Neurol.
4, 289–290.
Sarnat, H. B., and Flores-Sarnat, L. (2001). A new classification of
malformations of the nervous system. Integration of morpho-
logical and molecular genetic criteria. Eur. J. Paediatr. Neurol.
5, 57–64.
Snow, D. M., Steindler, D. A., and Silver, J. (1990). Molecular
and cellular characterization of the glial roof plate of
the spinal cord and optic tectum: A possible role for a
proteoglycan in the development of an axon barrier. Dev. Biol.
138, 359–376.
Tanabe, Y., and Jessell, T. M. (1996). Diversity and pattern in the
developing spinal cord. Science 274, 1115–1123.
Central Nervous System,
Overview
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CENTRAL NERVOUS SYSTEM (brain and spinal
cord) in a very real sense makes us what we are. It
receives and interprets a wide range of inputs from
our environment and experiences and allows us to
respond in an appropriate and meaningful way. It
interprets what we see, hear, taste, feel, and experi-
ence both subjectively and objectively. It is the seat of
our enjoyments, disappointments, and pleasures and,
through complex circuits, gives us a personality. The
central nervous system consists of the spinal cord,
brainstem (medulla, pons, and midbrain), cerebellum,
thalamus, and cerebral hemisphere.
NEUROGENESIS
The central nervous system arises from a plate of
neuroectoderm on the posterior aspect of the
developing embryo. The edges of this plate fold
toward the midline and join to form the neural tube.
The spinal cord and brain arise from caudal and
rostral portions of this tube, respectively. The cavity
of the neural tube becomes the central canal and
ventricles of the adult.
 CENTRAL NERVOUS SYSTEM, OVERVIEW 553

The brain and spinal cord arise from neuroblasts

and glioblasts of the neural tube. Progenitor cells of
the glioblast lineage become radial glial (essential
during development) and the astrocytes and oligo-
dendrocytes of the adult. Microglial cells appear in
the developing nervous system after it is invaded by
blood vessels, suggesting they are of mesodermal
origin. Neuroblasts without processes (apolar neuro-
blasts), following a series of developmental steps,
become the neurons characteristic of the adult
nervous system.
Radial glial cells extend from the internal surface
of the cavity of the neural tube to its external surface
and form a framework for cell migration. The neural
tube consists of (from internal to external) a
ventricular zone (radial glial cell bodies and neuro-
blasts), an intermediate zone (migrating neuroblasts),
and a marginal zone largely free of cell bodies.
As neuroblasts differentiate they migrate from the
ventricular zone toward the marginal zone on radial
glial cell processes. Exuberate neuroblast prolifera-
tion, and proper migration (spatially and tempo-
rally), results in a normal adult brain and spinal cord.
Failure of proper neural tube closure, or of neuro-
blast migration, results in a variety of defects. For
example, improper neural tube closure results in
dysraphic defects such as spina bifida occulta or
anencephaly. Failure of proper neuroblast migration
on radial glia may result in brain abnormalities such
as lissencephaly, pachygyri, or microgyri. Many
developmental defects result in disabilities.

SPINAL CORD
The spinal cord extends from the medulla to the level
of the second lumbar vertebra, a distance of
approximately 44 cm (Fig. 1). Thirty-one pair of
spinal nerves (8 cervical, 12 thoracic, 5 lumbar, 5
sacral, and 1 coccygeal) connect the spinal cord with
the body. Although small (approximately 1 cm or less
in diameter), the spinal cord is the conduit through
which spinal reflexes flow, ascending information is
conducted to the brain, and descending tracts
influence the activity of spinal motor neurons.
Spinal reflexes require sensory input and motor
outflow. In a monosynaptic reflex (knee jerk reflex),
the sensory fiber originates from a muscle spindle
and synapses directly on anterior horn motor
neurons innervating extensor muscles of the thigh.
Figure 1
In a polysynaptic reflex, such as that initiated by a The major divisions of the central nervous system as seen in the
painful stimulus, sensory fibers convey impulses to median sagittal plane (reproduced with permission from Haines,
posterior horn interneurons, which in turn synapse 2002).
554 CENTRAL NERVOUS SYSTEM, OVERVIEW
on anterior horn motor neurons or with other
interneurons. Posterior horn neurons that receive
painful input also contribute to the pathway that
conveys this type of information to higher levels of
the neuraxis.
Two spinal cord pathways, especially important in
the diagnosis of the neurologically impaired patient,
convey sensory information to the brain. Fibers of
the anterolateral system originate from cells of the
posterior horn, cross the midline, ascend on the
contralateral side, and convey pain and thermal
sensations that eventually reach the somatosensory
cortex. The posterior column system, the fasciculi
gracilis and cuneatus, is composed of the central
processes of primary sensory fibers that convey
discriminative touch, vibratory sense, and proprio-
ception; these fibers ascend on the ipsilateral side of
the spinal cord.
Descending spinal cord pathways of particular
clinical relevance are the corticospinal, rubrospinal,
vestibulospinal, and reticulospinal tracts/fibers. Cor-
ticospinal fibers originate in the somatomotor cortex
and decussate at the spinal cord–medulla junction to
form the lateral corticospinal tract on the side of the
spinal cord contralateral to their origin. Rubrospinal
fibers originate in the midbrain, decussate, and
descend to cervical cord levels. Vestibulospinal and
reticulospinal fibers arise from the pons and medulla,
are largely uncrossed, and influence spinal motor
neurons that innervate postural (extensor) muscles.
Hemisection of the spinal cord results in a contral-
ateral loss of pain and thermal sense and an
ipsilateral loss of discriminatory touch, vibratory
sense, and motor control, all below the injury level.
MEDULLA OBLONGATA
The medulla oblongata (medulla) extends from the
spinal cord–medulla junction to the pons (Fig. 1).
The pyramids, which contain corticospinal fibers,
and the inferior olive are landmarks on the anterior
and anterolateral aspects of the medulla. Located
posteriorly, the tubercles gracilis and cuneatus over-
lay the nuclei gracilis and cuneatus. The fibers
comprising the posterior column synapse in these
nuclei, which in turn project across the midline to
form the medial lemniscus. This pathway is the
posterior column–medial lemniscus system. As ante-
rolateral system fibers pass through the medulla,
some synapse in the medullary reticular formation.
In addition to anterolateral system input, the
medullary reticular formation gives rise to medullary
(lateral) reticulospinal fibers. The medial vestibular
nucleus of the medulla is the source of the medial
vestibulospinal tract.
Cranial nerves that exit the medulla are (from
caudal to rostral) the hypoglossal (XII), accessory
(XI), vagus (X), and glossopharyngeal (IX). The
cranial nerves exiting at the pons–medulla junction
are (from medial to lateral) the abducens (VI), facial
(VII), and vestibulocochlear (VIII). The nuclei of
cranial nerves XII, X, IX, and part of VIII are located
in the medulla, and the motor neurons of nerve XI
are found in the cervical spinal cord. Part of the
trigeminal complex, the spinal trigeminal tract and
nucleus, is also found in the lateral medulla adjacent
to the anterolateral system. The 12th nerve is motor
to the tongue, and the 11th nerve innervates the
sternocleidomastoid and trapezius muscles. The 10th
nerve provides visceromotor fibers to the gut,
innervation of throat and vocal muscles, and conveys
general and special sensory information. The ninth
nerve conveys general and special sensations and is
motor to the stylopharyngeus muscle. Lesions in the
medulla frequently present as a long tract deficit
(pain, motor for the body) on one side of the body
and a cranial nerve deficit on the opposite side of the
head (alternating or crossed deficits).
PONS AND CEREBELLUM
The pons (Fig. 1) is rostral to the medulla and
characterized by an external portion, the basilar
pons, and an internal part, the pontine tegmentum.
The latter contains reticular nuclei and cranial nerve
nuclei of the pons (V) and pons–medulla junction
(VI–VIII). Anterolateral system fibers ascend through
the tegmentum and the medial lemniscus ascends at
the interface of the tegmental and basilar pons.
Corticospinal fibers descend through the basilar pons
(close to the root of the abducens nerve) to enter the
medullary pyramid. Other descending tracts from the
pons include medial reticulospinal fibers and the
lateral vestibulospinal tract.
The nuclei of cranial nerves exiting the pons–
medulla junction are located mainly in the caudal
pons (except for some portions of VIII). The sixth
nerve innervates the lateral rectus muscle. The
seventh nerve is motor to the muscles of facial
expression, conveys taste from much of the tongue,
and contains general sensory and visceromotor
fibers. The eighth nerve is concerned with hearing
(cochlear portion) and balance and equilibrium
(vestibular portion).

The trigeminal nerve (V) exits the lateral aspect of
the pons. The fifth nerve is the only cranial nerve
whose central nuclei extend through all parts of the
brainstem (medulla, pons, and midbrain). General
sensation from the face and oral cavity, surface of the
tongue, and teeth is conveyed on the fifth nerve. This
nerve is also motor to the muscles of mastication.
Crossed deficits, similar to those seen in medulla
lesion, are also seen following pontine lesions.
The cerebellum is located above, but is not part of,
the brainstem (Fig. 1). The cerebellum is attached to
the brainstem by cerebellar peduncles. The inferior
and middle peduncles are afferent to the cerebellum,
whereas the superior peduncle is efferent from the
cerebellum. The cerebellum influences somatomotor
activity. Its function can be described as muscle
synergy; that is, muscles working together to perform
smooth, coordinated, and purposeful movements.
MIDBRAIN
The rostral portion of the brainstem, the midbrain,
extends from the pons to interface with the thalamus
in the base of the cerebral hemisphere (Fig. 1).
Corticospinal fibers in the midbrain are located in
the crus cerebri, where they are close to fibers of the
oculomotor nerve. Anterolateral system fibers and
the medial lemniscus are adjacent to each other in
lateral midbrain areas. Rubrospinal fibers originate
from the red nucleus of the midbrain, cross the
midline, and descend to the spinal cord. The
midbrain also contains the substantia nigra. The
dopamine-containing cells of this nucleus project to
the neostriatum (part of the basal nuclei). A loss of
these cells and fibers results in the motor deficits seen
in Parkinson’s disease.
The cranial nerves of the midbrain are trochlear
(IV) and oculomotor (III). The fourth nerve exits just
caudal to the inferior colliculus; the superior and
inferior colliculi are midbrain structures related to
visual and auditory functions, respectively. Trochlear
fibers innervate the superior oblique muscle. The
third nerve contains somatomotor fibers that inner-
vate inferior oblique, superior, medial, and inferior
recti muscles and visceromotor fibers that influence
the sphincter puppillae muscle. Cranial nerves III, IV,
and VI innervate the extraocular muscles.
THALAMUS
The thalamus (Fig. 1) is composed of a dorsal
thalamus (or thalamus), hypothalamus, subthalamus
CENTRAL NERVOUS SYSTEM, OVERVIEW 555
(ventral thalamus), and epithalamus. The dorsal
thalamus has extensive connections with the cerebral
cortex. All sensory modalities (vision, taste, general
and visceral sensation, auditory, etc.) with the
exception of olfaction are relayed to the cortex by
nuclei of the dorsal thalamus (Table 1). Motor
signals from the cerebellum and basal nuclei are also
relayed to motor areas of the cerebral cortex via the
dorsal thalamus. The optic nerve (II, vision) is the
cranial nerve associated with the thalamus.
Before considering the dorsal thalamus, other
thalamic regions are reviewed. Brain structures
related to the hypothalamus include the optic
chiasm, infundibulum, and mammillary bodies. The
hypothalamus is involved in endocrine function,
body temperature and blood pressure regulation,
food intake, water and electrolyte balance, sleep and
waking mechanisms, and aspects of circadian rhyth-
mus, sexual function, and reproduction. The sub-
thalamus (ventral thalamus) functions in the motor
sphere. This nucleus connects with the basal nuclei,
which in turn project to nuclei of the dorsal
thalamus. This circuit influences the activity of the
motor cortex via thalamocortical connections. Sub-
thalamic lesions result in ballism or hemiballistic
movements. The epithalamus is quite small, located
at the caudomedial aspect of the dorsal thalamus,
and functions in concert with the limbic lobe.
The main nuclei of the dorsal thalamus, their
input, and cortical targets (gyri and/or lobes) are
summarized in Table 1. The various nuclei of the
dorsal thalamus receive a wide range of inputs and
through thalamocortical connection distribute speci-
fic information to particular gyri comprising the
lobes of the cerebral cortex (Table 1). In turn, the
cerebral cortex projects to many targets in the brain,
brainstem, and spinal cord, including many nuclei of
the dorsal thalamus. The geniculate nuclei, some-
times designated as metathalamus, are more com-
monly included as part of the dorsal thalamus.
CEREBRAL HEMISPHERE
This is the largest part of the central nervous system
(Fig. 1). It is composed of the gyri and sulci of the
cerebral cortex, subcortical white matter, basal nuclei
(ganglia), and the hippocampal formation and
amydaloid complex. The cranial nerve of the hemi-
sphere is nerve I (olfactory).
Classically, the cerebral cortex is divided into four
lobes (frontal, parietal, temporal, and occipital), each
named according to an overlying bone of the skull.
556 CENTRAL NERVOUS SYSTEM, OVERVIEW

Table 1 THE INPUT TO AND CORTICAL TARGETS OF THE MAJOR THALAMIC NUCLEI

Afferent input Thalamic nucleus Cortical target

Auditory Medial geniculate Transverse temporal gyrus

Visual Lateral geniculate Upper/lower banks of calcarine sulcus
(occipital lobe)
Pain and thermal sense from body Ventral posterolateral Postcentral and posterior paracentral gyri
Pain and thermal sense from head Ventral posteromedial Postcentral gyrus
Discriminative touch and proprioception Ventral posterolateral Postcentral and posterior paracentral gyri
from body
Discriminative touch and proprioception Ventral posteromedial Postcentral gyrus
from head
Cerebellar (motor) input Ventral lateral Precentral and anterior paracentral gyri
Basal nuclei (motor input) Ventral lateral Precentral and anterior paracentral gyri
Input from superior colliculus, occipital, and Pulvinar Occipital, temporal, and parietal lobes
parietal lobes
Input from hippocampal formation and Anterior Cingulate gyrus
amygdaloid complex
Input from amygdaloid complex, ventral Dorsomedial Frontal lobe
pallidum, and substantia nigra
Input from basal nuclei, spinal cord, Centromedian Frontal lobe, other cortical areas plus basal
reticular formation, cerebral cortex, and nuclei
substantia nigra

Advances in the understanding of cortical function
have led many authors to identify five lobes (the
classic four plus a limbic lobe) or six lobes (classic
plus limbic and insular lobes). Functions associated
with representative gyri of some lobes are summar-
ized in Table 1. The frontal lobe contains the primary
somatomotor cortex for the body, the frontal eye
field, and a region involved in motor aspects of
speech; lesions of this latter area result in Broca’s
(nonfluent) aphasia. The parietal lobe contains the
somatosensory cortex and an area involved in
receptive aspects of speech. The temporal lobe
contains the primary auditory cortex. Injury of the
caudal aspect of the temporal lobe and adjacent
portions of the inferior parietal lobule results in
Wernicke’s (fluent) aphasia. Other important struc-
tures in the temporal lobe are the hippocampal
formation and amygdaloid complex. The occipital
lobe contains primary visual cortex and visual
association areas. Large areas of cortex function in
relation to vision and visual association areas. The
limbic lobe forms the innermost aspect of the
hemisphere, and lesions in this area may result in
behavioral changes. The function of the insular lobe
is not well understood, but it does receive olfactory
and viscerosensory input.
The subcortical white matter is organized into the
internal capsule, which contains thalamocortical
connections, and large numbers of descending fibers;
it is the major highway in and out of the cerebral
cortex. Damage to this structure results in sensory
and/or motor deficits.
The basal nuclei are found within the cerebral
hemisphere. They receive input from the cerebral
cortex, substantia nigra, and subthalamic nucleus
and influence motor function through connections
with those nuclei of the dorsal thalamus that project
to the motor cortex. Genetic disorders, such as
Huntington’s disease, or degenerative disorders, such
as Parkinson’s disease, affect the basal nuclei and
result in characteristic movement deficits.
—Duane E. Haines
See also–Autonomic Nervous System, Overview;
Brain Anatomy; Central Nervous System
Infections, Overview; Central Nervous System
Malformations; Central Nervous System Tumors,
Epidemiology; Nervous System,
Neuroembryology of; Parasympathetic System,
Overview; Spinal Cord Anatomy; Sympathetic
System, Overview; Vertebrate Nervous System,
Development of
Further Reading
Bear, M. F., Connors, B. W., and Paradiso, M. A. (2001).
Neuroscience: Exploring the Brain, 2nd ed. Lippincott Williams
& Wilkins, Baltimore.
 CENTRAL NERVOUS SYSTEM TUMORS, EPIDEMIOLOGY
Gilman, S. (1996). Manter and Gatzs’ Essentials of Clinical
Neuroanatomy and Neurophysiology, 9th ed. Davis, Philadel-
phia.
Haines, D. E. (2000). Neuroanatomy: An Atlas of Structions,
Sections and Systems, 5th ed. Lippincott Williams & Wilkins,
Baltimore.
Haines, D. E. (2002). Fundamental Neuroscience, 2nd ed.
Churchill Livingstone, New York.
Kandel, E. R., Schwartz, J. H., and Jessell, T. M. (2000). Principles
of Neural Science, 4th ed. McGraw-Hill, New York.
Leblanc, A. (1995). The Cranial Nerves: Anatomy, Imaging,
Vascularisation, 2nd ed. Springer-Verlag, Berlin.
Central Nervous System
Tumors, Epidemiology
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IT WAS ESTIMATED that in 2000, 16,500 individuals
in the United States would be diagnosed with a
malignant primary nervous system tumor and 13,000
of these would die from the disease. When benign as
well as malignant brain tumors are included, the
incidence is more than twice that for malignant brain
tumors alone. Only about half of patients with
malignant brain tumors are still alive 1 year after
diagnosis. Epidemiology studies the distribution of
primary tumors of the brain, cranial meninges, and
cranial nerves (hereafter called brain tumors) in
human populations to obtain clues as to the causes of
these tumors. This entry summarizes key descriptive
epidemiological findings related to the patterns of
brain tumor occurrence and also reports suggestive
etiological findings from analytical epidemiological
studies.
Although the incidence of brain tumors, particu-
larly the more lethal subtypes, increased in recent
decades, it appears that trends in childhood brain
tumors and adult tumors increased due to the
introduction of diagnostic improvements, including
computed tomography (CT) scans in the mid-1970s
and magnetic resonance imaging (MRI) in the mid-
1980s. This issue and the recent explosion of
epidemiological and molecular genetic studies of
brain tumors have focused attention on this impor-
tant human cancer that until only a few decades ago
was relatively little studied. Despite this surge of
interest, the etiology of the majority of nervous
system tumors remains unknown. Inherited syn-
dromes that predispose affected individuals to brain
tumor development and/or the presence of nervous
557
system tumors in other family members appear to be
present in fewer than 5% of brain tumor patients.
Some environmental agents, in particular ionizing
radiation, are clearly implicated in the etiology of
brain tumors but also appear to account for few cases.
Numerous other physical, chemical, and infectious
agents that have long been suspected risk factors have
not been established as etiologically relevant.
This entry focuses on tumors of the brain, cranial
nerves, and cranial meninges, which account for
95% of all central nervous system (CNS) tumors.
These tumors are unique because of their location
within the bony structure of the cranium. Symptoms
depend on location of the tumor. Furthermore,
histologically benign tumors can result in similar
symptomatology and outcome as malignant tumors
because growth of both normal and tumor tissue is
confined to the cranial space. For this reason, some
cancer registries voluntarily include both benign and
malignant intracranial tumors. For simplicity, this
group of tumors will be called brain tumors or, when
benign tumors are excluded, brain cancer. The term
central nervous system tumors (or cancer) indicates
that tumors of the spinal cord and spinal meninges
are included along with brain tumors, and the term
nervous system tumors indicates that tumors of the
peripheral nerves are included as well.
DESCRIPTIVE EPIDEMIOLOGY
Variation in Inclusion Criteria
The descriptive epidemiology of CNS tumors has
been difficult to study because of the wide variation
in specific tumors included in published frequency
rates. Quantitatively, the most important variation is
estimated to be approximately 50% and relates to
the inclusion or exclusion of benign tumors. This
critical difference has often been ignored in compar-
isons across geographic areas. Benign tumors are
included from descriptive data for Los Angeles
County discussed in this entry. It should be noted
that pineal and pituitary tumors, included in some
standard definitions of brain and CNS tumors, are
not included. As will become clear from later
discussion of analytical (i.e., etiological) studies, more
is known about the etiology of benign histological
types such as meningiomas than about the etiology of
neuroepithelial tumors, which are more common
than meningiomas and usually malignant.
Another variation relates to whether or not
clinically diagnosed tumors are included. The
566 CEREBELLAR DISORDERS
Further Reading
Davis, F., and Preston-Martin, S. (1998). Epidemiology—Incidence
and survival in central nervous system neoplasia. In Russell and
Rubinstein’s Pathology of Tumors of the Nervous System (D. D.
Bigner, Ed.), 6th ed., Vol. 1, pp. 5–45. Arnold, London.
Inskip, P. D., Tarone, R. E., Hatch, E. E., et al. (2001). Cellular-
telephone use and brain tumors. N. Engl. J. Med. 344, 79–86.
Kheifets, L., Sussman, S., and Preston-Martin, S. (1999). Child-
hood brain tumors and residential electromagnetic fields
(EMF). Rev. Environ. Contam. Toxicol. 159, 111–129.
Kleihues, P., and Cavenee, W. K. (Eds.) (2000). Pathology and
Genetics of Tumours of the Nervous System. IARC, Lyon,
France.
Legler, J. M., Gloeckler Ries, L. A., Smith, M. A., et al. (1999).
Brain and other central nervous system cancers: Recent
trends in incidence and mortality. J. Natl. Cancer Inst. 91,
1382–1390.
Preston-Martin, S., and Mack, W. (1996). Neoplasms of the
nervous system. In Cancer Epidemiology and Prevention (D.
Schottenfeld and J. F. Fraumeni, Jr., Eds.), 2nd ed. Oxford Univ.
Press, New York.
Preston-Martin, S., Pike, M. C., Ross, R. K., et al. (1990).
Increased cell division as a cause of human cancer. Cancer Res.
50, 7413–7419.
Schlehofer, B., Blettner, M., Preston-Martin, S., et al. (1999). The
role of medical history in brain tumor development: Results
from the international adult brain tumor study. Int. J. Cancer.
82, 155–160.
Smith, M. A., Freidlin, B., Ries, L. A., et al. (1998). Trends in
reported incidence of primary malignant brain tumors in
children in the United States. J. Natl. Cancer Inst. 90,
1249–1251.
Cerebellar Disorders
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CEREBELLUM is a brain structure located behind
the cerebral hemispheres and overlying the brain-
stem. It consists of two large hemispheres, an
anterior lobe, and a midline portion called the
vermis. The vermis functions in the control of
balance and eye movements, the anterior lobe is
particularly important to gait function, and the
lateral parts, or hemispheres, are involved in motor
planning and fine coordination of muscles.
Syndromes with pure cerebellar signs are rare
because the cerebellum is connected to numerous
other structures. Cerebellar disorders often affect
more than one of the functionally different subdivi-
sions of the cerebellum and are particularly likely to
involve the brainstem regions of the nearby medulla
and pons due to pressure or obliteration of blood
vessels that supply contiguous brain areas. Pressure
effects are common in the posterior region of the
brain because expansion is anatomically limited by
the skull and the stiff structure, called the tentorium,
that separates the cerebellum from the cerebral
hemispheres.
Based on anatomical divisions, cerebellar disorders
can be divided into three classic syndromes. Although
these syndromes are prototypic, many patients will
have overlap of one with the other and may also
show signs of brain damage outside the cerebellar
system if other regions have been simultaneously
damaged. The three divisions are variably named but
relate to predominant involvement of the vermis,
anterior lobe, or hemispheres.
Lesions of the lower vermis, also called the
vestibulocerebellum or archicerebellum, cause the
so-called flocculonodular syndrome. Brain tumors or
hemorrhage from a stroke or leaking blood vessel
provoke postural instability or ataxia so that the
head and trunk sway during sitting, standing, and
walking. Patients frequently fall backwards or to the
side when sitting and cannot support themselves. The
classic example is the brain tumor known as a
medulloblastoma, which occurs most often in the
midline of the cerebellum in children between 5 and
10 years of age. In these children, cerebellar
symptoms are first limited to unsteadiness of gait
and stance, and in most cases there is little or no
incoordination of the extremities when the patient is
lying in bed. Severe postural sway is present when
they try to sit, and even with their eyes open they
cannot maintain a steady posture. Slurred speech is
frequently present.
Damage to the anterior lobe causes the paleocer-
ebellar syndrome, a specific problem of unsteady
stance and gait without abnormal sitting. This
syndrome of the anterior lobe is mainly observed in
chronic alcoholics, although it can be seen in other
medical conditions. Unlike patients with the vermis
syndrome, patients use their eyes to help stabilize
themselves and fall more when their eyes are shut.
Dysarthria and dysmetric saccades are frequently
associated cerebellar signs, but they have relatively
preserved fine coordinated movements of the upper
limbs.
Damage to the cerebellar hemispheres or their
connecting pathways causes the neocerebellar
syndrome with poor coordination of the extremi-
ties, termed limb ataxia. This damage can occur
bilaterally or unilaterally; when the syndrome is
unilateral, the damage to the cerebellar hemisphere
is on the same side as that which shows the clinical

signs. This neocerebellar syndrome may be caused
by hemorrhage, ischemic strokes, brain tumors, or
degenerative disorders such as multiple sclerosis.
The severe disturbances of limb movements occur
without weakness and include decreased muscle
tone (hypotonia), poor timing of movements that
require sequencing (asynergia), and coordinated
changes in muscle activation (dysdiadochokinesia).
A severe tremor can occur as the patient attempts to
move the limb and perform motor tasks. Although
this syndrome develops with diseases located with-
in the cerebellar hemispheres, damage to the
incoming and outgoing pathways, as seen with
occlusion of the superior cerebellar artery or with
multiple sclerosis, can cause the same clinical
picture.
In primary degenerative disorders of the cerebellar
systems (also called cerebellar atrophy, cerebellar
degeneration, spinocerebellar atrophy, and spinocer-
ebellar degeneration), there is usually symmetrical
involvement of both hemispheres and the vermis so
that bilateral limb incoordination and ataxia of
stance and gait predominate. Dysarthria and oculo-
motor disturbances are also frequently present.
Additional signs that indicate neurological deficits
outside the primary cerebellar systems, such as
weakness, ophthalmoplegia, and peripheral neuro-
pathy, are common in these disorders, many of which
are hereditary in origin. Disorders include Fried-
reich’s ataxia, Charcot–Marie–Tooth disease, and
olivopontocerebellar atrophy. Recent genetic ad-
vances have resulted in the identification of an
increasingly large array of different disorders that
can be categorized as cerebellar ataxias of genetic
origin.
Paroxysmal or episodic forms of ataxia are
cerebellar syndromes that occur intermittently and
then symptomatically clear. In children, these are
often due to metabolic disorders, and among adults
the same types of symptoms can be drug induced or
related to cerebrovascular diseases.
One remarkable feature of many cerebellar
disorders is the functional compensation that
occurs after injury. In contrast to many other
neurological disorders, subjects often show marked
improvement over time when a cerebellar insult is a
single event, such as a stroke; even when the
disorder is progressive, the subject continually
compensates with resultant very mild progression
of symptoms. This pattern is particularly marked in
children.
—Christopher G. Goetz
CEREBELLAR HEMATOMA 567
See also–Ataxia; Brain Tumors, Clinical
Manifestations and Treatment; Cerebellar
Hematoma; Cerebellum; Charcot-Marie-Tooth
Disease; Dysarthria; Gait and Gait Disorders;
Friedreich’s Ataxia
Further Reading
Griggs, R. C., and Nutt, J. G. (1995). Episodic ataxias as
channelopathies. Ann. Neurol. 37, 285–287.
Harding, A. E. (1993). Clinical features and classification of
inherited ataxias. In Advances in Neurology (A. E. Harding and
T. Deufel, Eds.), pp. 1–14. Raven Press, New York.
Klockgether, T. (2003). Ataxias. In Textbook of Clinical Neurol-
ogy (C. G. Goetz, Ed.), pp. 680–694. Saunders, Philadelphia.
Nutt, J. G. (2003). Gait and balance. In Textbook of Clinical
Neurology (C. G. Goetz, Ed.), pp. 301–314. Saunders,
Philadelphia.
Wallesch, C. W., and Bartels, C. (1997). Inherited cerebellar
diseases. Int. Rev. Neurobiol. 41, 441–453.
Cerebellar Hematoma
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBELLAR HEMORRHAGE accounts for approxi-
mately 10% of all intracerebral hemorrhage, and the
anatomy of the posterior fossa makes cerebellar
hemorrhage potentially more dangerous than supra-
tentorial bleeding. Although cerebellar hemorrhage
typically occurs in known hypertensive patients,
multiple other etiologies exist.
ETIOLOGY
Unless the patient with cerebellar hemorrhage is
known to be hypertensive, other potential causes for
bleeding should be sought. Other causes of cerebellar
hemorrhage and hematoma include tumor, aneur-
ysm, vascular malformation, amyloid angiopathy,
coagulopathy, angiitis, sympathomimetic intoxica-
tion, and trauma. Of course, patients who are
typically normotensive may present with profoundly
high systemic blood pressure after hemorrhage into
the cerebellum as a result of elevated intracranial
pressure.
CLINICAL PRESENTATION
After sustaining cerebellar hemorrhage, a patient
may complain of ipsilateral occipital headache,
persistent vertigo with vomiting, and the inability

signs. This neocerebellar syndrome may be caused
by hemorrhage, ischemic strokes, brain tumors, or
degenerative disorders such as multiple sclerosis.
The severe disturbances of limb movements occur
without weakness and include decreased muscle
tone (hypotonia), poor timing of movements that
require sequencing (asynergia), and coordinated
changes in muscle activation (dysdiadochokinesia).
A severe tremor can occur as the patient attempts to
move the limb and perform motor tasks. Although
this syndrome develops with diseases located with-
in the cerebellar hemispheres, damage to the
incoming and outgoing pathways, as seen with
occlusion of the superior cerebellar artery or with
multiple sclerosis, can cause the same clinical
picture.
In primary degenerative disorders of the cerebellar
systems (also called cerebellar atrophy, cerebellar
degeneration, spinocerebellar atrophy, and spinocer-
ebellar degeneration), there is usually symmetrical
involvement of both hemispheres and the vermis so
that bilateral limb incoordination and ataxia of
stance and gait predominate. Dysarthria and oculo-
motor disturbances are also frequently present.
Additional signs that indicate neurological deficits
outside the primary cerebellar systems, such as
weakness, ophthalmoplegia, and peripheral neuro-
pathy, are common in these disorders, many of which
are hereditary in origin. Disorders include Fried-
reich’s ataxia, Charcot–Marie–Tooth disease, and
olivopontocerebellar atrophy. Recent genetic ad-
vances have resulted in the identification of an
increasingly large array of different disorders that
can be categorized as cerebellar ataxias of genetic
origin.
Paroxysmal or episodic forms of ataxia are
cerebellar syndromes that occur intermittently and
then symptomatically clear. In children, these are
often due to metabolic disorders, and among adults
the same types of symptoms can be drug induced or
related to cerebrovascular diseases.
One remarkable feature of many cerebellar
disorders is the functional compensation that
occurs after injury. In contrast to many other
neurological disorders, subjects often show marked
improvement over time when a cerebellar insult is a
single event, such as a stroke; even when the
disorder is progressive, the subject continually
compensates with resultant very mild progression
of symptoms. This pattern is particularly marked in
children.
—Christopher G. Goetz
CEREBELLAR HEMATOMA 567
See also–Ataxia; Brain Tumors, Clinical
Manifestations and Treatment; Cerebellar
Hematoma; Cerebellum; Charcot-Marie-Tooth
Disease; Dysarthria; Gait and Gait Disorders;
Friedreich’s Ataxia
Further Reading
Griggs, R. C., and Nutt, J. G. (1995). Episodic ataxias as
channelopathies. Ann. Neurol. 37, 285–287.
Harding, A. E. (1993). Clinical features and classification of
inherited ataxias. In Advances in Neurology (A. E. Harding and
T. Deufel, Eds.), pp. 1–14. Raven Press, New York.
Klockgether, T. (2003). Ataxias. In Textbook of Clinical Neurol-
ogy (C. G. Goetz, Ed.), pp. 680–694. Saunders, Philadelphia.
Nutt, J. G. (2003). Gait and balance. In Textbook of Clinical
Neurology (C. G. Goetz, Ed.), pp. 301–314. Saunders,
Philadelphia.
Wallesch, C. W., and Bartels, C. (1997). Inherited cerebellar
diseases. Int. Rev. Neurobiol. 41, 441–453.
Cerebellar Hematoma
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBELLAR HEMORRHAGE accounts for approxi-
mately 10% of all intracerebral hemorrhage, and the
anatomy of the posterior fossa makes cerebellar
hemorrhage potentially more dangerous than supra-
tentorial bleeding. Although cerebellar hemorrhage
typically occurs in known hypertensive patients,
multiple other etiologies exist.
ETIOLOGY
Unless the patient with cerebellar hemorrhage is
known to be hypertensive, other potential causes for
bleeding should be sought. Other causes of cerebellar
hemorrhage and hematoma include tumor, aneur-
ysm, vascular malformation, amyloid angiopathy,
coagulopathy, angiitis, sympathomimetic intoxica-
tion, and trauma. Of course, patients who are
typically normotensive may present with profoundly
high systemic blood pressure after hemorrhage into
the cerebellum as a result of elevated intracranial
pressure.
CLINICAL PRESENTATION
After sustaining cerebellar hemorrhage, a patient
may complain of ipsilateral occipital headache,
persistent vertigo with vomiting, and the inability
568 CEREBELLAR HEMATOMA
to sit, stand, or walk. Hydrocephalus and reticular
activating system dysfunction may result in a
decreased level of consciousness. Dysphagia, dysar-
thria, ipsilateral abducens and facial nerve palsy, and
decreased corneal blink reflex reflect cranial nerve
dysfunction from brainstem compression. Other
signs of brainstem compression include contralateral
weakness, decerebrate posturing, nystagmus, gaze
preference to the contralateral side, ocular bobbing,
and reactive pinpoint pupils. Gait ataxia may be the
only sign of cerebellar dysfunction, and in such cases
hemorrhage may go unrecognized unless specifically
considered. Uncommonly, limb ataxia and dysmetria
are prominent findings.
DIAGNOSIS
Cerebellar hemorrhage and hematoma are confirmed
by noncontrast computed tomography (Fig. 1). The
lesion is customarily hyperdense in relation to brain
parenchyma, and intraventricular or subarachnoid
hemorrhage is often seen. Acute hydrocephalus from
Figure 1
Axial noncontrast computed tomography revealing hyperdense
acute cerebellar hematoma with temporal horn dilatation as well
as brainstem and fourth ventricular compression.
fourth ventricular compression, intraventricular he-
matoma, or subarachnoid hemorrhage is common in
patients with cerebellar hematoma, especially the
larger lesions, and computed tomography shows
dilated third and lateral ventricles in such cases
(Fig. 2). If hemorrhage has unusual features (e.g., it
has occurred in a nonhypertensive, it is atypical in
location, or there is a significant component of
subarachnoid or intraventricular blood), magnetic
resonance imaging, magnetic resonance angiography,
and conventional angiography should be used to
evaluate for concomitant pathology.
PATHOPHYSIOLOGY
Heros describes three stages of posterior fossa
mass effect in cerebellar hemorrhage and infarc-
tion (the other major acute cause of posterior
fossa mass effect, morbidity, and mortality). As
noted previously, direct cerebellar destruction
results in the signs and symptoms of cerebellar
dysfunction. Intraventricular and subarachnoid
hemorrhage as well as direct compression of the
fourth ventricle may lead to acute hydrocephalus,
cortical dysfunction, and brainstem herniation.
Also, mass effect on the brainstem may depress
consciousness, cause cranial nerve dysfunction,
and lead to long tract findings. Hypertensive
cerebellar hemorrhage is typically focused in the
dentate nucleus and is thought to arise from an
artery or an arterialized vein.
TREATMENT
An aggressive neurosurgical approach should be
taken in those with signs and symptoms of hydro-
cephalus or brainstem compression. The great
majority of patients with cerebellar hemorrhage or
infarction are operated on, and observation is
reserved for only the smallest of hematomas (with
no mass effect) or for elderly or alcoholic patients in
whom pronounced cerebellar atrophy renders the
space-occupying lesion more innocuous. A standard
midline or paramedian suboccipital craniectomy for
hematoma evacuation, with external ventricular
drainage at the time of surgery, is the treatment of
choice. Other treatments include percutaneous drai-
nage, craniectomy without ventriculostomy (with
prophylactic occipital Frazier burr hole), ventricu-
lostomy without craniectomy (with risk of upward
herniation), or medical management. Medical man-
agement should only be attempted in those with

Figure 2
Axial noncontrast computed tomography, cranial to Fig. 1, reveals
ventriculomegaly consistent with acute hydrocephalus.
relatively small hematomas, no evidence of hydro-
cephalus, and a clear sensorium. Stereotactic percu-
taneous drainage of cerebellar hematoma utilizing
tissue plasminogen activator and an indwelling
catheter is a relatively new therapeutic option. In
the acute treatment setting, careful observation in the
intensive care unit is mandatory for patients treated
either medically or surgically. Rapid deterioration
with little or no warning may occur in those with
either cerebellar hematoma or infarction. If surgery
is performed for hematoma evacuation, biopsies
should be taken to ensure there is no concurrent
pathology.
PROGNOSIS
Condition at presentation seems to be the most
important determinant of prognosis. Not surpris-
ingly, those comatose at presentation typically do
poorly, and those who are relatively awake and alert
at presentation without evidence of brainstem
compression or hydrocephalus have a better outlook.
A subset of patients who become comatose under
CEREBELLUM 569
medical supervision and who subsequently undergo
craniectomy with hematoma evacuation may recover
relatively well if prompt medical/surgical attention is
available.
—Robert J. Wienecke and Christopher M. Loftus
See also–Cerebellar Disorders; Cerebellum;
Hydrocephalus; Intracerebral Hemorrhage,
Primary; Subarachnoid Hemorrhage
Further Reading
Fisher, C. M., Picard, E. H., Polak, A., et al. (1965). Acute
hypertensive cerebellar hemorrhage: Diagnosis and surgical
treatment. J. Nervous Mental Dis. 140, 38–57.
Heros, R. C. (1982). Cerebellar hemorrhage and infarction. Stroke
13, 106–109.
Kobayashi, S., Sato, A., Kageyama, Y., et al. (1994). Treatment of
hypertensive cerebellar hemorrhage—Surgical or conservative
management? Neurosurgery 34, 246–250.
Loftus, C. M. (1996). Management of intracerebellar hematomas
and infarcts. In Primer on Cerebrovascular Diseases (K. M. A.
Welch, L. Caplan, D. Reis, B. Weir, and B. Siesjö, Eds.), pp.
503–508. Academic Press, New York.
Yokote, H., Komai, N., Nakai, E., et al. (1989). Stereotactic
evacuation of hypertensive cerebellar hemorrhage using plas-
minogen activator. No Shinkei Geka 17, 421–426.
Cerebellum
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE HUMAN CEREBELLUM (‘‘little brain’’) is a
significant part of the central nervous system
both in size and in neural structure. It occupies
approximately one-tenth of the cranial cavity, sitting
astride the brainstem, beneath the occipital cortex,
and contains more neurons than the whole of the
cerebral cortex. It consists of an extensive cortical
sheet, densely folded around three pairs of nuclei.
The cortex contains only five main neural cell types
and is one of the most regular and uniform structures
in the central nervous system (CNS), with an
orthogonal ‘‘crystalline’’ organization. Major con-
nections are made to and from the spinal cord,
brainstem, and sensorimotor areas of the cerebral
cortex.
The most common causes of damage to the
cerebellum are stroke, tumors, or multiple sclerosis.
These result in prominent movement disorders,
the principal symptoms being ataxia, tremor, and

Figure 2
Axial noncontrast computed tomography, cranial to Fig. 1, reveals
ventriculomegaly consistent with acute hydrocephalus.
relatively small hematomas, no evidence of hydro-
cephalus, and a clear sensorium. Stereotactic percu-
taneous drainage of cerebellar hematoma utilizing
tissue plasminogen activator and an indwelling
catheter is a relatively new therapeutic option. In
the acute treatment setting, careful observation in the
intensive care unit is mandatory for patients treated
either medically or surgically. Rapid deterioration
with little or no warning may occur in those with
either cerebellar hematoma or infarction. If surgery
is performed for hematoma evacuation, biopsies
should be taken to ensure there is no concurrent
pathology.
PROGNOSIS
Condition at presentation seems to be the most
important determinant of prognosis. Not surpris-
ingly, those comatose at presentation typically do
poorly, and those who are relatively awake and alert
at presentation without evidence of brainstem
compression or hydrocephalus have a better outlook.
A subset of patients who become comatose under
CEREBELLUM 569
medical supervision and who subsequently undergo
craniectomy with hematoma evacuation may recover
relatively well if prompt medical/surgical attention is
available.
—Robert J. Wienecke and Christopher M. Loftus
See also–Cerebellar Disorders; Cerebellum;
Hydrocephalus; Intracerebral Hemorrhage,
Primary; Subarachnoid Hemorrhage
Further Reading
Fisher, C. M., Picard, E. H., Polak, A., et al. (1965). Acute
hypertensive cerebellar hemorrhage: Diagnosis and surgical
treatment. J. Nervous Mental Dis. 140, 38–57.
Heros, R. C. (1982). Cerebellar hemorrhage and infarction. Stroke
13, 106–109.
Kobayashi, S., Sato, A., Kageyama, Y., et al. (1994). Treatment of
hypertensive cerebellar hemorrhage—Surgical or conservative
management? Neurosurgery 34, 246–250.
Loftus, C. M. (1996). Management of intracerebellar hematomas
and infarcts. In Primer on Cerebrovascular Diseases (K. M. A.
Welch, L. Caplan, D. Reis, B. Weir, and B. Siesjö, Eds.), pp.
503–508. Academic Press, New York.
Yokote, H., Komai, N., Nakai, E., et al. (1989). Stereotactic
evacuation of hypertensive cerebellar hemorrhage using plas-
minogen activator. No Shinkei Geka 17, 421–426.
Cerebellum
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE HUMAN CEREBELLUM (‘‘little brain’’) is a
significant part of the central nervous system
both in size and in neural structure. It occupies
approximately one-tenth of the cranial cavity, sitting
astride the brainstem, beneath the occipital cortex,
and contains more neurons than the whole of the
cerebral cortex. It consists of an extensive cortical
sheet, densely folded around three pairs of nuclei.
The cortex contains only five main neural cell types
and is one of the most regular and uniform structures
in the central nervous system (CNS), with an
orthogonal ‘‘crystalline’’ organization. Major con-
nections are made to and from the spinal cord,
brainstem, and sensorimotor areas of the cerebral
cortex.
The most common causes of damage to the
cerebellum are stroke, tumors, or multiple sclerosis.
These result in prominent movement disorders,
the principal symptoms being ataxia, tremor, and
570 CEREBELLUM
hypotonia. Affective, cognitive, and autonomic
symptoms are also common. Childhood cancers,
developmental disorders, and ion channel disorders
also affect the cerebellum.
Despite its remarkable structure and well-under-
stood physiology, the role of the cerebellum is far
from clear. This challenge has attracted many
scientists and the cerebellum is also remarkable for
the number of conflicting theories put forward to
account for it.
HISTORY
The early anatomists recognized the distinct nature
of the cerebellum. Accurate drawings of its gross
structure originate from Vieussens in 1684, the first
book devoted solely to the cerebellum was published
in 1776 by M. V. G. Malacarne, and the principal
cell type was named by Jan Purkyne (Purkinje) in
1837. At approximately the same time, Marie-Jean-
Pierre Flourens (1824) described the results of
experimental ablation of the cerebellum on the
coordination of movements. In 1900, Charles Sher-
rington stated that the cerebellum is the ‘‘head
ganglion’’ of the proprioceptive system, neatly
encapsulating the notion that the cerebellum strongly
influences spinal sensorimotor functions.
GROSS ANATOMY
Cortex
The cerebellar cortex is an extensive three-layered
sheet with a surface approximately 15 cm laterally
and 180 cm rostrocaudally but densely folded around
three pairs of nuclei. The cortex is divided into three
transverse lobes: Anterior and posterior lobes are
separated by the primary fissure, and the smaller
flocculonodular lobe is separated by the poster-
olateral fissure (Fig. 1). The anterior and posterior
lobes are folded into a number of lobules and further
folded into a series of folia. This transverse organiza-
tion is then divided at right angles into broad
longitudinal regions. The central vermis, named for
its worm-like appearance, is most obvious in the
posterior lobe. On either side is the paravermal or
intermediate cortex, which merges into the lateral
hemispheres.
Deep Nuclei of the Cerebellum
Each cerebellar cortical region projects in a systema-
tic manner to the underlying deep nuclei, which
Figure 1
The gross anatomy of the human cerebellum, shown in dorsal view
on the left and ventrally on the right (modified with permission
from Kandel and Schwartz, Principles of Neural Science, Elsevier,
New York, 1985).
provide the output fibers from the cerebellum. The
lateral hemisphere projects predominantly to the
dentate nucleus; the paravermis projects to the
interpositus nucleus, which in man is divided into
globose and emboliform nuclei; and the vermis
projects to the fastigial nucleus. The flocculonodular
cortex projects to the lateral vestibular nucleus
(Dieter’s nucleus)—functionally a displaced deep
cerebellar nucleus.
Gross organization is mirrored phylogenetically.
The oldest part, the archi- or vestibulocerebellum, is
retained as the flocculonodulus. It is closely con-
nected with the vestibular system and predominantly
involved in balance. The paleo- or spinocerebellum
corresponds to the anterior vermis, pyramid, uvula,
and paraflocculus and is concerned with balance,
posture, and orientation. It receives spinal proprio-
ceptive inputs as well as auditory and visual input,
and it projects back to the spinal cord via the red
nucleus. The neocerebellum (caudal vermis, paraver-
mis, and lateral hemispheres) has developed in
terrestrial animals for independent control of the
limbs and in mammals has expanded further in
concert with the development of fine control of the
distal musculature. The paravermis and lateral hemi-
spheres affect ipsilateral muscles, and their dysfunc-
tion results in movement deficits of the limb on the
 CEREBELLUM 571

same side as the lesion. The vermis and flocculono-
dulus influence muscles of the trunk and the eyes, and
therefore lesions can have bilateral effects.
The gross anatomy of the cerebellum varies across
vertebrate species in line with their sensorimotor
specialization. Fish use a sensory ‘‘lateral line organ’’
for detecting vibration in the water, and electro-
receptive mormyrid fish have further developed this
system to allow sampling of the surrounding
environment with electric pulses. The valvula cere-
belli (a medial region of the anterior cerebellum) in
these species is enormous. Certain bats also have
large cerebellar volumes perhaps related to their use
of auditory echo location. In cetaceans (whales and
dolphins) the dorsal paraflocculus is greatly ex-
panded. In primates, the lateral hemispheres (the
ponto- or cerebrocerebellum) have expanded drama-
tically approximately in proportion to the expanse of
the neocortex.
CYTOARCHITECTURE
The perpendicular arrangement of transverse and
longitudinal axes is maintained in the cellular
organization of the cortex. The most prominent cell
type of the cortex is the GABAergic Purkinje cell (P
cell; Fig. 2), which has its soma in the middle cortical
layer (the Purkinje or ganglionic layer) and a large
flattened dendritic tree lying fan-like in the sagittal
plane of the upper layer (the molecular layer). P cells
form the only output from the cortex, sending
inhibitory axons to the cerebellar nuclei. The
glutamatergic granule cells, the most numerous cell
type, have their soma and a sparse dendritic arbor
within the granular layer and then send single axons
to the molecular layer. Here, the axons bifurcate into
two unmyelinated parallel fibers running transversely
along the folia, passing through the dendritic trees of
the P cells. Each parallel fiber extends 2–4 mm across
the cortex, with more superficial fibers traveling
furthest. P cell dendritic trees lie across a beam of
parallel fibers. Each parallel fiber makes excitatory
synaptic contact with the dendrites of perhaps 200
Purkinje cells along this beam, whereas each P cell
receives 200,000 parallel fiber synapses. Parallel fiber
activity can evoke in the P cell a series of ‘‘simple
spikes’’ whose frequency reflects the strength of the
input. Parallel fibers also make excitatory synaptic
contact with the other three GABAergic cell types of
the cortex, all with cell bodies within the molecular

Figure 2
(A) The cerebellar cortex. Inputs are shown in blue, output (Purkinje cells) in red. Inhibitory interneurones are black; granule cells are green
(reproduced with permission from Eccles et al., The Cerebellum as a Neuronal Machine, Springer-Verlag, Berlin, 1967). (B) The cerebellar
circuit. Arrows indicate the direction of transmission across each synapse; color coding is as in Fig. 2A (modified with permission from
Voogd and Glickstein, TICS 2, 307–313, 1998). 1–3, Sources of mossy fibers; Ba, basket cell; BR, brush cell; cf, climbing fiber; CN,
cerebellar nuclei; Go, Golgi cell; IO, inferior olive; mf, mossy fiber; pf, parallel fibers; PN, pontine nuclei; sb and smb, spiny and smooth
branches of P cell dendrites, respectively; St, stellate cell; PC, Purkinje cell; bat, basket cell terminal; pcc, P cell collateral; no, nucleo-olivary
pathway; nc, collateral of nuclear relay cell. (See color plate section.)
572 CEREBELLUM

layer: the Golgi, stellate, and basket cells (Fig. 2).

The Golgi cells have an approximately cylindrical
dendritic arbor, whereas the stellate and basket cells
have a sagittally flattened or elliptic arbor. The Golgi
cells inhibit neighboring granule cells and therefore
help to limit the activity within the parallel fibers.
The basket cells and stellate cells send axons across
the folium at right angles to the parallel fibers,
inhibiting neighboring Purkinje cells. Together these
interneurons sharpen the zone of activation caused
by the granule cells so that a beam of active Purkinje
cells is created, bordered by inhibited cells. Two less
well-documented and less numerous cell types, the
unipolar brush cells and Lugano cells, lie below the
Purkinje cell layer: The first is an excitatory inter-
neuron feeding onto granule cells and the latter an
inhibitory cell feeding back from P cell collaterals
onto stellate and basket cells.

INPUTS
Mossy and Climbing Fibers
The two major inputs to the cortex are the mossy
fibers and climbing fibers. Mossy fibers originate
from many extracerebellar sites and branch repeat-
edly to reach one or more narrow sagittal strips of
cortex, where they make excitatory contact with the
dendrites of the granule cells. The complex of mossy
fiber terminal and granule cell dendrites is called a
synaptic glomerulus. Mossy fibers also send collat-
erals to the cerebellar nuclei so that inputs reach
these nuclei directly via a cortical loop involving
granule cells and Purkinje cells (Fig. 2B). Mossy
fibers reaching the intermediate cerebellar cortex and
the fastigial and interposed nuclei carry visual,
somatic, auditory, and vestibular information as well
as outputs from the sensory motor cortex. Mossy
fibers reaching the lateral cortex and the dentate
nucleus carry information from prefrontal, premotor,
parietal, and occipital cortex.
Climbing fibers arise solely from the inferior olive.
The inferior olive receives inputs from many areas,
carrying vestibular, spinal, cranial, and much cortical
descending information. Its cells can have quite
complex properties, but they have a precise topo-
graphical arrangement (Fig. 3). Each climbing fiber
projects to one or more contralateral parasagittal
strips of cerebellar cortex, branching to reach
approximately 10 P cells. They also send collateral
connections to the corresponding deep cerebellar
nucleus. The terminals of the climbing fiber on the
Figure 3
Olivocerebellar and corticonuclear projections. Climbing fiber
projection from regions of the contralateral inferior olive (bottom)
to the cerebellar cortex (top) are color coded. Sagittal
olivocerebellar zones (A, X, B, etc.) are labeled at top right.
Cerebellar output nuclei are shown in the middle. DAO and MAO,
dorsal and medial accessory olive, respectively; PO, principal olive;
IA and IP, anterior and posterior interposed nucleus, respectively;
DC and DR, caudal and rostral dentate nuclei, respectively; F,
fastigial nucleus (reproduced with permission from Voogd and
Glickstein, TICS 2, 307–313, 1998). (See color plate section.)
Purkinje cell form an extensive complex of up to 300
synapses around its soma and primary dendrites.
Climbing fibers typically fire at low rates of only 1–
10 spikes per second and often with low probability
to a particular stimulus, but each climbing fiber
action potential reliably causes a complex spike in
the Purkinje cell. They are particularly responsive to
unexpected sensory stimuli, such as gentle touch of
the skin for somatosensory cells or motion of the
visual image on the retina for visual cells. Many are
 CEREBELLUM 573

nociceptive. However, sensitivity is strongly modu-
lated during motor activity so that stimulation
during active movement can fail to trigger responses.
This very low firing rate signal has proven difficult to
decode, and there are many different opinions about
what information is carried by the climbing fibers.
The cortex also receives diffuse projections of
noradrenergic fibers from locus coeruleus, serotoner-
gic fibers from the Raphe complex, and a small
dopaminergic input from the mesencephalic tegmen-
tum. The role of these inputs is not clear.
nuclei as well as climbing fibers from parts of the
inferior olive related to the vestibular nuclei (Fig. 3).
It also receives mossy fiber inputs carrying visual
information from lateral geniculate nucleus and
superior colliculus. The flocculonodular cortex pro-
jects back mostly to the lateral vestibular nucleus and
hence to the medial descending spinal pathways. The
vestibular nuclei also project via the medial long-
itudinal fasciculus to the ocular motor nuclei III, IV,
and VI. Its action is therefore mainly on axial
muscles and on eye movement, controlling balance
and coordinating head–eye movement.

CONNECTIVITY
The cerebellum connects to the brainstem via three
large paired roots—the superior, middle, and inferior
peduncles (brachium conjunctivum, brachium pon-
tis, and restiform body, respectively; Fig. 1).
Vestibulocerebellum
The vestibulocerebellar cortex receives some mossy
fibers that arise directly from the vestibular appara-
tus and others that are derived from the vestibular
Spinocerebellum
Most ascending somatosensory and proprioceptive
inputs reach the vermis and paravermis to form
topographic maps on both the anterior and posterior
lobes (Fig. 4A). There are also considerable vestibu-
lar, visual, and auditory inputs, the latter two
reaching mainly the posterior lobe. The maps drawn
on the cerebellar cortex have been gradually refined
with improved recording techniques, and it is now
known that mossy fiber input actually reaches

Figure 4
Representation of sensory information in the cerebellar cortex. (A) Two somatotopic maps are found in the anterior and posterior lobes, with
exteroceptive and vestibular information distributed in between (modified with permission from Kandel and Schwartz, Principles of Neural
Science, Elsevier, New York, 1985). (B) These maps are fractured in detail, forming a mosaic over the cortex (reproduced with permission
from Voogd and Glickstein, TICS 2, 307–313, 1998). Tactile inputs to the rat cerebellum were mapped by W. Welker onto the cerebellar
cortex by recordings from individual granule cells. The rat cerebellum has massive facial inputs and very small limb and trunk input.
574 CEREBELLUM
discrete patches of granule cells forming a mosaic or
‘‘fractured somatotopic map’’ (Fig. 4B). Quite distant
body parts can therefore be mapped onto adjacent
patches approximately 50–100 mm wide. This map is
then blurred by the granule cells projecting their
parallel fibers over several millimeters.
Two pairs of spinocerebellar tracts arise directly
from the spinal cord: the dorsal and ventral
spinocerebellar tracts, which carry information from
the hindlimbs and lower trunk, and the cuneo- and
rostrospinocerebellar tracts carrying corresponding
information from the forelimbs and upper trunk.
The dorsal spinocerebellar tract (DSCT) arises from
Clarke’s nucleus and provides rapidly adapting
cutaneous and muscle mechanoreceptor information
to the cerebellum via the inferior peduncle. The
ventral spinocerebellar tract (VSCT) arises from
more lateral (‘‘border’’) cells of the spinal gray
matter and carries muscle spindle, cutaneous, and
particularly Golgi tendon organ inputs via the
superior cerebellar peduncle, but the cells have
extensive connections in the cord. It has been
suggested that whereas the DSCT carries precise
proprioceptive feedback, the VSCT integrates des-
cending, spinal, and proprioceptive signals to
provide feedback of the motor commands reaching
the motor neurons. If proprioceptive input is
eliminated by cutting the dorsal roots, the cerebellar
input from DSCT is interrupted, whereas that from
VSCT is maintained.
There is also indirect mossy fiber input from the
lateral reticular nucleus (LRN), again via the inferior
cerebellar peduncle. Like the inferior olive, the LRN
receives input from spinal cord, cranial nuclei, and
cerebral cortex, but unlike the inferior olive, its cells
have large multimodal receptive fields.
The anterior and posterior vermis project to the
fastigial nucleus, the lateral vestibular nuclei, and the
brainstem reticular formation. Some outputs also
relay via the thalamus to the motor cortex. The
outflow therefore affects the medial descending
systems of the brainstem and cortex, modulating
the descending signals to axial muscles that mediate
postural control.
The paravermal cortex projects to the interpositus
nucleus and then on to the magnocellular red nucleus
with additional outputs to LRN and to the motor
cortex via the ventrolateral thalamus. The paraver-
mal outflow therefore indirectly modulates rubro-
spinal and lateral corticospinal descending systems.
Its major influence is on ipsilateral distal limb
musculature.
Cerebellar connections form a number of closed
loops. One is from the interpositus nucleus to LRN
(either directly or via the red nucleus) and back to the
intermediate cortex as mossy fibers. Another loop is
formed by mossy fibers that project directly from the
deep cerebellar nuclei back to the cortex. Although
the function of these loops is not clear, one
suggestion is that they provide reverberating circuits
to generate prolonged motor control signals. A
second class of closed loops is formed by indirect
projections from the cerebellar cortex to the inferior
olive, projecting back as climbing fibers.
Cerebrocerebellar Connections
Wide areas of the cerebral cortex project to the
cerebellar hemispheres via the contralateral pontine
nuclei, and these provide quantitatively the largest
input to the human cerebellum. These include
secondary sensory cortices, especially visual but also
premotor and motor cortical areas, and a large
projection from the posterior parietal cortex. The
cerebrocerebellum receives little somatosensory in-
put from the spinal cord. The pontine inputs reach
the contralateral cerebellar cortex via the middle
cerebellar peduncle. The output from the hemi-
spheres projects to the dentate nucleus and from
there to the ventrolateral thalamus and hence back to
the premotor and motor cortices. Some output also
projects to the parvocellular red nucleus and hence to
the inferior olive. Recent evidence of projection to
cortical regions other than senorimotor has emerged,
and it seems likely that the closed loops between
sensorimotor cerebral areas and the cerebellum are
matched by closed loops with frontal, cingulate,
parahippocampal, and occipitotemporal prestriate
areas. Certain cerebral areas do not project to
cerebellum, including primary sensory cortices and
orbitofrontal and inferior temporal areas; these also
appear not to receive cerebellar outputs.
The cerebrocerebellar function is thought to relate
more to the preplanning and refinement of motor
programs being developed by the cerebral cortex
than with the control of ongoing movements. Inputs
to the hemispheres are particularly important in
visually guided movements and precede any motor
activity.
DEVELOPMENT
Studies of the development of the cerebellum have
rapidly advanced with the identification of genes
important for its growth and cellular organization.

Proteins expressed in the embryonic mes- and
metencephalon are crucial for its gross structure.
Other genes are crucial for Purkinje cell development
and migration, granule cell development, and neu-
ron–glial interactions.
The cerebellum arises from the dorsal alar plate of
the neural tube, with neural cells derived from at
least two germinal zones. The neuroepithelial ven-
tricular zone gives rise to cells that form the
cerebellar nuclei. Soon after, the Purkinje cells
emerge, forming a sheet-like layer. Later, Golgi cells
also form from the same germinal zone. A secondary
germinal matrix, the external granular layer (EGL),
comes from the rhombic lip and the EGL cells
migrate over the cerebellar surface to provide the
abundant granule cells as well as stellate and basket
cells. Granule cell neuroblasts migrate inwards past
the Purkinje cells, and this is a crucial process for the
final organization of the Purkinje cell layer and their
dendritic arbors.
A number of knockout mutations have been found
in the mouse that illuminate some of these stages.
Knockout of En-1 or Wnt-1, expressed at the
junction of the mesencephalon and metencephalon,
leads to near total agenesis of the cerebellum.
Development and regulation of the different cere-
bellar neural populations is still unclear but seems
closely bound to the fate of Purkinje cells. In mutant
mice such as meander tail or weaver, P cell
development and migration are impaired, which
leads to either reduced production of granule cells
or their subsequent death. Weaver, staggerer, and
several other mutations affect P cell survival through
ion channel function.
The compartmental organization of the cerebellar
cortex is complex. Several proteins (e.g., zebrin) are
expressed in narrow sagittal stripes, closely related to
but probably independent of the olivocerebellar
zones (Fig. 3). The developmental rules for the
organization of the climbing fiber input from the
olive are unclear.
CLINICAL
Motor
The cerebellum can be affected by neoplasms or
paraneoplastic disorders, vascular damage (stroke),
inflammatory diseases such as multiple sclerosis, and
long-term alcohol abuse or other toxic substances.
The exposed cerebellar tonsils can be damaged
mechanically by violent acceleration and also by
CEREBELLUM 575
tumors or fluid buildup that force the brainstem
backwards. This is most dangerous if pressure in the
spinal fluid is suddenly reduced by a lumbar
puncture, and it can result in the brainstem and
cerebellar tonsils herniating through the foramen
magnum. Because different parts of the cerebellum
are involved in the control of vestibular, postural,
and distal muscles, lesions of the cerebellum will
variously affect primarily balance, posture, or the
skilled control of the limbs. Congenital deformation
(or even absence) of the cerebellum has much less
effect than acute damage, but even in adulthood the
effects of lesions are reduced greatly over time.
Purkinje cells and granule cells are both sensitive
to toxic substances. P cells are very sensitive to
ischemia, bilirubin, ethanol, and diphenylhydantoin.
Granule cells appear sensitive to methyl halides,
thiophene, methyl mercury, 2-chloropropionic acid,
and trichlorfon. Both are sensitive to excitotoxic
chemicals. Acute effects of cannabinoids are depen-
dent on the G protein-coupled cannabinoid receptor
CB1, which is found at high densities in the
cerebellum.
An important clinical analysis of the cerebellum
was performed in the years following World War I by
Gordon Holmes, who studied gunshot-wounded
soldiers. He described three classic symptoms:
ataxia, intention tremor, and hypotonia.
Ataxia refers to the imperfect coordination of
movements, with poor timing, clumsiness, and
unsteadiness. Cerebellar patients tend to overshoot
when pointing at targets (hypermetric movements).
They also have increased reaction times, disturbed
temporal patterns of EMG activity and hence
abnormal patterns of joint accelerations, and diffi-
culties in performing rapid alternating movements
(dysdiadochokinesia).
Intention tremor probably results from continual
hypermetric corrections of position. Unlike tremor
associated with Parkinson’s disease, intention tremor
is not seen when the limb is at rest.
Hypotonia is a loss of muscle tone and it is
associated with rapid fatigue of the muscles. It results
from the loss of facilitating drive from the cerebellar
nuclei to gamma motor neurons. If the hemispheres
are affected, the ipsilateral limbs are affected,
whereas postural deficit follows damage to the
vermis. Hypotonia is found particularly with lesions
of the posterior lobe. It is evident as a ‘‘pendular’’
knee-jerk in which the leg continues to swing because
of the reduced braking action of the muscles. In
alcoholic cerebellar damage, and in patients with
576 CEREBELLUM
lesions of the anterior lobe, hypertonia may result
through disinhibition of Deiter’s nucleus and hence
excitation of alpha motor neurons. Other cerebellar
symptoms are nystagmus and dysarthria.
Hereditary Ataxias
A mixed group of inherited disorders related to
degeneration of the cerebellum and its afferent or
efferent connections and characterized by progres-
sive ataxia have been identified and linked to
approximately 10 different genes. They can be
categorized as autosomal recessive or dominant
ataxias.
Friedreich’s ataxia is the most common of the
recessive ataxias and is caused by mutation causing
GAA trinucleotide repeats in a gene on chromosome
9. Onset is in childhood or early adulthood, marked
by degeneration of large fibers in the spinocerebellar,
posterior columns, and pyramidal tracts with later
mild cerebellar degeneration.
The autosomal dominant cerebellar ataxias [AD-
CAs or spinocerebellar ataxias (SCA)] are designated
by different clinical signs (SCA-1, -2, -3, -6, and -7)
but all appear to be caused by inheritance of unstable
CAG trinucleotide repeat sequences, albeit in differ-
ent chromosomes, leading to dysfunction within the
Purkinje cell nuclei. Pathological changes are also
found outside the cerebellum, including in the basal
ganglia, brainstem, spinal cord, and peripheral
nervous system.
Variants of the autosomal dominant disorders,
episodic ataxia types EA-1 and -2 and SCA-6, lead to
brief episodes of ataxia, often triggered by stress,
exercise, or fatigue and with near-normal symptoms
during remission. These disorders are thought to be
due by mutations affecting ion channel function—
K þ channels in granule cells in the case of EA-1 and
voltage-gated Ca2 þ channels on Purkinje cells for
EA-2 and SCA-6—and can often be clinically treated
accordingly.
Nonmotor
In the past few years, there has been a change in
opinion about the extent of cerebellar function. Early
awareness of its involvement in autonomic, vasomo-
tor, and affective processes was largely ignored as
research concentrated on aspects of motor control.
However, it is now accepted that it has roles in many
cognitive functions: language processing, classic
conditioning, problem solving and planning, work-
ing memory, attention shifting, and others. There is
reported volume loss in the vermis of a proportion of
schizophrenic patients and children with attentional
deficit hyperactive disorder as well as more wide-
spread depletion with autism. Clinical stimulation of
the vermis can reduce fear and aggression in
emotionally disturbed patients. Tumor resection in
children can lead to behavioral and linguistic
problems, especially for midline tumors. Anterior
lobe lesions seem to lead to few cognitive symptoms,
whereas symptoms are more frequently seen follow-
ing posterior lobe damage. The term cerebellar
cognitive affective syndrome covers signs of deficient
executive function, impaired spatial cognition, per-
sonality changes with flattening of affect, and
language deficits, leading to a net reduction in
intellectual function.
SYNAPTIC PLASTICITY
There is good evidence for long-term changes in the
efficacy of synapses between the parallel fibers and
Purkinje cells. If the climbing fiber is active during
parallel fiber input, the strength of the synapse from
parallel fiber to Purkinje cell is reduced by a process
called long-term depression (LTD). This changes the
relationship between mossy fiber input to the cortex
and Purkinje cell output and thus modifies P cell
inhibition of the cerebellar nuclei. The climbing
fibers may therefore provide an error signal to
modulate or ‘‘instruct’’ the Purkinje cells. Indeed,
the climbing fibers are most active in situations in
which changes in motor behavior are required, for
example, in learning new motor skills or adapting
reflex behaviors. Synaptic plasticity is suspected at
other sites in the cerebellum. Evidence from studies
of the modification of the vestibulo-ocular reflex
indicates that a change at the level of the cerebellar
targets (the deep cerebellar nuclei or vestibular
nuclei) is required, but the mechanism for this
plasticity is unknown. There is also evidence for
long-term potentiation at the synapse between mossy
fiber and granule cells and perhaps onto stellate and
basket cells as well. There seems to be important
structural plasticity between climbing fibers and
Purkinje cells.
Parallel Fiber/Purkinje Cell LTD
The molecular basis of long-term change at the
excitatory synapse between parallel fibers and
Purkinje cells is reasonable well understood. It is
dependent on phosphorylation of postsynaptic iono-
tropic AMPA glutamate receptors and thus a
reduction in synaptic efficacy. There are two ways

to induce plasticity. In one, a use-dependent homo-
synaptic form, plasticity is triggered by powerful
parallel fiber input sufficient to depolarize the
postsynaptic P cell dendrites and induce calcium
entry via voltage-sensitive channels. The second form
is heterosynaptic, requiring the conjoint excitation of
the P cell by parallel fiber activity and by climbing
fiber input. The complex spike depolarization of the
P cell dendritic tree produced by the climbing fiber
input again causes Ca2 þ influx. Then, there is a
second messenger cascade of events involving protein
kinase C that links AMPA receptor and G–protein-
coupled metabotropic mGluR1 activation, Ca2 þ
entry or release from intracellular stores, and AMPA
receptor phosphorylation. This process is also linked
to nitric oxide (NO) production, although not from P
cells but perhaps from adjacent parallel fibers or glia.
NO is highly diffusable and may be an important
messenger to induce synaptic changes in adjacent
cells.
LTD has been well studied in culture and slice
preparations, and pharmacological manipulations in
vivo during adaptation of motor reflexes and studies
of knockout mutations (e.g., the mGluR1 receptor)
are largely consistent. It is generally recognized to be
the key process by which the cerebellum could show
experience-dependent changes to underpin its role in
motor learning.
THEORIES OF CEREBELLAR FUNCTION
Many theories of cerebellar function have been
proposed based mainly on clinical evidence or on
extensive anatomical and physiological information.
No one theory manages to fully account for all
reported aspects of cerebellar function.
Comparator
An early suggestion was that the cerebellum formed a
comparator in a servo-loop involved in a comparison
of the actual movement with a desired plan. This
theory is supported by the many loops formed by
connections to or within the cerebellum that could
provide the necessary pathways for a servo-loop and
also by clinical evidence. Cerebellar patients exhibit
behavior similar to that of malfunctioning servo-
controlled devices, most noticeably in the overshoot
and intention tremor of their limbs. However, this
theory does not account for the complexities of
cellular physiology of the cerebellum or for evidence
of learning within the cerebellum.
CEREBELLUM 577
Timing Theories
The cerebellum could provide a mechanism for
timing: Mossy fiber inputs are delayed by the slow
conduction of action potentials along the unmyeli-
nated parallel fibers, and so Purkinje cells lying along
a parallel fiber beam could read off delayed versions
of the information. Cerebellar patients do have
problems in the timing of their voluntary movements
and in temporal estimation or discrimination. How-
ever, the time delays caused by even the longest
parallel fibers are too short to explain these
problems. If the cerebellum is involved in timing
motor action, it is not as straightforward as
originally thought.
Parameter Control
An alternative proposal is that the cerebellum
indirectly affects motor performance by setting
parameters such as the gain of reflex loops. Evidence
for this theory can be found in the hypo- and
hypertonia that result from cerebellar lesions, due to
its influence on the balance of alpha and gamma
drive to the motoneurons, and in the control of the
vestibulo-ocular reflex (VOR).
The VOR is responsible for the steady gaze
position of the eyes; it generates eye movements that
compensate for motion of the head and thus allows
fixation of visual targets during movement. The
reflex is plastic and readily adapts to the changed
visual input induced by wearing, for example, strong
reading glasses (or even inverting glasses so that
the eyes must move in the opposite direction to
maintain gaze). When the glasses are removed after
adaptation, the VOR reflex gain returns to its normal
level. Lesion experiments have shown the flocculo-
nodulus to be necessary for VOR adaptation.
Climbing fibers carry retinal slip signals to the
flocculus, which is thought to represent the ‘‘motor
error’’ in the VOR; mossy fibers carry vestibular and
eye velocity signals; and output from the flocculus
projects via the vestibular nuclei to oculomotor
neurons. The VOR must also be suppressed to allow
moving targets to be followed, and flocculonodular
Purkinje cells are necessary for and most active
during VOR suppression.
Learning Machine
The remaining theories can all be grouped within the
idea of the cerebellum as a learning machine, based
on synaptic plasticity in the cerebellar cortex. This
basic learning mechanism could then support a wide
578 CEREBRAL ANGIOGRAPHY
variety of cerebellar functions, including the VOR
reflex described previously. The very divergent
mossy fiber projections and specific climbing fiber
inputs are also suggestive of an associative learning
role because they could provide the mechanism to
allow Purkinje cells to pair specific unconditional
stimuli carried by the climbing fibers with condi-
tional sensory stimuli carried by the mossy fibers.
Detailed support for this proposal is available from
studies of the nictitating membrane eye-blink reflex
in rabbits. Lesions of topographically related parts
of the pons, cerebellar cortex, interpositus nucleus,
and inferior olive can affect the acquisition and
retention of this reflex.
Related proposals are that the cerebellum is
involved in learning motor programs, in coordinate
transformations, or in forming predictive internal
models. Computational theories based on forward
and inverse internal models of the motor system have
been advanced to cover several areas of cerebellar
operation and are proving useful in guiding inter-
pretation of electrophysiological data.
A precise answer to the question, What does
the cerebellum do? is not possible. What seems
clear is that the answer should combine parts of
all these theories. Its role as a predictive model seems
to fit most easily with much of the data. Such
a predictive internal model would involve both
learning and timing mechanisms, could be involved
in setting motor parameters, and if damaged could
lead to the impaired motor performance seen
clinically.
—R. C. Miall
See also–Brain Anatomy; Central Nervous
System, Overview; Cerebellar Disorders;
Cerebellar Hematoma; Cerebral Cortex:
Architecture and Connections; Friedreich’s
Ataxia; Learning, Motor; Learning, Overview;
Plasticity; Vestibular Reflexes
Further Reading
Altman, J., and Mayer, S. A. (1997). Development of the
Cerebellar System; In Relation to Its Evolution, Structure,
and Functions. CRC Press, Boca Raton, FL.
Holmes, G. (1939). The cerebellum of man. Brain 62, 1–30.
Ito, M. (1984). The Cerebellum and Neural Control. Raven Press,
New York.
Lewis, S. (Ed.) (1998). Cerebellum. Trends Neurosci. 21, 367–419.
Rahman, S. (Ed.) (1998). Cerebellum. Trends Cognit. Sci. 2,
305–371.
Schmahmann, J. D. (Ed.) (1997). The Cerebellum and Cognition.
Academic Press, San Diego.
Cerebral Angiography
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL ANGIOGRAPHY has long been the standard
imaging method for the study of cerebrovascular
disease. Currently, it remains the benchmark for
providing accurate diagnostic information regarding
the cerebrovascular system. As important, angiogra-
phy provides the underlying basis for neurointerven-
tional techniques, which have evolved to a level at
which they are able to effectively prevent and treat
many ischemic and hemorrhagic cerebrovascular
disorders.
HISTORY
The clinical use of angiography to study the vascular
system in living patients dates to the 1920s, when
suitable radiopaque contrast media first became
available. In 1927, Egaz Moniz reported the first
angiogram of the cerebral circulation, ushering in
clinical imaging of cerebrovascular disease. Initially
requiring surgical exposure of the carotid artery for
injection of contrast, cerebral angiography evolved
to the use of direct carotid and vertebral puncture.
These techniques were supplanted in 1953 by
Seldinger’s technique of femoral catheter insertion
over an intravascular wire placed by needle puncture.
Further development of flexible catheters and steer-
able guidewires permitted selective injection of
vessels supplying all parts of the central nervous
system. The development of nonionic contrast
materials and more sophisticated angiographic ima-
ging units has made cerebral angiography a safe and
routinely performed procedure that provides the
most accurate and detailed information currently
available for the study of the cerebral vasculature.
TECHNICAL ASPECTS
Cerebral angiography is most often performed via
puncture of the femoral artery using the Seldinger
technique. For diagnostic angiography, a 4- or 5-
French catheter is used, whereas interventional
procedures often require larger diameter catheters.
The use of hydrophilic-coated guidewires and cathe-
ters has contributed considerably to the ease and
safety of the procedure. Despite technical advances,
meticulous angiographic technique, including fre-
quent flushing of the catheter with heparinized
578 CEREBRAL ANGIOGRAPHY
variety of cerebellar functions, including the VOR
reflex described previously. The very divergent
mossy fiber projections and specific climbing fiber
inputs are also suggestive of an associative learning
role because they could provide the mechanism to
allow Purkinje cells to pair specific unconditional
stimuli carried by the climbing fibers with condi-
tional sensory stimuli carried by the mossy fibers.
Detailed support for this proposal is available from
studies of the nictitating membrane eye-blink reflex
in rabbits. Lesions of topographically related parts
of the pons, cerebellar cortex, interpositus nucleus,
and inferior olive can affect the acquisition and
retention of this reflex.
Related proposals are that the cerebellum is
involved in learning motor programs, in coordinate
transformations, or in forming predictive internal
models. Computational theories based on forward
and inverse internal models of the motor system have
been advanced to cover several areas of cerebellar
operation and are proving useful in guiding inter-
pretation of electrophysiological data.
A precise answer to the question, What does
the cerebellum do? is not possible. What seems
clear is that the answer should combine parts of
all these theories. Its role as a predictive model seems
to fit most easily with much of the data. Such
a predictive internal model would involve both
learning and timing mechanisms, could be involved
in setting motor parameters, and if damaged could
lead to the impaired motor performance seen
clinically.
—R. C. Miall
See also–Brain Anatomy; Central Nervous
System, Overview; Cerebellar Disorders;
Cerebellar Hematoma; Cerebral Cortex:
Architecture and Connections; Friedreich’s
Ataxia; Learning, Motor; Learning, Overview;
Plasticity; Vestibular Reflexes
Further Reading
Altman, J., and Mayer, S. A. (1997). Development of the
Cerebellar System; In Relation to Its Evolution, Structure,
and Functions. CRC Press, Boca Raton, FL.
Holmes, G. (1939). The cerebellum of man. Brain 62, 1–30.
Ito, M. (1984). The Cerebellum and Neural Control. Raven Press,
New York.
Lewis, S. (Ed.) (1998). Cerebellum. Trends Neurosci. 21, 367–419.
Rahman, S. (Ed.) (1998). Cerebellum. Trends Cognit. Sci. 2,
305–371.
Schmahmann, J. D. (Ed.) (1997). The Cerebellum and Cognition.
Academic Press, San Diego.
Cerebral Angiography
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL ANGIOGRAPHY has long been the standard
imaging method for the study of cerebrovascular
disease. Currently, it remains the benchmark for
providing accurate diagnostic information regarding
the cerebrovascular system. As important, angiogra-
phy provides the underlying basis for neurointerven-
tional techniques, which have evolved to a level at
which they are able to effectively prevent and treat
many ischemic and hemorrhagic cerebrovascular
disorders.
HISTORY
The clinical use of angiography to study the vascular
system in living patients dates to the 1920s, when
suitable radiopaque contrast media first became
available. In 1927, Egaz Moniz reported the first
angiogram of the cerebral circulation, ushering in
clinical imaging of cerebrovascular disease. Initially
requiring surgical exposure of the carotid artery for
injection of contrast, cerebral angiography evolved
to the use of direct carotid and vertebral puncture.
These techniques were supplanted in 1953 by
Seldinger’s technique of femoral catheter insertion
over an intravascular wire placed by needle puncture.
Further development of flexible catheters and steer-
able guidewires permitted selective injection of
vessels supplying all parts of the central nervous
system. The development of nonionic contrast
materials and more sophisticated angiographic ima-
ging units has made cerebral angiography a safe and
routinely performed procedure that provides the
most accurate and detailed information currently
available for the study of the cerebral vasculature.
TECHNICAL ASPECTS
Cerebral angiography is most often performed via
puncture of the femoral artery using the Seldinger
technique. For diagnostic angiography, a 4- or 5-
French catheter is used, whereas interventional
procedures often require larger diameter catheters.
The use of hydrophilic-coated guidewires and cathe-
ters has contributed considerably to the ease and
safety of the procedure. Despite technical advances,
meticulous angiographic technique, including fre-
quent flushing of the catheter with heparinized

saline, is important to minimize the formation of
intravascular clot, the most significant source of
neuroangiographic complications.
Arch aortography, once considered a standard part
of neuroangiography, has been found to have a very
low yield of significant abnormalities. Relatively
large amounts of contrast material are required for
aortic arch injection, and it is currently performed
only when specific indications of proximal disease of
the great vessels are present.
Selective catheterization of the carotid and/or
vertebral arteries usually gives adequate evaluation
of extracerebral vascular disease. In cases of intra-
cranial disease, internal carotid artery catheterization
or even more distal injection may be necessary for
optimal visualization.
Biplane digital subtraction angiographic units are
currently the optimal equipment for the performance
of neuroangiography. Biplane filming gives two image
planes with a single contrast injection and increases
the ease of obtaining oblique views. The digital
subtraction technique provides immediate images
with lower contrast dose than the older film screen
method of image production. The standard matrix
size of 1024 pixels provides adequate spatial resolu-
tion for both intracranial and extracranial evaluation.
In addition, most digital subtraction units are
capable of ‘‘live subtraction’’ whereby static struc-
tures, including bone, are subtracted from fluoro-
scopic images by the use of a ‘‘mask’’ image obtained
prior to contrast injection. Subsequent images are
subtracted by the computer from the mask image,
giving vastly improved visualization of vascular
structures. By injecting contrast during the period
that the mask image is acquired, a ‘‘road map’’ image
of the vessel to be catheterized may be placed on the
fluoroscopic screen and it remains there during the
catheterization procedure. This feature contributes
significantly to the ease and safety of diagnostic
angiographic procedures and is mandatory for the
performance of neurointerventional procedures.
RISKS AND COMPLICATIONS
As with all invasive procedures, some risk is associated
with cerebral angiography, although current techni-
ques have both low risk and low discomfort.
Currently, the major risk, that of permanent neurolo-
gical complication, is approximately 0.3% in patient
populations with cerebrovascular disease. Cerebral
angiographic risk has been found to be related to a
number of clinical features of the patient, the length of
CEREBRAL ANGIOGRAPHY 579
the procedure, and the experience of the neuroradiol-
ogist performing the study.
INDICATIONS
The widespread availability and improved accuracy
of noninvasive neuroimaging modalities, including
ultrasonography, magnetic resonance imaging
(MRI), and computed tomography (CT), have
limited the indications for diagnostic angiography
in many clinical situations for which it would
previously have been required for diagnosis. Diag-
nosis of intracranial hemorrhage, evaluation of
nonvascular neurological disease, or identification
of the effects of disease on brain parenchyma are
much more effectively accomplished with noninva-
sive modalities such as CT or MRI.
Although often useful for screening patients with
suspected cerebrovascular disease, there are signifi-
cant limitations to the ability of noninvasive imaging
to accurately evaluate the cerebral vasculature. Most
disorders directly involving the major vessels of the
cerebral vasculature still require angiography prior
to treatment even though the diagnosis may be
suggested by noninvasive modalities. For example,
although noninvasive imaging may suggest the
presence of high-grade carotid stenosis or raise
suspicion of an intracranial aneurysm, angiography
remains necessary prior to virtually all surgical
therapy to confirm the findings, exclude unnecessary
surgical procedures, and ensure the availability and
accuracy of all necessary vascular information to
plan and execute treatment.
The decline in the number of diagnostic neuroan-
giographic procedures performed has been balanced
by the rapid development and expansion of interven-
tional neuroradiological techniques. These proce-
dures offer many patients a chance for treatment at
the time when angiographic diagnosis is made or
confirmed. Neurointerventional treatments are used
in the management of both ischemic and hemorrhagic
vascular disorders and mandate a comprehensive
understanding of angiographic techniques and find-
ings in cerebrovascular disease for their appropriate
and effective application.
Indications for diagnostic cerebral angiography
generally include the evaluation of anatomical
vascular abnormalities that may cause intracranial
hemorrhage, such as arteriovenous malformations
and aneurysms, and evaluation of large-vessel
ischemic disease affecting either intracranial or
extracranial vasculature.
580 CEREBRAL ANGIOGRAPHY
EXTRACRANIAL CEREBROVASCULAR
DISEASE
Cerebral angiography remains the standard for
evaluation of most extracranial cerebrovascular
disease, including presurgical imaging of athero-
sclerosis and identification of fibromuscular dyspla-
sia. The remaining significant extracranial
cerebrovascular disorder, arterial dissection, is in
most cases best diagnosed by identifying intramural
hematoma on MRI, although angiography often
plays a role in endovascular management and
follow-up.
Current standards indicate that anatomical correc-
tion of internal carotid artery atherosclerotic stenosis
is indicated in symptomatic patients when the degree
of stenosis exceeds 70%. Clinical studies on which
this treatment recommendation is based rest on
angiographic confirmation of the severity of the
arterial stenosis.
INTRACRANIAL ISCHEMIC DISEASE
Many types of occlusive cerebrovascular disease
directly affect intracranial circulation, including
atherosclerosis, vasospasm, emboli, and vasculitis.
Angiographic findings in intracranial ischemic or
occlusive disease are classified into several groups
that reflect impairment of both the anatomy and the
physiology of cerebral blood flow. Angiographic
abnormalities include the following: the effect of
the pathological process on abnormally narrowing or
widening of the vessel lumen; delay of flow through
the vessel; the effects of flow compromise on the
brain parenchyma, which may result in luxury
perfusion; and the presence of collateral routes of
blood flow to the ischemic region of the brain.
Specific findings depend on the location, type, and
severity of vascular compromise; the degree of
underlying parenchymal damage; and the response
of the cerebrovascular system to the pathological
process. Angiographic findings in intracranial occlu-
sive disease, although often obviously abnormal,
may be nonspecific and are best integrated with
clinical and noninvasive imaging information.
INTRACRANIAL HEMORRHAGIC DISORDERS
Cerebral angiography remains the standard for
evaluating anatomical lesions that may result in
intracranial hemorrhage, including aneurysms and
arteriovenous malformations (AVMs).
Intracranial saccular or berry aneurysms are
responsible for the majority of nontraumatic
subarachnoid hemorrhage, a condition that affects
approximately 30,000 patients per year in the
United States. The high recurrent hemorrhage rate
from a ruptured aneurysm (approximately 20% in
the first 2 weeks after the initial hemorrhage)
and high mortality associated with subarachnoid
hemorrhage often require emergent angiographic
evaluation. Angiography is necessary in virtually
all cases of intracranial aneurysm prior to perform-
ing definitive treatment by either surgical or
neurointerventional methods. It not only provides
information on the configuration of the aneurysm
lumen, shape, and neck size but also identifies
the relationship to adjacent arteries and enables
exclusion of other aneurysms or associated
vasospasm.
Angiography for the evaluation of intracranial
aneurysms must include visualization of all common
aneurysm sites, most of which are located proximally
on the intracranial vasculature. The most common
sites include the region of the anterior communicat-
ing artery complex, the supraclinoid internal carotid
artery, and the bifurcation of the middle cerebral
artery. Approximately 10% of intracranial aneur-
ysms involve the posterior circulation, most often at
the tip of the basilar artery or at the origin of the
posterior inferior cerebellar artery. Because saccular
aneurysms may be multiple in 20–30% of cases, all
potential aneurysm sites must be visualized angio-
graphically in order to exclude these potentially
lethal lesions.
AVMs represent the most common clinically
symptomatic type of cerebrovascular malformation,
most often presenting with intracranial hemor-
rhage. Although the diagnosis of AVM may fre-
quently be made on MRI, complete evaluation of
the lesion requires angiography. Angiographic eva-
luation of AVM must delineate the feeding arteries,
including those providing only collateral flow to the
lesion; the size of the AVM and speed of arteriove-
nous shunting through the nidus; the venous
drainage of both the AVM and the normal brain;
and associated lesions, including feeding artery
aneurysms. In addition, embolization of the AVM
in preparation for surgical or radiosurgical therapy
may often be performed at the time of diagnostic
angiography.
Although it is the oldest method of imaging the
cerebral vessels, angiography remains the standard
for accurate evaluation of the cerebral vasculature.

Technical improvements, the development of
neurointerventional techniques, and advances in
integrating invasive with noninvasive imaging in-
formation have significantly increased the usefulness
of angiography in recent years and promise to
continue to do so in the future.
—Robert W. Hurst
See also–Angiography; Arteriovenous
Malformations (AVM); Cerebellar Hematoma;
Cerebral Blood Flow, Measurement of; Cerebral
Vasospasm; Dissection, Arterial; Embolism,
Cerebral; Magnetic Resonance Angiography
(MRA); Magnetic Resonance Imaging (MRI);
Neuroimaging, Overview; Vasculitis, Cerebral
Further Reading
Akers, D., Markowitz, I., and Kerstein, M. (1987). The value of
aortic arch study in the evaluation of cerebrovascular insuffi-
ciency. Am. J. Surg. 154, 230–236.
Dion, J., Gates, P., Fox, A., et al. (1987). Clinical events following
cerebral angiography: A prospective study. Stroke 18, 997–
1002.
ECST Collaborative Group (1991). MRC European carotid
surgery trial: Interim results for symptomatic patients with
severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet
337, 1235–1243.
Ferris, E. (1974). Arteritis. In Radiology of the Skull and Brain (T.
Newton and D. Potts, Eds.), Vol. 2, pp. 2566–2597. Mosby,
Great Neck, NY.
Fields, W., and Lemak, N. (1989). A History of Stroke. Oxford
Univ. Press, Oxford.
Hankey, G., Warlow, C., and Molyneux, A. (1990). Complications
of cerebral angiography for patients with mild carotid territory
ischemia being considered for carotid endarterectomy. J.
Neurol. Neurosurg. Psychiatr. 53, 542–546.
Kassell, N., Adams, H., Torner, J., et al. (1981). Influence of timing
of admission after aneurysmal subarachnoid hemorrhage on
overall outcome: Report of the Cooperative Aneurysm Study.
Stroke 12, 620–623.
Lassin, N. (1966). The luxury-perfusion syndrome and its possible
relation to acute metabolic acidosis localised within the brain.
Lancet 2, 1113–1115.
McCormick, W. (1966). The pathology of vascular (‘‘arteriove-
nous’’) malformations. J. Neurosurg. 24, 807–816.
Moniz, E. (1934). L’angiographie Cerebrale. Libraires de L’acade-
mie de Medecine, Paris.
North American Symptomatic Endarterectomy Trial Collaborators
(1991). Beneficial effect of carotid endarterectomy in sympto-
matic patients with high grade carotid stenosis. N. Engl. J. Med.
325, 445–453.
Perret, G., and Nashioka, H. (1966). Report on the Cooperative
Study of Intracranial Aneurysms and Subarachnoid Hemor-
rhage, Section VI. Arteriovenous malformations: An analysis of
545 cases of cranio-cerebral arteriovenous malformations and
fistulae reported to the cooperative study. J. Neurosurg. 25,
467–490.
CEREBRAL BLOOD FLOW, MEASUREMENT OF 581
Cerebral Blood Flow,
Measurement of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
APPROXIMATELY 15–20% of human cardiac output
is delivered to the brain, which accounts for only 2%
of total body weight. The discrepancy is due to the
high cerebral metabolic rate (CMR) that requires
20% of the total metabolic requirements of the
body. Since oxygen stored in the brain is minimal,
cerebral blood flow (CBF) must be maintained in
order to deliver oxygen and glucose, which are
essential for maintaining brain tissue metabolism,
electrolyte equilibrium, neurotransmitter synthesis,
and other requirements for neuronal function. Many
physiological and pathophysiological conditions
influence CBF and metabolism so that CBF and
CMR measurements, which became possible half a
century ago, have been widely used for neurological
research.
METHODOLOGY
Kety–Schmidt Method
In 1945, Kety and Schmidt introduced the N2O
method for measuring average CBF based on
inhalation of low concentrations of N2O gas while
arterial and cerebral venous blood samples were
being drawn. The principle of the method is that
inert and freely diffusible indicators such as N2O can
be used as tracers for measuring tissue perfusion
because their uptake into tissue from arterial blood
and release into cerebral venous blood depend solely
on tissue flow and the tissue solubility in blood and
brain or partition coefficient (l). The rate of change
of tracer concentrations in regional tissues of interest
is equal to differences in rates with which the tracer
is transported into tissue via arterial blood as well as
the rate of its washout from tissue to venous blood.
The concept of l as the partition coefficient is an
important parameter influencing perfusion measure-
ments because it is the ratio of the solubility of the
tracer in the brain to that in the blood. Using this
method, Kety and Schmidt first obtained mean values
of 54712 ml/100g/min for CBF among healthy
volunteers. The importance of their work is that it
established the basis for all modern absolute CBF
measurements.

Technical improvements, the development of
neurointerventional techniques, and advances in
integrating invasive with noninvasive imaging in-
formation have significantly increased the usefulness
of angiography in recent years and promise to
continue to do so in the future.
—Robert W. Hurst
See also–Angiography; Arteriovenous
Malformations (AVM); Cerebellar Hematoma;
Cerebral Blood Flow, Measurement of; Cerebral
Vasospasm; Dissection, Arterial; Embolism,
Cerebral; Magnetic Resonance Angiography
(MRA); Magnetic Resonance Imaging (MRI);
Neuroimaging, Overview; Vasculitis, Cerebral
Further Reading
Akers, D., Markowitz, I., and Kerstein, M. (1987). The value of
aortic arch study in the evaluation of cerebrovascular insuffi-
ciency. Am. J. Surg. 154, 230–236.
Dion, J., Gates, P., Fox, A., et al. (1987). Clinical events following
cerebral angiography: A prospective study. Stroke 18, 997–
1002.
ECST Collaborative Group (1991). MRC European carotid
surgery trial: Interim results for symptomatic patients with
severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet
337, 1235–1243.
Ferris, E. (1974). Arteritis. In Radiology of the Skull and Brain (T.
Newton and D. Potts, Eds.), Vol. 2, pp. 2566–2597. Mosby,
Great Neck, NY.
Fields, W., and Lemak, N. (1989). A History of Stroke. Oxford
Univ. Press, Oxford.
Hankey, G., Warlow, C., and Molyneux, A. (1990). Complications
of cerebral angiography for patients with mild carotid territory
ischemia being considered for carotid endarterectomy. J.
Neurol. Neurosurg. Psychiatr. 53, 542–546.
Kassell, N., Adams, H., Torner, J., et al. (1981). Influence of timing
of admission after aneurysmal subarachnoid hemorrhage on
overall outcome: Report of the Cooperative Aneurysm Study.
Stroke 12, 620–623.
Lassin, N. (1966). The luxury-perfusion syndrome and its possible
relation to acute metabolic acidosis localised within the brain.
Lancet 2, 1113–1115.
McCormick, W. (1966). The pathology of vascular (‘‘arteriove-
nous’’) malformations. J. Neurosurg. 24, 807–816.
Moniz, E. (1934). L’angiographie Cerebrale. Libraires de L’acade-
mie de Medecine, Paris.
North American Symptomatic Endarterectomy Trial Collaborators
(1991). Beneficial effect of carotid endarterectomy in sympto-
matic patients with high grade carotid stenosis. N. Engl. J. Med.
325, 445–453.
Perret, G., and Nashioka, H. (1966). Report on the Cooperative
Study of Intracranial Aneurysms and Subarachnoid Hemor-
rhage, Section VI. Arteriovenous malformations: An analysis of
545 cases of cranio-cerebral arteriovenous malformations and
fistulae reported to the cooperative study. J. Neurosurg. 25,
467–490.
CEREBRAL BLOOD FLOW, MEASUREMENT OF 581
Cerebral Blood Flow,
Measurement of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
APPROXIMATELY 15–20% of human cardiac output
is delivered to the brain, which accounts for only 2%
of total body weight. The discrepancy is due to the
high cerebral metabolic rate (CMR) that requires
20% of the total metabolic requirements of the
body. Since oxygen stored in the brain is minimal,
cerebral blood flow (CBF) must be maintained in
order to deliver oxygen and glucose, which are
essential for maintaining brain tissue metabolism,
electrolyte equilibrium, neurotransmitter synthesis,
and other requirements for neuronal function. Many
physiological and pathophysiological conditions
influence CBF and metabolism so that CBF and
CMR measurements, which became possible half a
century ago, have been widely used for neurological
research.
METHODOLOGY
Kety–Schmidt Method
In 1945, Kety and Schmidt introduced the N2O
method for measuring average CBF based on
inhalation of low concentrations of N2O gas while
arterial and cerebral venous blood samples were
being drawn. The principle of the method is that
inert and freely diffusible indicators such as N2O can
be used as tracers for measuring tissue perfusion
because their uptake into tissue from arterial blood
and release into cerebral venous blood depend solely
on tissue flow and the tissue solubility in blood and
brain or partition coefficient (l). The rate of change
of tracer concentrations in regional tissues of interest
is equal to differences in rates with which the tracer
is transported into tissue via arterial blood as well as
the rate of its washout from tissue to venous blood.
The concept of l as the partition coefficient is an
important parameter influencing perfusion measure-
ments because it is the ratio of the solubility of the
tracer in the brain to that in the blood. Using this
method, Kety and Schmidt first obtained mean values
of 54712 ml/100g/min for CBF among healthy
volunteers. The importance of their work is that it
established the basis for all modern absolute CBF
measurements.
582 CEREBRAL BLOOD FLOW, MEASUREMENT OF
Lassen–Ingvar Method
In 1961, Lassen and Ingvar described their method for
measuring regional CBF (rCBF) by injection of a bolus
of radioactive tracer via internal carotid artery. The
tracers, 133Xe or 88Kr, diffuse rapidly across capillary
walls and distribute in the tissue according to local
perfusion. They are subsequently cleared from tissue
by unlabeled arterial blood arriving after the bolus.
The clearance rate (k) is proportional to f (rCBF) and
inversely proportional to the solubility coefficient l
for gray and white matter. Cortical CBF is measured
from the initial, fast clearance curve recorded by
multiple scintillation detectors placed over the side of
the head. This method eliminates or minimizes
extracerebral contamination as well as Compton
scatter with interhemispheric cross talk. (Compton
scatter is the scatter of x-rays or other radionuclide
emission by tissue, bone, or fluid so that distortion of
imaging occurs. In local CBF measurements, this can
distort results.) Using this method, in vivo assessments
of human rCBF were achieved so that cerebral
autoregulatory phenomena could be measured as well
as regional activation of CBF by different stimuli. The
method has been abandoned because of its invasive-
ness and potential dangerous complications.
Hydrogen Clearance Methods
The hydrogen clearance technique was used for
tissue blood flow measurements utilizing intracereb-
ral electrodes or paired electrodes mounted in
cerebral venous and arterial blood. Advantages of
hydrogen clearance methods are that the flow in
small or large tissue volume can be measured
continuously, the simplicity of data analysis, and
the ability to concurrently measure brain oxygen
metabolism since electrodes can also be used for
measuring PO2.
Microsphere CBF Determinations
The radioactive microsphere technique is based on
flow-dependent embolization of end organ capillaries
by gamma-emitting particles, which have a specific
gravity similar to that of erythrocytes and thus do
not alter rheology. A number of investigations have
verified the method and applied it to experimental
CBF research.
Autoradiographic Measurement
of Local CBF
The autoradiographic method for measuring rCBF is
a powerful experimental method for animal models
with microscopic resolution to quantitate local
distribution of radiolabeled diffusible indicators in
tissue sections of brain. The theoretical basis and
principle of this method were formulated and applied
by Kety and colleagues. In 1958, Freygang and
Sokoloff used this method to determine normal rCBF
values in the conscious cat, observing that light
thiopental anesthesia lowered rCBF in gray matter
structures, whereas 5% CO2 and 10% O2 inhalation
both increased gray matter blood flow. Others
showed that visual stimulation with light activated
the opticogeniculato-occipital cortex pathways. The
primary disadvantage of this method is that rCBF
can only be assessed after sacrifice of the animal.
CBF by 133Xenon Inhalation or
Intravenous Injection
The measurement of rCBF in humans by inhalation
or intravenous injection of 133Xe is combined with
external recording by multiple scintillation detectors
mounted over the scalp. After administration of
133
Xe, its clearance was followed by multiple (up to
254) scintillation detectors during 10 min of inhala-
tion of the gas in air. Arterial concentrations of the
tracer were monitored from continuous sampling of
end-tidal air. Because the brain is composed of gray
and white matter compartments with different
metabolic demands and xenon l, Obrist suggested
a two-compartment model for analysis. The major
disadvantage of this method is the ‘‘slippage’’ that
occurs when gray and white matter clearance become
reduced and cannot be separated.
Single Photon Emission
Computed Tomography
This approach is noninvasive because it is based on
inhalation rather than intravenous injection of the
tracer, similar to the conventional 133xenon techni-
que. However, extracerebral contamination and
intrahemispheric cross talk are eliminated by the
tomographic principle utilizing a specialized tomo-
graphic device—single photon emission computed
tomography (SPECT). Because 133Xe has low gamma
ray energy, other isotopes that became trapped in the
brain in distributions proportional to rCBF but with
better energy and stability were developed for
measuring rCBF. However, resolution of SPECT is
less than optimal for providing anatomical refer-
ences. Furthermore, SPECT provides only relative,
not absolute, rCBF measurements since the isotopes
are retained in the brain and are not freely diffusible
according to the requirement of Kety’s principle.

Stable Xenon CT CBF Method
Xenon gas is a stable, lipid-soluble, inhaled, freely
diffusible x-ray contrast indicator, so its location,
concentration, and diffusion may be detected and
quantified with high-resolution CT scanners. In the
late 1970s, Drayer et al. and Meyer et al. measured
local CBF after inhalation of xenon gas by measuring
time-dependent changes of its concentration in
different brain tissues using CT scan and showing
proportional changes in Hounsfield units. These local
changes of tissue concentrations for xenon gas over
time provide tissue saturation changes proportional
to local CBF utilizing the basic Kety’s formula: local
CBF ¼ lk, where l is the blood–brain partition
coefficient for xenon, and k is the local flow rate
constant. The arterial saturation curve was recorded
from end-tidal concentrations for xenon measured by
a thermoconductivity analyzer. The advantages of
stable xenon CT CBF measurements are that the
procedure is noninvasive, cost-effective, and safe in
human subjects using low (26%) concentrations of
xenon. It affords both high-resolution CBF images
and the ability to correlate local CBF data directly
with local anatomy of the brain. Poor signal-to-noise
ratio was a disadvantage with early CT scanners but
not with the latest models. However, beam-hard-
ening effects from overlying bone or calcification
may impede local CBF measurements, particularly in
the posterior forsa.
Positron Emission Tomography
False localization and distortion from Compton
scatter are problems with conventional extracranial
detection systems. Positron emission tomography
(PET) minimizes these problems by coincidently
recording pairs of photons with opposite directional
emissions from annihilation of radioactive tracers
emitting positrons. PET lacks good anatomical
resolution, so superimposed magnetic resonance
images are used for accurate localization purposes.
The advantage of PET is that it can accurately
measure not only rCBF but also regional cerebral
metabolism concurrently. This has made it possible
to differentiate irreversible damage from viable tissue
on the basis of the CBF metabolic patterns. However,
PET is extremely expensive, invasive, and requires
prolonged immobilization.
Magnetic Resonance Imaging
Utilizing magnetic resonance imaging (MRI)-based
perfusion imaging methods with combined assess-
CEREBRAL BLOOD FLOW, MEASUREMENT OF 583
ments of relative changes in tissue perfusion,
correlated with morphological features, metabolism,
and function, are possible. Unlike conventional MRI,
which is insensitive to hyperacute ischemia, diffu-
sion-weighted imaging (DWI) and perfusion-
weighted imaging (PWI) MRI scans can detect early
zones of ischemia minutes after the stroke event. PWI
can provide information about capillary perfusion in
the brain, and relative CBF measures by this method
have linear relationships with absolute CBF mea-
sured by PET. DWI is sensitive to molecular diffusion
of water and detects changes in diffusion in ischemic
brain tissue such as cytotoxic edema. Furthermore,
the method has excellent spatial resolution. Using
blood oxygenation level-dependent local changes
and different activation techniques, functional MRI
has proved extremely useful for mapping rapid local
changes of activity in the human brain that produce
local changes in brain capillary oxygenation. Finally,
proton spin tagging may provide true measures of
flow to the brain.
NORMAL CBF VALUES
Quantitative CBF data obtained with the previously
mentioned methods have provided a great deal of
current knowledge about CBF and demonstrated that
rCBF in gray matter (approximately 45–60 ml/100 g/
min) is at least two or three times greater than that in
white matter (20–26 ml/100 g/min). The close spatial
and temporal relationships between local changes in
stimulated neuronal activity with rCBF increase have
also been recognized. Local CBF typically increases
by 50% or more in gray matter within a few seconds
of activated zones showing increased electrical
activity.
ABNORMAL CBF CHANGES WITH DISEASES
Many neurological diseases are related to and/or
accompanied by changes in rCBF; thus, rCBF
measurements contribute to diagnosis and enhance
knowledge of the pathophysiology of many neuro-
logical disorders.
Cerebrovascular disease is the prototypical disease
for CBF research. For acute ischemic stroke, rCBF
changes correlate well with the observed neurologi-
cal deficits and histopathological changes. Regions
with local CBF lower than 10–12 ml/100 g/min will
rapidly lead to irreversible ischemic damage. Border-
ing regions with rCBF values of 12–22 ml/100 g/min
are considered a penumbra with possible recovery.
584 CEREBRAL BLOOD VESSELS: ARTERIES
CBF measurements are an important tool for
detecting transient ischemic attacks, ischemic pe-
numbras, evolution of infarctions, early postischemic
hyperperfusion, spreading depression, diaschiasis,
recanalization–reperfusion, ischemic tolerance,
chronic ischemia, incomplete infarction, steal phe-
nomena, vasospasm after subarachnoid hemorrhage,
and silent stroke.
Progressive CBF declines are closely related to
cerebral aging, vascular dementia (VAD), Alzhei-
mer’s disease, and psychobehavioral disorders. Alz-
heimer’s disease is associated with a general CBF
decline mainly located in temporal, frontal, and
parietal cortical regions. VAD has multifocal or
patchy cortical and/or subcortical ischemic lesions
producing severe rCBF declines. Accelerated rates of
decline in global CBF, particularly in frontal cortex
and white matter, are risk factors for cognitive
impairments in geriatric populations.
Epileptic seizures with paroxysmal electroence-
phalograph activity are associated with temporary
local or global large increments in CBF and
metabolism. Migraine subjects show not only hyper-
perfusion accompanying the headache episode but
also abnormal reactions to vasodilatory agents.
During migraine aura there are corresponding rCBF
reductions, followed by hyperemia usually beginning
in occipital cortex.
Intracerebral infections, brain tumors, head trau-
ma, intracerebral hemorrhage, intracranial hyperten-
sion, hydrocephalus, subdural and epidural
hematomas, and other neurological and/or systemic
diseases have been well studied by CBF measure-
ments, and associated intracerebral hemodynamic
changes have been identified. CBF measurements
also have significance in studies of coma, cardiac
arrest, and confirmation of brain death.
—John Stirling Meyer and Yansheng Li
See also–Cardiac Arrest Resuscitation;
Cardiovascular Regulation; Cerebral
Angiography; Cerebral Blood Vessels: Arteries;
Cerebral Blood Vessels: Veins and Venous
Sinuses; Cerebral Metabolism and Blood Flow;
Cerebral Microcirculation; Magnetic Resonance
Imaging (MRI); Positron Emission Tomography
(PET)
Further Reading
Agnoli, A., Prencipe, M., Priori, A. M., et al. (1969). Measure-
ments of rCBF by intravenous injection of 133-xenon. In
Cerebral Blood Flow (M. Brock, C. Fieschi, D. H. Ingvar, N. A.
Lassen, and K. Schurmann, Eds.), pp. 31–34. Springer-Verlag,
Berlin.
Calamante, F., Thomas, D. L., Pell, G. S., et al. (1999). Measuring
cerebral blood flow using magnetic resonance imaging techni-
ques. J. Cerebral Blood Flow Metab. 19, 701–735.
Drayer, B. P., Wolfson, S. K., Reinmuth, O. M., et al. (1978).
Xenon enhanced CT for analysis of cerebral integrity, perfusion,
and blood flow. Stroke 9, 123–130.
Freygang, W. H., and Sokoloff, L. (1958). Quantitative measure-
ment of regional circulation in the central nervous system by the
use of radioactive inert gas. Adv. Biol. Med. Phys. 6, 263–279.
Kety, S. S., and Schmidt, C. F. (1945). The determination of
cerebral blood flow in man by the use of nitrous oxide in low
concentrations. Am. J. Physiol. 143, 53–66.
Lassen, N. A., and Ingvar, D. H. (1961). The blood flow of the
cerebral cortex determined by radioactive krypton. Experientia
17, 42–45.
Mallett, B. L., and Veal, N. (1963). Investigation of cerebral blood
flow in hypertension, using radioactive-xenon inhalation and
extracranial recording. Lancet 1, 1081–1082.
Meyer, J. S., Sakai, F., Yamamoto, M., et al. (1979). High
resolution three dimensional cerebral blood flow measured by
brief stable xenon inhalation and computerized tomography.
Ann. Neurol. 6, 151.
Meyer, J. S., Rauch, G. M., Crawford, K., et al. (1999). Risk
factors accelerating cerebral degenerative changes, cognitive
decline and dementia. Int. J. Geriatr. Psychiatr. 14, 1050–1061.
Obrist, W. D., Thompson, H. K., King, H. C., et al. (1967).
Determination of regional cerebral blood flow by inhalation of
133
xenon. Circ. Res. 20, 124–135.
Cerebral Blood Vessels:
Arteries
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
FOUR MAJOR VESSELS supply the brain: two internal
carotid arteries (the anterior circulation) and two
vertebral arteries (the posterior or vertebrobasilar
circulation). The division between anterior and
posterior circulations is in part artificial because the
four major vessels eventually feed into an arterial
circle at the base of the brain (the circle of Willis) and
because collateral circulation may develop in occlu-
sive disease. However, as a useful generalization, the
internal carotid arteries and their branches supply
the bulk of rostral telencephalic structures, including
the frontal and parietal lobes, the basal ganglia,
insula, parts of the temporal and occipital lobes, as
well as much of the diencephalon. In turn, the
posterior or vertebrobasilar system supplies caudal
and ventral structures, including medial and inferior
surfaces of the temporal lobes; medial, inferior, and
584 CEREBRAL BLOOD VESSELS: ARTERIES
CBF measurements are an important tool for
detecting transient ischemic attacks, ischemic pe-
numbras, evolution of infarctions, early postischemic
hyperperfusion, spreading depression, diaschiasis,
recanalization–reperfusion, ischemic tolerance,
chronic ischemia, incomplete infarction, steal phe-
nomena, vasospasm after subarachnoid hemorrhage,
and silent stroke.
Progressive CBF declines are closely related to
cerebral aging, vascular dementia (VAD), Alzhei-
mer’s disease, and psychobehavioral disorders. Alz-
heimer’s disease is associated with a general CBF
decline mainly located in temporal, frontal, and
parietal cortical regions. VAD has multifocal or
patchy cortical and/or subcortical ischemic lesions
producing severe rCBF declines. Accelerated rates of
decline in global CBF, particularly in frontal cortex
and white matter, are risk factors for cognitive
impairments in geriatric populations.
Epileptic seizures with paroxysmal electroence-
phalograph activity are associated with temporary
local or global large increments in CBF and
metabolism. Migraine subjects show not only hyper-
perfusion accompanying the headache episode but
also abnormal reactions to vasodilatory agents.
During migraine aura there are corresponding rCBF
reductions, followed by hyperemia usually beginning
in occipital cortex.
Intracerebral infections, brain tumors, head trau-
ma, intracerebral hemorrhage, intracranial hyperten-
sion, hydrocephalus, subdural and epidural
hematomas, and other neurological and/or systemic
diseases have been well studied by CBF measure-
ments, and associated intracerebral hemodynamic
changes have been identified. CBF measurements
also have significance in studies of coma, cardiac
arrest, and confirmation of brain death.
—John Stirling Meyer and Yansheng Li
See also–Cardiac Arrest Resuscitation;
Cardiovascular Regulation; Cerebral
Angiography; Cerebral Blood Vessels: Arteries;
Cerebral Blood Vessels: Veins and Venous
Sinuses; Cerebral Metabolism and Blood Flow;
Cerebral Microcirculation; Magnetic Resonance
Imaging (MRI); Positron Emission Tomography
(PET)
Further Reading
Agnoli, A., Prencipe, M., Priori, A. M., et al. (1969). Measure-
ments of rCBF by intravenous injection of 133-xenon. In
Cerebral Blood Flow (M. Brock, C. Fieschi, D. H. Ingvar, N. A.
Lassen, and K. Schurmann, Eds.), pp. 31–34. Springer-Verlag,
Berlin.
Calamante, F., Thomas, D. L., Pell, G. S., et al. (1999). Measuring
cerebral blood flow using magnetic resonance imaging techni-
ques. J. Cerebral Blood Flow Metab. 19, 701–735.
Drayer, B. P., Wolfson, S. K., Reinmuth, O. M., et al. (1978).
Xenon enhanced CT for analysis of cerebral integrity, perfusion,
and blood flow. Stroke 9, 123–130.
Freygang, W. H., and Sokoloff, L. (1958). Quantitative measure-
ment of regional circulation in the central nervous system by the
use of radioactive inert gas. Adv. Biol. Med. Phys. 6, 263–279.
Kety, S. S., and Schmidt, C. F. (1945). The determination of
cerebral blood flow in man by the use of nitrous oxide in low
concentrations. Am. J. Physiol. 143, 53–66.
Lassen, N. A., and Ingvar, D. H. (1961). The blood flow of the
cerebral cortex determined by radioactive krypton. Experientia
17, 42–45.
Mallett, B. L., and Veal, N. (1963). Investigation of cerebral blood
flow in hypertension, using radioactive-xenon inhalation and
extracranial recording. Lancet 1, 1081–1082.
Meyer, J. S., Sakai, F., Yamamoto, M., et al. (1979). High
resolution three dimensional cerebral blood flow measured by
brief stable xenon inhalation and computerized tomography.
Ann. Neurol. 6, 151.
Meyer, J. S., Rauch, G. M., Crawford, K., et al. (1999). Risk
factors accelerating cerebral degenerative changes, cognitive
decline and dementia. Int. J. Geriatr. Psychiatr. 14, 1050–1061.
Obrist, W. D., Thompson, H. K., King, H. C., et al. (1967).
Determination of regional cerebral blood flow by inhalation of
133
xenon. Circ. Res. 20, 124–135.
Cerebral Blood Vessels:
Arteries
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
FOUR MAJOR VESSELS supply the brain: two internal
carotid arteries (the anterior circulation) and two
vertebral arteries (the posterior or vertebrobasilar
circulation). The division between anterior and
posterior circulations is in part artificial because the
four major vessels eventually feed into an arterial
circle at the base of the brain (the circle of Willis) and
because collateral circulation may develop in occlu-
sive disease. However, as a useful generalization, the
internal carotid arteries and their branches supply
the bulk of rostral telencephalic structures, including
the frontal and parietal lobes, the basal ganglia,
insula, parts of the temporal and occipital lobes, as
well as much of the diencephalon. In turn, the
posterior or vertebrobasilar system supplies caudal
and ventral structures, including medial and inferior
surfaces of the temporal lobes; medial, inferior, and

lateral surfaces of the occipital lobes; and parts of
diencephalon. The brainstem and cerebellum are
wholly supplied by the vertebrobasilar system.
INTERNAL CAROTID ARTERY
In the neck, the internal carotid artery (ICA; Fig. 1)
arises from the common carotid artery (CCA),
posterior and lateral to the other terminal CCA
branch, the external carotid artery (ECA), at the
upper level of the thyroid cartilage. At the ICA
origin, the CCA bulges slightly: the distal 2–4 cm of
CCA and the first 2–4 cm of ICA comprise the
carotid bulb, which is of interest because it is the
location of most carotid stenoses. Blood flow at the
carotid bulb is complex; flow distal to the bulb is
normally laminar. As ICA ascends in the neck,
it typically does not branch and does not taper. It
passes into the skull through the carotid canal, at
which point it enters the petrous temporal bone.
Figure 1
The carotid bulb and course of the internal carotid artery (ICA).
The circle indicates the ICA’s entrance into the petrous carotid
canal, the arrow marks its entrance into the cavernous sinus, and
the thick arrow indicates approximately where the ICA penetrates
dura. 1, Common carotid artery; 2, external carotid artery (ECA;
its numerous branches are unlabeled); 3, carotid bulb; 4, ICA; 5,
intrapetrous ICA; 6, cavernous ICA or carotid siphon (insert
identifies five divisions: c1–c5); 7, inferolateral trunk or lateral
main stem artery (note an anastomosis with an ECA branch); 8,
meningohypophyseal trunk; 9, ophthalmic artery; 10, anterior
clinoid process; 11, posterior communicating artery; 12, anterior
choroidal artery (redrawn with permission from Osborn, 1994,
p. 120).
CEREBRAL BLOOD VESSELS: ARTERIES 585
The so-called intraosseus or intrapetrous segment
of ICA takes two turns, the first anteromedial and the
second superior, to enter the cavernous sinus. An
aberrant ICA course within petrous bone is a normal
variant, and it can present as a pulsatile mass behind
the tympanic membrane. Intraosseus ICA gives off
the caroticotympanic branch that supplies the middle
and inner ear and occasionally gives off a vidian
branch that passes through the foramen lacerum to
anastomose with branches of ECA.
Once the ICA exits the petrous bone apex through
the carotid canal, it enters the cavernous sinus. The
cavernous segment of ICA extends from the petrous
apex inferiorly to the anterior clinoid process super-
iorly, and its course follows an S-shaped curve,
divided into five segments: ascending (c5), posterior
genu (c4), horizontal (c3), anterior genu (c2), and a
remaining c1 segment (Fig. 1). The so-called carotid
siphon includes both the cavernous segment of ICA
and its brief course beyond the cavernous sinus. The
cavernous ICA yields several branches, which may
not be visualized in angiograms. A meningohypo-
physeal artery or inferolateral trunk arises from
segment c4 and supplies cranial nerves III, IV, and VI
as well as the Gasserian ganglion of cranial nerve V.
Small capsular branches arise from c2 or c3 segments
to supply the anterior pituitary.
The ICA terminates as a bifurcation into anterior
cerebral and middle cerebral arteries (ACA and
MCA, respectively) after it penetrates dura at the
level of the anterior clinoid process. Before the
bifurcation but after it leaves the cavernous sinus, the
ICA gives off four major branches: superior hypo-
physeal artery, ophthalmic artery (OA), posterior
communicating artery (PCommA), and the anterior
choroidal artery (AChA). The latter three are of
clinical interest.
OA, generally thought to be the first major
intracranial branch at the carotid siphon, travels
along the optic nerve and enters with it through the
optic foramen to supply the eye and orbit. OA is
well-known to have numerous distal anastomoses
with branches of ECA.
PCommA generally branches from the ICA just
below the origin of AChA and travels posterolater-
ally just above cranial nerve III to join the posterior
cerebral artery (PCA). Despite its short length,
PCommA provides branches that supply parts of
the thalamus, hypothalamus, optic chiasm, and the
pituitary stalk. Two common and important variants
have been observed: one or the other PCommA is
hypoplastic in as many as 30% of cases; in 20–25%,
586 CEREBRAL BLOOD VESSELS: ARTERIES

PCA arises directly from the ICA in a persistent fetal

origin of PCA.
AChA courses posteriorly within the suprasellar
cistern just under the optic tract; as it approaches the
lateral geniculate body, it turns sharply laterally to
enter the choroidal fissure of the temporal horn of
the lateral ventricle. As its name implies, it supplies
choroid plexus not only in the temporal horn but
also in the trigone; it also feeds the optic tract,
cerebral peduncle, uncus, and parahippocampal
gyrus. Perforating AChA branches may also supply
parts of thalamus and the posterior limb of the
internal capsule. AChA is a branch of the ICA and
thus a part of the anterior circulation, but it
anastomoses with medial and lateral posterior
choroidal arteries, which arise from the posterior
circulation (specifically PCA).

CIRCLE OF WILLIS
The circle of Willis is a wreath of interconnected
arteries that surrounds the optic chiasm, tuber
cinereum, and the region between the cerebral
peduncles at the ventral surface of the diencephalon.
It is formed by anastomotic branches of the two
ICAs, the horizontal (A1) segments of the ACAs, the
anterior communicating artery (ACommA), the two
PCommAs, the horizontal segments (P1) of both
PCAs, and the basilar artery (Fig. 2). Penetrating
vessels from the arteries of the circle of Willis supply
structures within its wreath, such as the optic chiasm.
We address MCA, ACA, and PCA separately.
Territories supplied by these vessels can be described
only generally since variability is common. Border
zones between vascular distributions (e.g., the over-
lapping distal vascular territories of MCA, ACA, and
PCA) are also quite variable.
MCA
MCA is the largest ICA branch, and it represents the
lateral continuation of the ICA into the Sylvan
fissure. Its course is characterized by an abrupt turn
in the area of the insula, which is the consequence of
a complex folding of telencephalon during develop-
ment (Fig. 3). German anatomist E. Fischer usefully
divided MCA (as well as ACA and PCA) into
segments: an M1 (horizontal) segment extends to a
so-called bifurcation or trifurcation in which M1
divides into insular or M2 branches (which move
upward over the insula and loop downward back to
the Sylvan fissure) and temporal branches, especially
the anterior temporal artery, which supply the lateral
Figure 2
The circle of Willis. 1, Internal carotid artery; 2, middle cerebral
artery; 3, ophthalmic artery; 4, optic nerve (cranial nerve II); 5, A1
(horizontal) segment of the anterior cerebral artery; 6, anterior
communicating artery; 7, A2 (postcommunical) segment of
anterior cerebral artery; 8, optic chiasm; 9, posterior
communicating artery; 10, P1 (horizontal or peduncular) segment
of the posterior cerebral artery; 11, P2 (postcommunical) segment
of the posterior cerebral artery; 12, superior cerebellar artery; 13,
basilar artery; 14, anterior inferior cerebellar artery; 15, vertebral
artery. The circle represents the foramen magnum. Note that
penetrating vessels arising from the circle of Willis supply
structures inside its wreath at the base of the brain (redrawn with
permission from Osborn, 1994, p. 126).
surface of the temporal lobe. Opercular (M3)
branches are the terminal extensions of M2 vessels
that hug the parietal operculum and then emerge
from the Sylvan fissure at the lateral surface of the
brain (Fig. 4).
In the area of the insula in angiograms, approxi-
mately six MCA branches form a Sylvan triangle
whose boundaries include (inferiorly) the lower
branches of the MCA and (superiorly) the looping
M2 insular branches as they reverse their course
toward the Sylvan fissure. These two borders appear
to converge on an apex (or Sylvan point) at which the
most posterior MCA branch emerges from the Sylvan
fissure. Upward or downward displacement of the
Sylvan triangle is an angiographic hallmark of space-
occupying lesions in the hemisphere.

Figure 3
Middle cerebral artery (MCA), with attention to its relation with
the insula. In this schematic depiction of the Sylvan triangle, the
frontal and parietal opercula have been dissected away to show the
looping course of insular MCA branches as they make their way to
the lateral cortical surface. Dots at the end of the arteries indicate
points of exit from the Sylvan fissure (redrawn with permission
from DeArmond et al., 1976, p. 174).
MCA branches supply premotor, motor, sensory,
auditory, and integrative associative areas and a
variety of other critical loci of cerebral function
extending from the frontal to occipital lobe over the
lateral convexity of the brain. Penetrating branches
from the M1 segment, the lateral lenticulostriate
arteries, supply deep structures, including much of the
lentiform nucleus (putamen, globus pallidus, and
caudate), internal capsule, extreme capsule, and, less
consistently, lateral thalamus. Other major branches
fan over the cortex from the Sylvan fissure and are
organized approximately in their relationship to
fissures or lobes [e.g., pre-Rolandic, central or
Rolandic, and post-Rolandic (posterior parietal)
arteries (all of which supply territories superior to
the Sylvan fissure) and posterior temporal and angular
gyrus arteries, which supply more posterior locales].
ACA
The A1 (or horizontal) segment of ACA extends
from the ACA origin to the origin of ACommA
(Fig. 5). The A2 segment ascends from the origin of
ACommA to its bifurcation into the pericallosal and
callosomarginal arteries. Cortical ACA branches
supply the anterior two-thirds of the medial cerebral
hemispheres as well as a narrow strip of cortical
tissue over convexities. Medial lenticulostriate ar-
teries arise from the A1 segment, pass through the
anterior perforated substance, and supply the head of
CEREBRAL BLOOD VESSELS: ARTERIES 587
the caudate and the anterior limb of the internal
capsule. The recurrent artery of Heubner, so called
because of a meandering and variable course, arises
from either A1 or A2 and eventually enters the
medial anterior perforated substance to supply the
anterior limb of internal capsule, anterior putamen,
globus pallidus, and head of caudate. Orbitofrontal
(or orbital) and frontopolar arteries arise from the
A2 segment to supply the orbital gyri and frontal
pole, respectively. Anatomical variations of ACA and
ACommA have been described in one-third of
autopsy dissections.
PCA
A short P1 (peduncular) segment extends from the
origin of PCA (off the basilar artery) to the junction
with PCommA (Figs. 6 and 7). Thalamoperforating
arteries arise from the P1 segment and the basilar
artery apex to supply the thalamus and midbrain.
The P2 (postcommunical) segment begins at the
branch point of PCommA; it wraps around the
midbrain, above the free edge of the tentorium
Figure 4
Middle cerebral artery (MCA) segments. The circumflex course of
the MCA is represented in schematized form. 1, M1 (horizontal or
sphenoidal) segment, from which lateral lentriculostriate (LLS)
arteries arise. These endarteries supply deep structures, including
putamen, lateral globus pallidus, lateral and dorsal aspects of the
head of the caudate nucleus, and parts of the internal capsule. 2,
M2 (insular) segment. At the trifurcation indicated by the asterisk,
M2 vessels begin their upward course along the insula. The
anterior temporal artery (ATA) arises at the trifurcation to exit the
Sylvan fissure at the temporal operculum. 3, M3 (opercular)
segment. In anteroposterior arteriograms, the course of the M3
segment arteries gives the impression of the arms of a candelabra.
4, M4 (terminal) segment, which gives rise to the major terminal
MCA branches (not shown). These exit the Sylvan fissure variably
to supply much of the lateral surface of the brain (redrawn with
permission from Krayenbühl and Yas¸argil, 1972, p. 83).
588 CEREBRAL BLOOD VESSELS: ARTERIES

Figure 5
Anterior cerebral artery (ACA), segments and major branches. 1, A1 (horizontal or precommunical) segment (i.e., the portion of the vessel
before the branch point of the anterior communicating artery); 2, A2 (postcommunical) segment, which technically ends at the origin of the
callosomarginal artery. Major ACA branches are represented in two views: 3, recurrent artery of Heubner (and penetrating A1 segment
vessels); 4, anterior communicating artery; 5, frontobasal (or orbitofrontal) artery; 6, frontopolar artery; 7, callosomarginal artery; 8,
pericallosal artery (or artery of the corpus callosum) (redrawn with permission from Krayenbühl and Yas¸argil, 1972, p. 99).

cerebelli, in the ambient cistern. It comes in close VERTEBRAL ARTERIES

proximity to cranial nerves III and IV and is situated
between the cerebral peduncle medially and the
hippocampus laterally. As the segment turns dorsally
toward the tectum, it approaches the underside of the
thalamus and eventually comes in close proximity to
the medial and lateral geniculate bodies and pulvinar.
This portion of PCA, now within the quadrigeminal
plate cistern, is sometimes referred to as a P3
(quadrigeminal) segment, which divides into tempor-
al and occipital cortical branches: Inferior temporal
arteries supply the undersurface of the temporal lobe,
the parieto-occipital artery supplies the posterior
third of the medial surface of the hemisphere as well
as the lateral occipital lobe, and the calcarine artery
supplies the occipital pole.
The medial posterior choroidal artery (MPChA)
arises from either P1 or proximal P2; one or two
lateral posterior choroidal arteries (LPChAs) arise
from P2 or from cortical branches (Fig. 7). All
posterior choroidal branches have a sweeping dorsal
and anterior course around the posterior thalamus
and will eventually anastomose with distal branches
of AChA from the anterior circulation. MPChA
supplies the tectum, posterior thalamus, pineal
gland, and the choroid plexus of third ventricle;
LPChAs supply the posterior thalamus and the
choroid plexus of the temporal horn and trigone.
Extracranial Course
The vertebral artery (VA) is the first branch of the
subclavian artery. It enters the transverse foramen
of the sixth cervical vertebra, ascends through
higher foramina, turns posteriorly after exiting the
C1 transverse foramen, and then kinks anteriorly
to penetrate the atlanto-occipital membrane and
dura at the foramen magnum (Fig. 8). Along its
extracranial course, it gives off a number of spinal,
meningeal, and muscular branches. Some degree of
asymmetry in size of VA is common; the left VA
may be dominant in approximately 50% of
people. Extracranially, as it turns anteriorly
toward the foramen magnum, VA gives off the
posterior meningeal artery, which courses along
the posterior arch of atlas. It supplies the falx
cerebri and, like other vessels that supply dural
structures, it can enlarge dramatically in dural
vascular malformations or as a result of dura-
based neoplasms.
Intracranial Course
Once within the cranial vault and intradural, the
principal intracranial VA branches are the anterior
spinal artery (ASpA) and the posterior inferior
cerebellar artery (PICA). ASpAs from both VAs join
 CEREBRAL BLOOD VESSELS: ARTERIES 589

hemispheric branches. The distal segments and

branches of PICA supply tonsil, vermis, and poster-
oinferior cerebellar hemisphere approximately to the
level of the primary horizontal fissure. The anterior
and lateral medullary segments supply principally the
posterolateral medulla.

BASILAR ARTERY
Approximately at the caudal border of the pons, the
two vertebral arteries merge into the basilar artery
(BA), which ascends along the ventral pons for
approximately 3 cm (Fig. 10). BA ectasia is common.
Important branches of the basilar include the
anterior inferior cerebellar arteries (AICAs), perfor-
ating branches, superior cerebellar arteries (SCAs),
and the posterior cerebral arteries (PCAs).

AICA
The AICA is the largest caudal branch of BA. In 60–
Figure 6 75% of cases, the AICA arises as a single vessel off
Posterior cerebral artery (PCA), segments and major branches. P1,
Precommunical or peduncular segment, which extends from the
BA. AICA often crosses cranial nerve VI and then
basilar artery (BA) bifurcation to the junction with the posterior moves laterally to the cerebellopontine angle cistern.
communicating artery; P2, ambient segment, which wraps around Along its proximal course, AICA supplies the lower
the midbrain in the tentorial incisura; P3, quadrigeminal segment, lateral pons. An important AICA branch, the internal
which runs behind the midbrain in the quadrigeminal plate cistern; auditory or labyrinthine artery, enters the internal
P4, represents terminal cortical branches; 1, posterior
communicating artery; 2, thalamoperforating arteries; 3, medial
acoustic meatus to supply cranial nerves VII and
posterior choroidal artery; 4, peduncular branches; 5, lateral VIII. AICA travels laterally in variable fashion over
posterior choroidal artery; 6, temporal cortical branches; 7, medial
occipital artery and branches, including parieto-occipital (8) and
calcarine arteries (9) (redrawn with permission from Krayenbühl
and Yas¸argil, 1972, p. 94).

to form a single vessel that sits in the anteromedial

sulcus of the spinal cord; it supplies a variable length
of the caudal ventral medulla and ventral cervical
cord. PICA typically arises as a single trunk from the
distal, intracranial VA, but it does not do so in all
cases. Variant PICA origins (e.g., a relatively
common origin in the extracranial VA) and other
PICA anomalies are associated with an increased
likelihood of intracranial aneurysms elsewhere in the
cerebral circulation.
PICA’s sinuous path can be roughly characterized
(Fig. 9): PICA wraps around the medulla (anterior Figure 7
and lateral medullary segments); it ascends to the Medial surface of brain and PCA vessels. 1, Posterior
level of the foramen of Luschka on the ventral communicating artery; 2, thalamoperforating arteries; 3, medial
posterior choroidal artery; 4, lateral posterior choroidal artery
surface of the cerebellar tonsil, gives off branches to
(note the anterior course of both the medial and the lateral
supply the fourth ventral choroid plexus, hairpins at posterior choroidal arteries); 5, temporal cortical branches; 6,
the superior pole of the tonsil, descends on the medial occipital artery; 7, splenial artery; 8, terminal cortical
underside of the vermis, and then gives off cerebellar branches (redrawn with permission from Osborn, 1994, p. 139).
590 CEREBRAL BLOOD VESSELS: ARTERIES

the ventral surface of the flocculus and supplies it and

other anterior, inferior, and lateral portions of the
cerebellar hemisphere and portions of the middle
cerebellar peduncle.
Perforating Branches
Short and long circumferential penetrating branches
supply the ventral pons and rostral brainstem along
the entire length of the BA.

Figure 8
Vertebral foramina and infratentorial vessels. 1, Vertebral artery
exiting the lateral vertebral foramen; 2, posterior meningeal artery;
3, foramen magnum; 4, vertebral artery; 5, basilar artery (the
opposite vertebral artery feeding into the basilar artery origin is
not shown); 6, anterior inferior cerebellar artery; 7, clivus; 8,
superior cerebellar artery supplying the superior vermis and the
superior surface of the cerebellar hemisphere; 9, posterior cerebral
artery. The meandering course of the posterior inferior cerebellar
artery (not numbered) is detailed in Fig. 9 (redrawn with
permission from Osborn, 1994, p. 142).
SCA
Paired SCAs arise as the penultimate branches of BA.
The SCA curves around the brainstem at the level of
the pontomesencephalic junction. It is in close
proximity to cranial nerves III and IV and the free
edge of the tentorium cerebelli. Its penetrating
branches supply the interpeduncular region, the crus
cerebri, superior and middle cerebellar peduncles,
tectum, and superior medullary velum. It descends
below the tentorium to supply the superior vermis
and the superior surface of the hemispheres. Pene-
trating branches from distal or ‘‘hemispheric’’ SCAs
will supply deep areas of cerebellum, to the level of
white matter and deep cerebellar nuclei.
PCA
Paired PCAs, when they arise from the basilar artery
(rather than from the anterior circulation in the case

Figure 9
Midsagittal brain section illustrating the major posterior circulation vessels. 1, Vertebral arteries; 2, posterior inferior cerebellar artery and
segments (2a, anterior medullary segment; 2b, lateral medullar segment; 2c, tonsillar segment; 2d, branch(es) to choroid; 2e, hemispheric
segment; 2f, vermian segment); 3, anterior inferior cerebellar artery; 4, basilar artery; 5, superior cerebellar artery; 6, posterior cerebral
artery; 7, calcarine artery; 8, posterior choroidal artery(ies); 9, carotid siphon; 10, anterior cerebral artery; 11, frontopolar artery; 12,
pericallosal artery (cutaway); 13, middle cerebral artery (redrawn with permission from DeArmond et al., 1976, p. 174).
 CEREBRAL BLOOD VESSELS: VEINS AND VENOUS SINUSES
Figure 10
Ventral surface of the brainstem and associated arteries. 1,
Vertebral arteries; 2, posterior inferior cerebellar artery; 3, anterior
spinal artery; 4, vertebral arteries joining to form the basilar
artery; 5, anterior inferior cerebellar artery extending across the
surface of the flocculus; 6, perforating branches; 7, superior
cerebellar artery; 8, posterior cerebral artery; 9, posterior
communicating artery; 10, middle cerebral artery (redrawn with
permission from Osborn, 1994, p. 142).
of persistent fetal origin of PCA), represent the
terminal branches of BA. The artery and its branches
were discussed previously.
—Edison Miyawaki and Jeffrey Statland
See also–Arterial Thrombosis, Cerebral; Basilar
Artery Thrombosis; Carotid Artery;
Cardiovascular Regulation; Cerebral Blood Flow,
Measurement of; Cerebral Blood Vessels: Veins
and Venous Sinuses; Cerebral Metabolism and
Blood Flow; Cerebral Microcirculation; Circle of
Willis
Acknowledgment
We thank Larry Howell for his help with the figures.
Further Reading
Carpenter, M. B., and Sutin, J. (1983). Human Neuroanatomy, 8th
ed., pp. 707–741. Williams & Wilkins, Baltimore.
DeArmond, S. J., Fusco, M. M., and Dewey, M. M. (1976).
Structure of the Human Brain, 2nd ed., pp. 170–179. Oxford
Univ. Press, New York.
Kahle, W., Leonhardt, H., and Platzer, W. (1986). Color Atlas and
Textbook of Human Anatomy. Volume 3: Nervous System and
Sensory Organs, 3rd rev. ed., pp. 250–259. Thieme Verlag,
Stuttgart.
591
Krayenbühl, H., and Yas¸argil, M. G. (1972). Radiological
anatomy and topography of the cerebral arteries. Handbook
Clin. Neurol. 11, 65–101.
Nolte, J. (1999). The Human Brain: An Introduction to Its
Functional Anatomy, 4th ed., pp. 117–143. Mosby, St. Louis.
Osborn, A. G. (1994). Diagnostic Neuroradiology, pp. 117–153.
Mosby, St. Louis.
Cerebral Blood Vessels: Veins
and Venous Sinuses
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL VEINS run separately from cerebral ar-
teries. They arise from pial plexuses at the surface of
the brain and, unlike veins elsewhere in the body, are
entirely valveless. They run for a variable distance in
the pia mater, traverse the subarachnoid space, and
eventually drain into a system of sinuses, which are
also valveless. The veins traverse a potential space
between the arachnoid and undersurface of the dura;
this space is the locale for subdural hematomas. In
the context of trauma and other etiologies, blood can
track in this subdural space quickly and freely, and
clinical manifestations often result from mass effect
of the growing hematoma. The sinuses are created by
reflections of meningeal and periosteal layers of dura
mater, are relatively taut, are lined by endothelial
cells, and most do not collapse on sectioning. The
major sinuses drain ultimately into the internal
jugular vein, which exits the skull in the jugular
foramen.
CEREBRAL VEINS
The cerebral veins are approximately divided into
superficial cortical and deep groups.
Superficial Cortical Veins
These are mostly unnamed and are highly variable in
their anatomy, but three deserve particular attention.
They converge in the area of the Sylvan fissure
(Fig. 1). The superficial middle cerebral vein is the
largest of the three, and it drains into the cavernous
sinus. The superior anastomotic vein of Trolard
connects to the superficial middle cerebral vein and
can drain either superiorly into the superior sagittal
sinus or inferiorly into the superficial middle cerebral
vein and then to the cavernous sinus. The inferior
anastomotic vein of Labbé also connects to the
 CEREBRAL BLOOD VESSELS: VEINS AND VENOUS SINUSES
Figure 10
Ventral surface of the brainstem and associated arteries. 1,
Vertebral arteries; 2, posterior inferior cerebellar artery; 3, anterior
spinal artery; 4, vertebral arteries joining to form the basilar
artery; 5, anterior inferior cerebellar artery extending across the
surface of the flocculus; 6, perforating branches; 7, superior
cerebellar artery; 8, posterior cerebral artery; 9, posterior
communicating artery; 10, middle cerebral artery (redrawn with
permission from Osborn, 1994, p. 142).
of persistent fetal origin of PCA), represent the
terminal branches of BA. The artery and its branches
were discussed previously.
—Edison Miyawaki and Jeffrey Statland
See also–Arterial Thrombosis, Cerebral; Basilar
Artery Thrombosis; Carotid Artery;
Cardiovascular Regulation; Cerebral Blood Flow,
Measurement of; Cerebral Blood Vessels: Veins
and Venous Sinuses; Cerebral Metabolism and
Blood Flow; Cerebral Microcirculation; Circle of
Willis
Acknowledgment
We thank Larry Howell for his help with the figures.
Further Reading
Carpenter, M. B., and Sutin, J. (1983). Human Neuroanatomy, 8th
ed., pp. 707–741. Williams & Wilkins, Baltimore.
DeArmond, S. J., Fusco, M. M., and Dewey, M. M. (1976).
Structure of the Human Brain, 2nd ed., pp. 170–179. Oxford
Univ. Press, New York.
Kahle, W., Leonhardt, H., and Platzer, W. (1986). Color Atlas and
Textbook of Human Anatomy. Volume 3: Nervous System and
Sensory Organs, 3rd rev. ed., pp. 250–259. Thieme Verlag,
Stuttgart.
591
Krayenbühl, H., and Yas¸argil, M. G. (1972). Radiological
anatomy and topography of the cerebral arteries. Handbook
Clin. Neurol. 11, 65–101.
Nolte, J. (1999). The Human Brain: An Introduction to Its
Functional Anatomy, 4th ed., pp. 117–143. Mosby, St. Louis.
Osborn, A. G. (1994). Diagnostic Neuroradiology, pp. 117–153.
Mosby, St. Louis.
Cerebral Blood Vessels: Veins
and Venous Sinuses
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL VEINS run separately from cerebral ar-
teries. They arise from pial plexuses at the surface of
the brain and, unlike veins elsewhere in the body, are
entirely valveless. They run for a variable distance in
the pia mater, traverse the subarachnoid space, and
eventually drain into a system of sinuses, which are
also valveless. The veins traverse a potential space
between the arachnoid and undersurface of the dura;
this space is the locale for subdural hematomas. In
the context of trauma and other etiologies, blood can
track in this subdural space quickly and freely, and
clinical manifestations often result from mass effect
of the growing hematoma. The sinuses are created by
reflections of meningeal and periosteal layers of dura
mater, are relatively taut, are lined by endothelial
cells, and most do not collapse on sectioning. The
major sinuses drain ultimately into the internal
jugular vein, which exits the skull in the jugular
foramen.
CEREBRAL VEINS
The cerebral veins are approximately divided into
superficial cortical and deep groups.
Superficial Cortical Veins
These are mostly unnamed and are highly variable in
their anatomy, but three deserve particular attention.
They converge in the area of the Sylvan fissure
(Fig. 1). The superficial middle cerebral vein is the
largest of the three, and it drains into the cavernous
sinus. The superior anastomotic vein of Trolard
connects to the superficial middle cerebral vein and
can drain either superiorly into the superior sagittal
sinus or inferiorly into the superficial middle cerebral
vein and then to the cavernous sinus. The inferior
anastomotic vein of Labbé also connects to the
592 CEREBRAL BLOOD VESSELS: VEINS AND VENOUS SINUSES

receives tributaries that drain insula, the ventral

basal ganglia, and the orbital surface of the frontal
lobe. It runs along the medial surface of the temporal
lobe and empties into the great cerebral vein of
Galen. Just beneath the splenium of the corpus
callosum, the unpaired great cerebral vein of Galen is
formed by the convergence of the aforementioned
major veins. It is a short (B1 cm) midline structure
that, together with the inferior sagittal sinus, drains
into the anterior portion of the straight sinus.

Dural Sinuses
The superior sagittal sinus (SSS) extends along the
Figure 1 superior border of the falx cerebri (Fig. 3). Its rostral
Major veins of the lateral cortical surface. The cerebral veins have portion may be hypoplastic as a normal variant. In
no valves and generally do not run with arteries. Venous anatomy
is highly variable between individuals, and many veins are
addition to superior superficial veins that empty into
unnamed, with several notable exceptions: 1, superficial middle it, the SSS also receives emissary veins that drain the
cerebral vein; 2, superficial anastomotic vein of Trolard; 3, inferior scalp. The inferior sagittal sinus (ISS) courses in the
anastomotic vein of Labbé. Superficial cortical veins (4) drain into inferior free edge of the falx cerebri but is not always
the superior sagittal sinus (not shown) in a characteristically present. The ISS joins the great vein of Galen to drain
oblique direction, against the direction of blood flow within the
sinus (redrawn with permission from Kahle et al., 1986, p. 257).
into the straight sinus (sinus rectus), which is formed
by reflected dura of the falx cerebri and the
tentorium cerebelli. Straight sinus runs in the midline
posteriorly and inferiorly toward a confluence of
superficial middle cerebral vein, runs along the sinuses called the torcula (confluens sinuum). The
Sylvan fissure posteriorly, and can drain either into SSS and straight sinus may drain directly into the
the transverse sinus or into the superficial middle
cerebral vein. Change in the direction of flow can
occur in these anastomotic veins to equalize pressure
differentials that may occur in the setting of sinus
occlusions, thromboses, space-occupying lesions, or
other factors. In general, superior superficial veins
drain upward toward the superior sagittal sinus.
They enter the sinus obliquely, and the direction of
flow within the veins is typically opposite that within
the sinus. Veins draining the inferior aspect of the
cortical convexity generally empty into the super-
ficial middle cerebral vein and then to the cavernous
sinus.

Deep Cortical Veins

Notable in this group are the internal cerebral veins,
the basal vein of Rosenthal, and the great cerebral
vein of Galen (Fig. 2). The internal cerebral veins are
paired midline vessels that arise at the foramina of
Munro. They receive tributaries that drain subcor-
tical and periventricular structures as well as the
choroid plexus within the lateral ventricles. They Figure 2
Internal or deep cerebral veins. The mesial temporal lobes are
travel posteriorly in the roof of the third ventricle,
retracted on either side. 1, Basal vein of Rosenthal; 2, great
enter the quadrigeminal plate cistern, and empty into cerebral vein of Galen; 3, internal cerebral vein(s); 4, deep middle
the great cerebral vein of Galen. The basal vein of cerebral vein; 5, superficial middle cerebral vein (cutaway)
Rosenthal arises at the medial temporal pole and (redrawn with permission from Kahle et al., 1986, p. 259).
 CEREBRAL BLOOD VESSELS: VEINS AND VENOUS SINUSES 593

torcula, but variants are common (e.g., the SSS often

drains into the right transverse sinus, and the straight
sinus often drains into the left transverse sinus). The
torcula divides into transverse (lateral) and occipital
sinuses; the latter is typically rudimentary.
The paired transverse sinuses are typically well
formed but often asymmetrical, with the right
usually dominant. The transverse sinus begins at
the occipital pole and runs along the lateral
tentorium cerebelli along a groove in the occipital
bone. It turns caudally at the level of the petrous
apex and is contiguous with the sigmoid sinus, which
is located in an S-shaped groove in the mastoid
portion of the temporal bone. The sigmoid sinuses
drain into their respective internal jugular veins.
The cavernous sinus is located on either side of the
sphenoid sinus and sella turcica (Fig. 4). It is an
irregular, compressible extradural space traversed by
multiple septations. Cranial nerves III, IV, and the Figure 4
Cavernous sinus in coronal section. Note its multiple septations
first division (and usually the second division) of
and the contiguity of venous channels to the opposite cavernous
cranial nerve V course within its lateral dural wall; sinus. 1, Sphenoid sinus; 2, pituitary within sella turcica; 3,
the internal carotid artery and cranial nerve VI lie Meckel’s cave, which contains the Gasserian (or semilunar)
within the sinus proper. The paired cavernous sinuses ganglion of cranial nerve V; 4, cranial nerve V, second (maxillary)
together represent a sinus confluence since venous division; 5, cranial nerve V, first (ophthalmic) division; 6, cranial
nerve IV; 7, cranial nerve III; 8, cranial nerve VI; 9, intracavernous
channels around the hypophysis connect the two
internal carotid artery, transected; 10, septated venous channels
structures; the term ‘‘circular’’ sinus is sometimes (redrawn with permission from Osborn, 1994, p. 149).

used to emphasize the connections around the

hypophysis. The cavernous sinuses are also contig-
uous with an additional (basilar or periclival) venous
plexus that extends inferiorly to the level of the
foramen magnum. Additional connecting channels
extend to plexuses within the vertebral canal.
Rostrally, the cavernous sinus receives ophthalmic
veins via the superior orbital fissure as well as other
contributions. Caudally, the cavernous sinus receives
ophthalmic veins via the superior orbital fissure as
well as other contributions, and it connects via the
superior and inferior petrosal sinuses to the trans-
verse sinus and internal jugular vein, respectively.
—Edison Miyawaki and Jeffrey Statland

Figure 3
Schema of the major venous sinuses. Darkened structures represent
deep cerebral veins as described in the legend to Fig. 2. 1, Superior
sagittal sinus; 2, superficial cortical veins; 3, inferior sagittal sinus;
4, great cerebral vein of Galen; 5, straight sinus (or sinus rectus); 6,
transverse sinus; 7, occipital sinus; 8, sigmoid sinus, draining to
internal jugular vein; 9, cavernous sinus; 10, inferior petrosal
sinus; 11, superior petrosal sinus; 12, basal vein(s) of Rosenthal;
13, choroidal veins; 14, internal cerebral vein(s); 15, torcula (or
confluens sinuum) (redrawn with permission from Nolte, 1999,
p. 139).
See also–Cardiovascular Regulation; Cerebral
Blood Vessels: Arteries; Cerebral Metabolism
and Blood Flow; Cerebral Microcirculation;
Cerebral Venous Thrombosis; Venous
Malformation
Acknowledgment
We thank Larry Howell for his help with the figures.
594 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS

Further Reading
Carpenter, M. B., and Sutin, J. (1983). Human Neuroanatomy, 8th
ed., pp. 707–741. Williams & Wilkins, Baltimore.
DeArmond, S. J., Fusco, M. M., and Dewey, M. M. (1976).
Structure of the Human Brain, 2nd ed., pp. 170–179. Oxford
Univ. Press, New York.
Kahle, W., Leonhardt, H., and Platzer, W. (1986). Color Atlas and
Textbook of Human Anatomy. Volume 3: Nervous System and
Sensory Organs, 3rd rev. ed., pp. 250–259. Thieme Verlag,
Stuttgart.
Krayenbühl, H., and Yas¸argil, M. G. (1972). Radiological
anatomy and topography of the cerebral veins. Handbook
Clin. Neurol. 11, 102–117.
Nolte, J. (1999). The Human Brain: An Introduction to Its
Functional Anatomy, 4th ed., pp. 117–143. Mosby, St. Louis.
Osborn, A. G. (1994). Diagnostic Neuroradiology, pp. 117–153.
Mosby, St. Louis.

Cerebral Cortex: Architecture

and Connections
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

THE CEREBRAL CORTEX plays a major role in

allowing organisms to cope effectively with com-
plex, changing environments. In particular, it
integrates information from the external and inter-
nal environments in ways that facilitate the success-
ful adaptation and execution of behavior. The
cerebral cortex is known to serve myriad functions,
such as attention, sensory analysis, perception,
emotion, memory, cognition, language, decision
making, and executive processes. One way of
attempting to place cortical function into a systema-
tic context is to view the cerebral cortex from the
perspective of its underlying architectonic–connec-
tional organization.
CORTICAL ARCHITECTURE
Following the advent of effective cell staining
methods in the late 19th century, several investiga-
tors (e.g., Campbell, Brodmann, Vogt and Vogt,
Economo and Koskinas, and Sarkissov) described the
cytoarchitectonic organization of the cerebral cortex.
This work resulted in specific parcellations of the
cortical mantle (Fig. 1) based on the differential
laminar distributions of neurons, and it allowed for
the establishment of general structure–function
relationships (Fig. 2). A specific line of neuroanato-
mical investigation addressed the question of
Figure 1
Cytoarchitectonic map of the human cerebral cortex by Brodmann
(1909). Each numerical designation refers to an architectonically
distinct region.
whether there are progressive changes in cortical
architecture, and it was found that the various
architectonic areas are interrelated systematically
with one another according to the nature of their
laminar differentiation. Using this approach, Dart
(1934) and Abbie (1940), on the basis of examina-
tions of reptilian and marsupial brains, respectively,
proposed that the cerebral cortex is characterized by
a dual pattern of progressive changes in lamination.
Furthermore, it was suggested that the cerebral
cortex has evolved from two primordial zones or
moieties, namely the archicortex (hippocampus) and
paleocortex (olfactory cortex) (Fig. 3A).
The concept of a dual origin of the cerebral cortex
has been extended to the primate brain. From the
archicortex and from the paleocortex, systematic
changes in laminar differentiation, termed architec-
tonic trends, can be observed. The term trend refers
594 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS

Further Reading
Carpenter, M. B., and Sutin, J. (1983). Human Neuroanatomy, 8th
ed., pp. 707–741. Williams & Wilkins, Baltimore.
DeArmond, S. J., Fusco, M. M., and Dewey, M. M. (1976).
Structure of the Human Brain, 2nd ed., pp. 170–179. Oxford
Univ. Press, New York.
Kahle, W., Leonhardt, H., and Platzer, W. (1986). Color Atlas and
Textbook of Human Anatomy. Volume 3: Nervous System and
Sensory Organs, 3rd rev. ed., pp. 250–259. Thieme Verlag,
Stuttgart.
Krayenbühl, H., and Yas¸argil, M. G. (1972). Radiological
anatomy and topography of the cerebral veins. Handbook
Clin. Neurol. 11, 102–117.
Nolte, J. (1999). The Human Brain: An Introduction to Its
Functional Anatomy, 4th ed., pp. 117–143. Mosby, St. Louis.
Osborn, A. G. (1994). Diagnostic Neuroradiology, pp. 117–153.
Mosby, St. Louis.

Cerebral Cortex: Architecture

and Connections
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

THE CEREBRAL CORTEX plays a major role in

allowing organisms to cope effectively with com-
plex, changing environments. In particular, it
integrates information from the external and inter-
nal environments in ways that facilitate the success-
ful adaptation and execution of behavior. The
cerebral cortex is known to serve myriad functions,
such as attention, sensory analysis, perception,
emotion, memory, cognition, language, decision
making, and executive processes. One way of
attempting to place cortical function into a systema-
tic context is to view the cerebral cortex from the
perspective of its underlying architectonic–connec-
tional organization.
CORTICAL ARCHITECTURE
Following the advent of effective cell staining
methods in the late 19th century, several investiga-
tors (e.g., Campbell, Brodmann, Vogt and Vogt,
Economo and Koskinas, and Sarkissov) described the
cytoarchitectonic organization of the cerebral cortex.
This work resulted in specific parcellations of the
cortical mantle (Fig. 1) based on the differential
laminar distributions of neurons, and it allowed for
the establishment of general structure–function
relationships (Fig. 2). A specific line of neuroanato-
mical investigation addressed the question of
Figure 1
Cytoarchitectonic map of the human cerebral cortex by Brodmann
(1909). Each numerical designation refers to an architectonically
distinct region.
whether there are progressive changes in cortical
architecture, and it was found that the various
architectonic areas are interrelated systematically
with one another according to the nature of their
laminar differentiation. Using this approach, Dart
(1934) and Abbie (1940), on the basis of examina-
tions of reptilian and marsupial brains, respectively,
proposed that the cerebral cortex is characterized by
a dual pattern of progressive changes in lamination.
Furthermore, it was suggested that the cerebral
cortex has evolved from two primordial zones or
moieties, namely the archicortex (hippocampus) and
paleocortex (olfactory cortex) (Fig. 3A).
The concept of a dual origin of the cerebral cortex
has been extended to the primate brain. From the
archicortex and from the paleocortex, systematic
changes in laminar differentiation, termed architec-
tonic trends, can be observed. The term trend refers
 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS 595

Figure 2
Diagrams of the lateral and medial surfaces of the cerebral hemisphere of rhesus monkey. (A) The locations of primary and second
(supplementary) sensorimotor cortices: areas AI and AII (ProK); somatic sensory areas SI and SII, and SSA (supplementary somatosensory
area); visual areas VI and MT; and motor areas MI, MII, and CMA (cingulate motor area or areas MIII and MIV). (B) The four major
subdivisions of association cortex: parasensory association areas [auditory association areas AAI and AAII, somatic sensory associations
areas SAI and SAII, and visual association areas VAI (V4, V3, V2) and VAII], frontal association areas (premotor and prefrontal), and
paralimbic association areas (cingulate gyrus, parahippocampal gyrus, temporal pole, and orbitofrontal cortex). This figure also shows the
approximate locations of multimodal areas: the parietotemporal region (areas TPO and PGa) in the superior temporal sulcus, the inferior
parietal lobule (area PG), and the premotor and prefrontal cortices. The Sylvian fissure is opened to expose the insula and the auditory areas.
AS, arcuate sulcus; CC, corpus callosum; CF, calcarine fissure; CING S, cingulate sulcus; CS, central sulcus; IPS, intraparietal sulcus; LF,
lateral (Sylvian) fissure; LS, lunate sulcus; OTS, occipitotemporal sulcus; POMS, medial parietooccipital sulcus; PS, principal sulcus; RhF,
rhinal fissure; STS, superior temporal sulcus [reproduced with permission from Pandya, D. N. (1999). Association cortex. In Elsevier’s
Encyclopedia of Neuroscience (G. Adelman and B. H. Smith, Eds.), 2nd ed., p. 139. Elsevier Science, Cambridge].

to a series of architectonic areas that appear to be
interrelated by systematic, progressive changes in
their laminar features. Each of these two trends,
archicortical and paleocortical, progresses through
the relatively undifferentiated, adjacent periallocor-
tex, then to proisocortex, and finally culminates in
fully differentiated, six-layered isocortex or neocor-
tex (Figs. 3A–3C). From the proisocortical areas,
successive waves of elaboration of cortical laminae
lead to the development of primary sensory and
motor regions. The overall pattern of laminar change
is evident as a progressive elaboration of supragra-
nular layers as one moves toward primary sensory
and motor regions (Fig. 3C).
According to the concept of the dual origin of the
cerebral cortex in primates, the temporal polar and
insular proisocortices stem from the olfactory moi-
ety. Further stepwise laminar progression from these
proisocortices is assumed to lead to the development
of visually related areas in the inferotemporal and
occipital regions serving central vision and involved
in object recognition and memory; auditory-related
areas of the anterior superior temporal region
relating to sound recognition and memory; the
596 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS
Figure 3
(A and B) Diagrammatic representations depicting the evolution of
cortical areas from archicortical (hippocampus) and paleocortical
(olfactory) moieties. (C) Block diagram showing the successive
steps of architectonic differentiation in the two cortical
architectonic trends. (D) Diagrammatic representation of further
architectonic progression from the two trends shown in A and B on
the lateral and medial surfaces of the cerebral hemisphere. The
Sylvian fissure is opened to reveal the insula. A, auditory
association area; G, gustatory area; OLF, olfactory cortex; PALL,
periallocortex; Pro, proisocortex; SSA, supplementary
somatosensory area; V, visual association area; VS, vestibular area.
For other abbreviations, see the legend to Fig. 2 [reproduced with
permission from Pandya, D. N., and Yeterian, E. H. (1990).
Architecture and connections of cerebral cortex: Implications for
brain evolution and functions. In Neurobiology of Higher
Cognitive Function (A. Scheibel and A. F. Wechsler, Eds.), pp. 56
and 57. Guilford, New York].
somatosensory and motor areas subserving head,
neck, and face in the ventral portion of the post- and
precentral gyri; and the gustatory and vestibular
areas. From this paleocortical trend would also
emerge the ventral portion of the prefrontal cortex.
From the proisocortex of the hippocampal trend,
which is located in the cingulate-retrosplenial cor-
tices, the dorsal and medial parietooccipital regions
serving peripheral or spatial vision, the caudal
superior temporal gyrus relating to audiospatial
function, and the dorsal portions of the post- and
precentral gyri subserving the trunk and limbs are
assumed to arise. The medial and dorsolateral
portions of the prefrontal cortex appear to emanate
from this medial proisocortex (Fig. 3D).
In addition to the general pattern of architectonic
differentiation in the archi- and paleocortical trends
as a whole, within each major sensory modality as
well as in the motor cortices, tripartite, parallel
sequences of architectonic differentiation can be
observed. Thus, within the paleocortical trend
(Fig. 4A) in the auditory-related areas of the rostral
superior temporal region, from the temporal polar
proisocortex one line of architectonic differentiation
progresses in the supratemporal plane in a sequential
manner, leading to primary auditory area AI. In this
line, termed the core line, the main architectonic
change is the acquisition of progressively more
numerous and more densely packed granular cells
in the supragranular layers. A second line of
differentiation emanating from the temporal polar
proisocortex, termed the belt line, is observed in the
auditory association areas of the superior temporal
gyrus. In this line, the predominant architectonic
changes involve the acquisition of third-layer neu-
rons along with an increased number of granule cells.
The third line, which begins in the temporal polar
proisocortex and is known as the root line, is
localized in the cortex of the circular sulcus in the
Sylvian fissure. In this line, the differentiation
between supra- and infragranular layers is somewhat
less than that in the auditory core and belt lines. With
respect to the archicortical trend, the caudal portion
of the superior temporal region also shows tripartite
organization and is thought to stem from the caudal
cingulate-retrosplenial proisocortical region. The
visual areas of the occipital and inferotemporal
regions also appear to be organized according to
the concept of core, belt, and root lines (Fig. 4B).
One set of tripartite lines in the inferotemporal
region originates from the temporal polar proisocor-
tex (paleocortical trend) and serves the central visual
field. The other set is located in the dorsal and medial
occipital region, beginning in the caudal cingulate-
retrosplenial proisocortex (archicortical trend), and
 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS 597

Figure 4
Diagrammatic representations of the tripartite organization (root, core, and belt) within the paleocortical and archicortical trends in the
sensory and motor cortices. ARCHI, archicortical trend; PALEO, paleocortical trend; Pro, proisocortex; RSpl, retrosplenial cortex.

deals with peripheral vision. Likewise, in the
somatosensory system, two sets of tripartite archi-
tectonic lines can be identified (Fig. 4C). One set
progresses from insular proisocortex (paleocortical
trend) toward the postcentral gyrus and rostral
inferior parietal lobule, and it subserves head, neck,
and face. The second set originates from the
cingulate-retrosplenial proisocortex (archicortical
trend) and leads to the medial and dorsal postcentral
gyral regions relating to limb and trunk representa-
tions. Similarly, the motor cortices of the frontal lobe
are characterized by the presence of paleo- and
598 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS
archicortical trends and by tripartite lines within
both trends (Fig. 4D).
As mentioned previously, the prefrontal cortex can
be differentiated with respect to two architectonic
moieties (Fig. 5). From the paleocortical moiety on
the basal surface of the frontal lobe, the first stage in
the sequence of architectonic differentiation leads to
the orbital proisocortex. From there, the next stage
comprises the ventrolateral prefrontal areas, which
are characterized by further development of the
supragranular layers. The final stage consists of the
caudoventral prefrontal region, which has highly
developed supragranular layers (Fig. 5A). Similarly,
from the archicortical moiety in the rostral cingulate
region, the first stage leads to the development of
medial proisocortical areas, which show a stepwise
progression in laminar differentiation toward the
dorsolateral areas, which in turn culminate in the
caudodorsal prefrontal region (Fig. 5B). Finally,
cortical limbic regions are also organized according
to two architectonic trends. Archicortical limbic
regions stem from the cingulate-retrosplenial proiso-
cortex, whereas paleocortical limbic regions origi-
nate from the rostral parahippocampal and temporal
polar proisocortices.
CORTICAL CONNECTIONS
The intrinsic (i.e., short association) connections of
areas within the post-Rolandic cortices are organized
in a manner consistent with the concept of progres-
Figure 5
The progressive architectonic steps from the (A) orbital proisocortex and (B) medial proisocortex of the frontal lobe. For abbreviations, see
the legend to Fig. 2 [reproduced with permission from Pandya, D. N., and Yeterian, E. H. (1990). Architecture and connections of cerebral
cortex: Implications for brain evolution and functions. In Neurobiology of Higher Cognitive Function (A. Scheibel and A. F. Wechsler, Eds.),
p. 64. Guilford, New York].
sive architectonic trends. That is, the connections are
of two types, feedforward and feedback, with a
specific laminar organization of origins and termina-
tions. In all post-Rolandic sensory modalities, the
forward connections stem preferentially from supra-
granular neurons (layer II and III neurons) and
terminate in layers III and IV of adjacent regions in a
columnar manner. The feedback connections, in
contrast, originate in infragranular layers (layers V
and VI) and terminate mainly in layer I of the
architectonic precursor area. Figure 6 depicts the
nature of intrinsic feedforward and feedback con-
nectivity within the lateral occipital and inferotem-
poral cortices relating to the visual modality. A
similar pattern of feedforward and feedback intrinsic
connections has been demonstrated in the auditory
and somatosensory modalities. With regard to
feedforward connections, each modality, through a
series of sequential connections beginning in the
primary sensory region, ultimately reaches a limbic
cortical region as well as the amygdala. These
connections are complemented by sequential feed-
back connections that originate in the limbic cortices
and the amygdala and terminate in the first layer of
various sensory association regions, ultimately lead-
ing back to the primary sensory areas. Thus, whereas
the feedforward connections convey information
from the external environment to the limbic system,
the feedback connections send information regarding
the internal state of the organism to the primary
sensory and association regions.
 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS
Figure 6
The common pattern of laminar origins and terminations of
intrinsic connections in the visual areas of the occipital and
inferotemporal regions. For abbreviations, see the legend to Fig. 2
[reproduced with permission from Pandya, D. N., and Yeterian,
E. H. (1990). Architecture and connections of cerebral cortex:
Implications for evolution and functions. In Neurobiology of
Higher Cognitive Function (A. Scheibel and A. F. Wechsler, Eds.),
p. 64. Guilford, New York].
Long cortical association connections are also
organized in a manner consistent with the concept
of progressive laminar differentiation originating
from the archicortical and paleocortical moieties.
The primary sensory areas of the visual, auditory,
and somatosensory modalities are connected with
the surrounding root and belt regions. The root and
belt regions, in turn, are connected with parietotem-
poral multimodal areas, with the cinguloparahippo-
campal limbic regions, and with the prefrontal
cortex. Thus, in the occipitotemporal region belong-
ing to the paleocortical trend, the rostral belt area
(visual association area 3 or VA3) is connected with
the orbital prefrontal region, whereas the middle belt
area (VA2) is connected mainly with the ventrolateral
prefrontal region. The caudal belt area (VA1) is
connected with the caudoventral prefrontal region.
For the medial and dorsal occipital regions belonging
to the archicortical trend, the belt area is related
preferentially to the dorsal and medial prefrontal
regions (Fig. 7A).
In the somatosensory system, the belt areas
belonging to the paleocortical trend (ventral soma-
tosensory system) have a systematic relationship with
599
the frontal cortex (Fig. 7B). Thus, the rostral belt
area residing in the Sylvian operculum connects
preferentially with the orbitofrontal cortex. In
contrast, the middle belt area belonging to the
middle portion of the inferior parietal lobule (IPL)
relates mainly to the ventrolateral prefrontal region.
The belt area of the rostral IPL is connected
predominantly with the ventral premotor area.
Similarly, the medial and dorsal somatosensory
regions belonging to the archicortical trend (dorsal
somatosensory system) have systematic relationships
with the frontal cortex. The medial proisocortical
area is connected mainly with the medial frontal
region, whereas the intermediate belt area of the
caudal and medial parietal lobe projects preferen-
tially to the dorsolateral prefrontal region. The
rostral superior parietal lobule is related predomi-
nantly to the dorsal premotor area.
In the auditory system, the belt areas of the rostral
superior temporal gyrus (STG) belonging to the
paleocortical trend are related systematically to the
prefrontal cortex. The temporal polar region (audi-
tory association area 3 or AA3) is connected mainly
with the orbital and medial prefrontal areas, whereas
the middle portion of the STG (AA2) relates
preferentially to the ventrolateral and dorsolateral
prefrontal regions. The caudal belt area of the STG
(AA1), which belongs to the archicortical trend, is
connected mainly with the cingulate–proisocortical
area and with the caudal prefrontal region (Fig. 7C).
It appears that the post-Rolandic belt areas are
preferentially connected with frontal lobe areas that
occupy a similar level of architectonic differentiation
within a specific trend. These connections are
bidirectional (i.e., each prefrontal region that re-
ceives a post-Rolandic input projects back to the
areas that give rise to that input). Moreover, these
long association connections are conveyed via
specific fiber pathways (e.g., superior longitudinal
fasciculus, uncinate fasciculus, and cingulum bun-
dle). It is important to note that within both
prefrontal architectonic trends, there is a systematic
pattern of intrinsic cortical connectivity (Fig. 8).
Thus, a given prefrontal area has projections to its
adjacent precursor region as well as to a nearby
region that is more differentiated architectonically.
As mentioned previously, within each sensory
modality the core region is surrounded by a belt
and a root region. It is interesting to note that each
modality-specific root and belt region is bordered by
multimodal areas (Fig. 9). With respect to connec-
tions, the core areas are related to the root and belt
600 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS
Figure 7
The frontal lobe connections of association areas belonging to the
paleo- and archicortical trends. (A) Visual cortices. (B)
Somatosensory cortices. (C) Auditory cortices. Opt,
occipitoparietotemporal cortex; PV, peripheral vision. For other
abbreviations, see the legend to Fig. 2 [reproduced with permission
from Pandya, D. N., and Yeterian, E. H. (1990). Architecture and
connections of cerebral cortex: Implications for evolution and
functions. In Neurobiology of Higher Cognitive Function (A.
Scheibel and A. F. Wechsler, Eds.), pp. 66–68. Guilford, New York].
areas of their specific stage of architectonic differ-
entiation as well as to the root, core, and belt areas of
adjacent stages, thus forming essentially a ring of
connected areas around the core region (Figs. 10A
and 10B). The belt and root regions are connected
with the multimodal areas bordering the ring, thus
forming the outer ring or outer belt (Figs. 9B, 10B
and 10C). Like the modality-specific areas, the
multimodal areas seem to have differentiated pro-
gressively from the proisocortical regions. However,
whereas the inner ring belt areas are modality specific
(i.e., they are limited to the realm of a single sensory
modality), the surrounding multimodal regions, by
virtue of input from different modalities, allow for
the commingling of a number of sensory modalities,
thereby providing a substrate for complex intersen-
sory functions.
Laminar structure and connectional relationships
appear to be essential cornerstones of cerebral
cortical organization. It should be noted that each
layer within the post-Rolandic cortex has specific
cellular composition and connections and perhaps
specific associated functional roles. For example,
layer I, the so-called molecular layer, is known to be
cell sparse. It receives input from subcortical
structures, such as the reticular formation and the
intralaminar nuclei of the thalamus, and from the
infragranular layer neurons of precursor (less archi-
tectonically differentiated) regions from the proiso-
cortices outward as well as from the amygdala.
Within this layer are located the apical dendrites of
the neurons of underlying cortical layers involved in
the processing of incoming information. This sug-
gests that the functional roles of layer I may include
arousal, attention, relating the internal environment
to information coming in from the external world,
and activating from within previously stored infor-
mation. The second and third cortical layers receive
input from the external environment (via the
thalamus and the primary sensory association
regions) as well as from the opposite hemisphere.
The outflow of these layers is of three types: to the
opposite hemisphere; to adjacent precursor regions
(i.e., less differentiated regions); and to more distant
regions, including multimodal areas, limbic cortices,
and the frontal lobe. The neurons of layers II and III
may thus provide well-integrated, modality-specific
information to both nearby and distant regions for
further processing. Layer IV, the so-called granular
layer, receives input from the thalamus and the
opposite hemisphere as well as from layer III of
adjoining regions. Its outflow is of two types. Like
 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS 601

Figure 8
The intrinsic connections of (A) prefrontal paleocortical architectonic trend areas and (B) prefrontal archicortical architectonic trend areas.
For abbreviations, see the legend to Fig. 2 [reprinted with permission from Pandya, D. N., and Yeterian, E. H. (1990). Prefrontal cortex in
relation to other cortical areas in the rhesus monkey: Architecture and connections. In The Prefrontal Cortex: Its Structure, Function and
Pathology (H. B. M. Uylings et al., Eds.), Prog. Brain Res. 85, 70 and 71. Elsevier Science, Cambridge].
602 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS
Figure 9
(A) The locations of post-Rolandic multimodal areas in medial,
lateral, and ventral regions of the cerebral hemisphere. (B) The
connectional relationship between the auditory belt line regions
and the adjoining multimodal regions of the insula and the upper
bank of the superior temporal sulcus. AA, auditory association
region; AGI, agranular insula; CING RS, cingulate-retrosplenial
cortex; DGI, dysgranular insula; GI, granular insula; PARA HIPP
G, parahippocampal gyrus; SA, somatosensory association region;
TPO-PGa, multimodal region of STS; VA, visual association
region. For other abbreviations, see the legend to Fig. 2
[reproduced with permission from Pandya, D. N., and Yeterian,
E. H. (1990). Architecture and connections of cerebral cortex:
Implications for brain evolution and functions. In Neurobiology of
Higher Cognitive Function (A. Scheibel and A. F. Wechsler, Eds.),
pp. 71 and 73. Guilford, New York].
the third layer, it advances information to nearby
precursor (less differentiated) regions and sends
information horizontally within the same layer as
well as to adjacent layers to activate nearby modules
within those layers. This connectivity suggests that
layer IV, like layers II and III, synthesizes incoming
information from the external environment and feeds
that information forward within the cerebral cortex.
Whereas layer IV provides predominantly local
feedforward connectivity, layers II and III provide
both local and distant feedforward connectivity.
Layers V and VI receive input primarily from
intracortical circuitry within the region in which
they are located. The outflow of these layers is to
layer I of adjoining areas that are more differentiated
architectonically. Thus, on the basis of their con-
nectivity, layers V and VI appear to be involved in
cortical feedback. These layers also send outflow to
subcortical structures such as the thalamus, striatum,
and pons. The overall functional role of layers V and
VI may be to provide integrated information to more
differentiated cortical regions and to modulate the
activity of subcortical structures. It is important to
note that the function of the cerebral cortex likely
depends on the overall integration of the various
cortical laminae rather than the action of any specific
layer in isolation. Although this proposal regarding
the functional roles of cortical laminae is speculative,
it may provide a useful perspective in attempting to
relate cortical function to structure.
The concept of dual architectonic trends described
previously emphasizes that the cerebral cortex can be
viewed as either paleocortical or archicortical based
on laminar characteristics and differentiation along
with associated connectional features. Although this
concept was developed to aid in understanding the
morphological organization of the cerebral cortex, it
may provide a useful context for better under-
standing observations from clinical, experimental,
and neuroimaging settings. For example, the post-
Rolandic cortices are well-known to be involved in
sensory processing, but the function of specific
portions of these cortices can be differentiated in
accordance with their relationship to either the
paleo- or archicortical trend. In the cortical visual
system, areas linked with the paleocortical trend are
involved mainly in central vision (e.g., object
identification and memory). In contrast, visual
cortical areas associated with the archicortical trend
serve visuospatial processing and memory. Likewise,
in the auditory system, the rostral superior temporal
gyrus, which is linked with the paleocortical trend,
 CEREBRAL CORTEX: ARCHITECTURE AND CONNECTIONS 603

Figure 10
(A) The connectional pattern of a core area (KA or primary auditory cortex) of the superior temporal region. (B) The growth ring concept in
the cortical auditory system with regard to primary (core) regions. (C) (Left) The interrelationship between unimodal (root, core, and belt)
and multimodal regions of the insula and superior temporal sulcus (STS) and (right) the growth ring concept based on the relationship
between modality-specific and undifferentiated multimodal (MM) regions [reproduced with permission from Pandya, D. N., and Yeterian,
E. H. (1990). Architecture and connections of cerebral cortex: Implications for brain evolution and functions. In Neurobiology of Higher
Cognitive Function (A. Scheibel and A. F. Wechsler, Eds.), p. 69 (A and B) and 73 (C). Guilford, New York].

has been shown to play a role in auditory identifica-
tion and memory, whereas the caudal superior
temporal gyrus, which is associated with the
archicortical trend, serves audiospatial function and
perhaps auditory spatial memory. With regard to the
somatosensory system, the ventral somatosensory
areas, which are part of the paleocortical trend, are
involved in information processing relating to the
head, neck, and face. In contrast, the dorsal and
medial somatosensory areas, which belong to the
archicortical trend, serve the trunk and limbs. Within
the paleocortical trend of these three sensory
modalities, there appear to be differential levels of
processing complexity depending on where in the
trend a specific region is located. Thus, the highly
differentiated regions termed primary areas are each
involved in elementary sensory processing, whereas
less differentiated areas (i.e., those located more
closely to the proisocortices of each modality) appear
to serve more complex sensory processing, including
that of integrated images as well as memory.
The long association connections from post-
Rolandic regions to the frontal lobe are reflective of
the aforementioned functional differences within the
post-Rolandic cortices. Thus, the less differentiated
post-Rolandic cortices project to the less differen-
tiated prefrontal regions, mainly the orbital and
medial prefrontal cortices. Post-Rolandic areas of
intermediate differentiation project to similarly
differentiated prefrontal regions, predominantly the
ventrolateral and dorsolateral prefrontal regions.
Highly differentiated post-Rolandic cortices tend to
project to highly differentiated prefrontal and pre-
motor regions (i.e., areas within the caudal prefron-
tal and premotor regions). There are functional
correlates of this connectivity that reflect not only
the level of differentiation within the paleo- and
archicortical trends of the prefrontal cortex but also
the broad division between those trends. Within the
prefrontal cortex, areas linked with the paleocortical
trend tend to serve a stimulus-oriented function
(vision and audition) and processing related to the
head, neck, and face (somatosensation). In contrast,
areas linked with the archicortical trend tend to be
involved in spatial-related processes. Within each
trend, there are different functional roles in relation
to the degree of architectonic differentiation of the
areas involved. Within the paleocortical trend, the
less differentiated regions of the orbital frontal
cortex are involved in functions such as decision
604 CEREBRAL EDEMA
making and appreciating the emotional significance
of stimuli, whereas more caudal and lateral regions
with a high degree of differentiation appear to serve
attentional and perhaps communication (e.g., lin-
guistic) processes. Areas of intermediate differentia-
tion in the ventrolateral prefrontal region serve
response inhibition, stimulus selection, and possibly
self-regulation. Within the archicortical trend, less
differentiated areas of the medial prefrontal cortex
may serve processes such as drive, motivation, and
initiation, whereas more caudal and lateral regions
with high levels of differentiation may play a role in
spatial attention (e.g., visuospatial, audiospatial, and
somatospatial). Areas of intermediate differentiation
on the dorsolateral surface appear to be associated
with self-monitoring (i.e., planning and sequencing
of behavior) and with working memory.
This approach of examining cortical architecture
and connections from the standpoint of dual
architectonic trends provides a contextual frame-
work for interpreting other kinds of observations
regarding the cerebral cortex (e.g., clinical and
behavioral findings). However, this architectonic–
connectional perspective of the organization of the
cerebral cortex represents only a single viewpoint on
a highly complex structure. Undoubtedly, other key
aspects of the cerebral cortex (e.g., its physiology and
its chemical composition) can provide additional
insight into its organization and function. In recent
years, significant advances in neuroimaging and
other clinical techniques have provided knowledge
of cerebral cortical mechanisms not heretofore
possible. The challenge remains to be able to
interrelate systematically all of these levels of
analysis in order to attain a coherent and fully
integrated understanding of the cerebral cortex.
—D. N. Pandya and E. H. Yeterian
See also–Brain Anatomy; Brain Evolution,
Human; Central Nervous System, Overview
Further Reading
Alain, C., Arnott, S. R., Hevenor, S., et al. (2001). ‘‘What’’ and
‘‘where’’ in the human auditory system. Proc. Natl. Acad. Sci.
USA 98, 12301–12306.
Felleman, D. J., and Van Essen, D. C. (1991). Distributed
hierarchical processing in the primate cerebral cortex. Cerebral
Cortex 1, 1–47.
Jones, E. G., and Powell, T. P. S. (1970). An anatomical study of
converging sensory pathways within the cerebral cortex of the
monkey. Brain 93, 793–820.
Mesulam, M.-M. (1998). From sensation to cognition. Brain 121,
1013–1052.
Mishkin, M., Ungerleider, L. G., and Macko, K. A. (1983). Object
vision and spatial vision: Two cortical pathways. Trends
Neurosci. 6, 414–417.
Pandya, D. N., and Yeterian, E. H. (1985). Architecture and
connections of cortical association areas. In Cerebral Cortex,
Vol. 4, Association and Auditory Areas (A. Peters and E. G.
Jones, Eds.), pp. 3–61. Plenum, New York.
Petrides, M., and Pandya, D. N. (1994). Comparative architec-
tonic analysis of the human and macaque frontal cortex.
Handbook Neuropsychol. 9, 17–58.
Rauschecker, J. P., and Tian, B. (2000). Mechanisms and streams
for processing of ‘‘what’’ and ‘‘where’’ in auditory cortex. Proc.
Natl. Acad. Sci. USA 97, 11800–11806.
Romanski, L. M., Tian, B., Fritz, J., et al. (1999). Dual streams of
auditory afferents target multiple domains in the primate
prefrontal cortex. Nat. Neurosci. 2, 1131–1136.
Sanides, F. (1972). Representation in the cerebral cortex and its
areal lamination patterns. Struct. Funct. Nervous Tissue 5,
329–453.
Cerebral Edema
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL EDEMA refers to an increase in the water
content of cerebral tissue that causes the brain to
swell. Some form of cerebral edema is associated
with all types of brain injury, including trauma,
anoxia, tumors, and infections. The negative effects
of cerebral edema include mass effect, increased
intracranial pressure, impairment of cerebral micro-
circulation, anoxia, and direct cellular injury.
Normally, fluid exists in the brain in three
compartments: intracellular, extracellular extravas-
cular (interstitial), and intravascular. Typically, water
balance is controlled by the release of antidiuretic
hormone from the posterior pituitary and depends on
sodium levels and serum osmolarity. The blood–
brain barrier prevents and buffers water movement
across the capillary membranes of the cerebral
circulation, thereby regulating water balance in the
brain. Brain cells also possess mechanisms to control
the intracellular volume of water. Disruption of the
blood–brain barrier or damage to brain cells can
cause fluid to increase in the intracellular or
extracellular space, causing cerebral edema.
Cerebral edema can be categorized into several
types: cytotoxic, vasogenic, and interstitial. Cyto-
toxic edema is also known as intact-barrier edema,
meaning that the blood–brain barrier is intact.
Cytotoxic edema is caused by the intracellular
uptake of water, resulting in cellular swelling. It is
604 CEREBRAL EDEMA
making and appreciating the emotional significance
of stimuli, whereas more caudal and lateral regions
with a high degree of differentiation appear to serve
attentional and perhaps communication (e.g., lin-
guistic) processes. Areas of intermediate differentia-
tion in the ventrolateral prefrontal region serve
response inhibition, stimulus selection, and possibly
self-regulation. Within the archicortical trend, less
differentiated areas of the medial prefrontal cortex
may serve processes such as drive, motivation, and
initiation, whereas more caudal and lateral regions
with high levels of differentiation may play a role in
spatial attention (e.g., visuospatial, audiospatial, and
somatospatial). Areas of intermediate differentiation
on the dorsolateral surface appear to be associated
with self-monitoring (i.e., planning and sequencing
of behavior) and with working memory.
This approach of examining cortical architecture
and connections from the standpoint of dual
architectonic trends provides a contextual frame-
work for interpreting other kinds of observations
regarding the cerebral cortex (e.g., clinical and
behavioral findings). However, this architectonic–
connectional perspective of the organization of the
cerebral cortex represents only a single viewpoint on
a highly complex structure. Undoubtedly, other key
aspects of the cerebral cortex (e.g., its physiology and
its chemical composition) can provide additional
insight into its organization and function. In recent
years, significant advances in neuroimaging and
other clinical techniques have provided knowledge
of cerebral cortical mechanisms not heretofore
possible. The challenge remains to be able to
interrelate systematically all of these levels of
analysis in order to attain a coherent and fully
integrated understanding of the cerebral cortex.
—D. N. Pandya and E. H. Yeterian
See also–Brain Anatomy; Brain Evolution,
Human; Central Nervous System, Overview
Further Reading
Alain, C., Arnott, S. R., Hevenor, S., et al. (2001). ‘‘What’’ and
‘‘where’’ in the human auditory system. Proc. Natl. Acad. Sci.
USA 98, 12301–12306.
Felleman, D. J., and Van Essen, D. C. (1991). Distributed
hierarchical processing in the primate cerebral cortex. Cerebral
Cortex 1, 1–47.
Jones, E. G., and Powell, T. P. S. (1970). An anatomical study of
converging sensory pathways within the cerebral cortex of the
monkey. Brain 93, 793–820.
Mesulam, M.-M. (1998). From sensation to cognition. Brain 121,
1013–1052.
Mishkin, M., Ungerleider, L. G., and Macko, K. A. (1983). Object
vision and spatial vision: Two cortical pathways. Trends
Neurosci. 6, 414–417.
Pandya, D. N., and Yeterian, E. H. (1985). Architecture and
connections of cortical association areas. In Cerebral Cortex,
Vol. 4, Association and Auditory Areas (A. Peters and E. G.
Jones, Eds.), pp. 3–61. Plenum, New York.
Petrides, M., and Pandya, D. N. (1994). Comparative architec-
tonic analysis of the human and macaque frontal cortex.
Handbook Neuropsychol. 9, 17–58.
Rauschecker, J. P., and Tian, B. (2000). Mechanisms and streams
for processing of ‘‘what’’ and ‘‘where’’ in auditory cortex. Proc.
Natl. Acad. Sci. USA 97, 11800–11806.
Romanski, L. M., Tian, B., Fritz, J., et al. (1999). Dual streams of
auditory afferents target multiple domains in the primate
prefrontal cortex. Nat. Neurosci. 2, 1131–1136.
Sanides, F. (1972). Representation in the cerebral cortex and its
areal lamination patterns. Struct. Funct. Nervous Tissue 5,
329–453.
Cerebral Edema
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL EDEMA refers to an increase in the water
content of cerebral tissue that causes the brain to
swell. Some form of cerebral edema is associated
with all types of brain injury, including trauma,
anoxia, tumors, and infections. The negative effects
of cerebral edema include mass effect, increased
intracranial pressure, impairment of cerebral micro-
circulation, anoxia, and direct cellular injury.
Normally, fluid exists in the brain in three
compartments: intracellular, extracellular extravas-
cular (interstitial), and intravascular. Typically, water
balance is controlled by the release of antidiuretic
hormone from the posterior pituitary and depends on
sodium levels and serum osmolarity. The blood–
brain barrier prevents and buffers water movement
across the capillary membranes of the cerebral
circulation, thereby regulating water balance in the
brain. Brain cells also possess mechanisms to control
the intracellular volume of water. Disruption of the
blood–brain barrier or damage to brain cells can
cause fluid to increase in the intracellular or
extracellular space, causing cerebral edema.
Cerebral edema can be categorized into several
types: cytotoxic, vasogenic, and interstitial. Cyto-
toxic edema is also known as intact-barrier edema,
meaning that the blood–brain barrier is intact.
Cytotoxic edema is caused by the intracellular
uptake of water, resulting in cellular swelling. It is

a manifestation of cell damage. It occurs when the
concentration of osmotically active solutes such as
sodium becomes greater in brain cells than in
plasma, causing water to move from the blood into
brain cells. This is usually caused by damage to
sodium–potassium adenosine triphosphatase, which
activates the sodium–potassium pump of the brain
cell. Failure of the sodium–potassium pump leads to
increased intracellular sodium, which in turn leads
to movement of water into the cell. The intracel-
lular space then expands and extracellular space
shrinks.
Cytotoxic edema is primarily associated with
hypoxia, trauma, and water intoxication. Hypoxia
causes ischemic cell damage, which induces edema
via the mechanism described previously. Trauma is
associated with cytotoxic edema if the circulation is
disrupted causing tissue anoxia. Water intoxication
can decrease the concentration of sodium in the
extracellular space while the concentration within
cells is relatively increased. In turn, water moves
from the extracellular space into the cells. Late
hypoxic edema and posttraumatic edema can be both
cytotoxic and vasogenic.
Vasogenic edema results from breakdown of the
blood–brain barrier. It is also known as open-barrier
edema. Normally, the blood–brain barrier segregates
brain interstitial fluid from the circulating blood,
regulating the composition of the extracellular space.
Injured astrocytes and inflammatory mediators can
cause breakdown of the blood–brain barrier. This
breakdown allows fluid and other molecules to
traverse from the intravascular space to the inter-
stitial space. Because the fluid balance is deranged in
the interstitial space, vasogenic edema is primarily
seen in white matter. It is associated with brain
tumors, abscesses, infarctions, trauma, and hemor-
rhages. The exact mechanism associated with tumors
is not fully understood, but it is believed that tumors
release factors that directly increase the permeability
of the blood–brain barrier. Cerebral edema in regions
adjacent to brain tumors and abscesses also may
result from osmotic gradients spreading through
white matter tracts and from cerebrospinal fluid
(CSF) absorption problems related to released
proteins. Trauma mechanically destroys brain tissue,
including the cerebrovascular endothelium and its
blood–brain barrier. Trauma-induced edema can also
be mediated by physiologically active compounds
released secondary to the injury, such as bradykinins,
arachidonic acid, histamine, and free radicals. This
form of edema usually reaches its maximum 48–72 hr
CEREBRAL EDEMA 605
after injury. Vasogenic edema is also associated with
late anoxic injury.
Interstitial edema in the periventricular regions is
secondary to obstructive hydrocephalus. This form
of cerebral edema is also known as hydrocephalic
edema. The increased intraventricular pressure
caused by hydrocephalus hinders movement of water
from the cerebral tissue into the ventricles. Water
accumulates in the interstitial space, most promi-
nently in the regions adjacent to the ventricles.
Treating hydrocephalus by shunting CSF decreases
the intraventricular pressure, thereby restoring the
normal flow of fluid into the ventricle and allowing
the periventricular edema to resolve.
Cerebral edema can be readily identified on
neuroimaging studies. On computed tomographic
scans, edema appears hypodense. It appears hypoin-
tense on T1-weighted magnetic resonance (MR)
images and hyperintense on T2-weighted MR
images. It is often diffuse within the cerebral tissue
with vague margins. Vasogenic edema is mostly
limited to white matter. Cytotoxic edema is most
evident in gray matter but may appear hypointense in
both white and gray matter. Interstitial edema from
hydrocephalus is most prominent adjacent to the
frontal horns of the lateral ventricles.
There are several different approaches to the
treatment of cerebral edema. Diuretics are a primary
treatment. Diuretics decrease the volume of the
intravascular space, in turn drawing fluid out of the
extracellular space. Mannitol and other osmotics
increase the osmolarity of the intravascular space,
increasing the ability to draw fluid into the vascular
space from the brain. Mannitol is excluded from CSF
more efficiently and therefore is used more exten-
sively. Mannitol also lowers blood viscosity, improv-
ing oxygen delivery and allowing vasoconstriction,
which lowers intracranial pressure. Diuretics such as
furosemide can also be used to induce diuresis and
natriuresis, thereby decreasing edema. Corticoste-
roids are most effective in treating vasogenic edema
related to tumors. They are less effective in treating
edema resulting from trauma or ischemia. The
mechanism of action of steroids in treating vasogenic
edema is not fully understood. They are believed to
primarily reduce tumor permeability, but they also
may directly stabilize brain capillaries or increase the
resistance of the surrounding white matter to the
spread of protein. Maintenance of cerebral blood
flow and oxygen delivery to brain tissue are also
important factors in treating edema to limit further
cellular anoxia. For severe edema with mass effect
606 CEREBRAL HEMISPHERIC INTERACTIONS
causing decreased level of consciousness, CSF drain-
age via a ventriculostomy may be needed.
Untreated edema can have several negative effects.
The presence of the additional water can cause
significant mass effect and injure adjacent cells. For
example, edema within or adjacent to the primary
motor cortex may cause arm or leg weakness by
impairing the function of primary motor neurons.
The increased fluid also acts as an additional mass
within the fixed skull. It can globally increase
intracranial pressure and manifest as changes in
cognition, level of consciousness, or, ultimately, brain
herniation and death. Edema may also compromise
regional cerebral microcirculation and blood flow,
causing further cellular anoxia and compounding
cytotoxic edema.
—Wendy Elder and Robert F. Spetzler
See also–Brain Injury, Traumatic; Brain Ischemic
Edema; Cerebral Metabolism and Blood Flow;
Head Trauma, Overview; Hydrocephalus
Further Reading
Black, K. (1996). Blood–brain barrier. In Youmans’ Neurological
Surgery (J. R. Youmans, Ed.), 4th ed., pp. 482–490. Saunders,
Philadelphia.
Hariri, R. J. (1994). Cerebral edema. Neurosurg. Clin. North Am.
5, 687–706.
Liau, L. M., Bergsneider, M., and Becker, D. P. (1996). Pathology
and pathophysiology of head injury. In Youmans’ Neurological
Surgery (J. R. Youmans, Ed.), 4th ed., pp. 1549–1594.
Saunders, Philadelphia.
Steen, S. N., and Zelman, V. (1996). Neuroanesthesia. In
Youmans’ Neurological Surgery (J. R. Youmans, Ed.), 4th ed.,
pp. 709–723. Saunders, Philadelphia.
Victor, V., and Ropper, A. H. (2001). Adams and Victor’s
Principles of Neurology. McGraw-Hill, New York.
Cerebral Hemispheric
Interactions
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TWO SIDES of the brain look very much like
mirror images of one another, but they function in
surprisingly different ways. This was not widely
appreciated until the 1860s, when Paul Broca
discovered that damage to the third convolution of
the left frontal lobe, now known as Broca’s area,
disrupts speech but leaves nonspeech movements of
the articulators unaffected. Soon afterward, Carl
Wernicke discovered that damage to a region around
the juncture of the parietal, temporal, and occipital
lobes, again usually in the left hemisphere, results in
deficits in comprehension. People with damage in
this area, known as Wernicke’s area, can often speak
fluently and grammatically but what they say makes
little sense. These and other language deficits caused
by brain damage are known as aphasias. The one-
time notion of Broca’s area as concerned with the
production of speech and Wernicke’s area with the
comprehension of speech has been modified by the
discovery that damage to Broca’s area may affect
both the production and comprehension of gramma-
tical structure. Studies based on cerebral blood flow
patterns in normal people confirm that these areas
are involved in both spoken and written language but
show that other areas, notably in the temporal lobe,
are also critically involved and that there is
considerable variability between individuals. Despite
conflicting evidence, what remains clear is that
propositional language is very largely a function of
the left hemisphere.
The role of the left hemisphere in language was
confirmed in studies of people with surgical section
of the corpus callosum and in some cases of the
other forebrain commissures as well. This so-called
‘‘split-brain’’ operation is sometimes carried out for
the relief of intractable, multifocal epilepsy. If a
word or a picture of an object is flashed to the left of
where a person is looking, it is relayed via
retinocortical pathways to the right side of the brain
and split-brained people are usually unable to say
what they have seen, presumably because the
information has no access to the speech centers on
the left. If the information is flashed to the right of
fixation it is relayed to the left hemisphere, and split-
brained people then have little trouble naming it.
Similarly, split-brained people are typically unable to
name objects placed in the left hand (but out of
view) but have little difficulty with objects in the
right hand.
Curiously, split-brained people may show compre-
hension of words to the left of visual fixation,
suggesting that the right hemisphere has some
capacity for receptive language. This seems to
contradict the extreme lack of comprehension that
often follows damage to the left hemisphere. One
possibility is that split-brained people are atypical in
having developed a right-hemispheric capacity for
comprehension. Another is that the right hemisphere
does normally have some capacity to comprehend
606 CEREBRAL HEMISPHERIC INTERACTIONS
causing decreased level of consciousness, CSF drain-
age via a ventriculostomy may be needed.
Untreated edema can have several negative effects.
The presence of the additional water can cause
significant mass effect and injure adjacent cells. For
example, edema within or adjacent to the primary
motor cortex may cause arm or leg weakness by
impairing the function of primary motor neurons.
The increased fluid also acts as an additional mass
within the fixed skull. It can globally increase
intracranial pressure and manifest as changes in
cognition, level of consciousness, or, ultimately, brain
herniation and death. Edema may also compromise
regional cerebral microcirculation and blood flow,
causing further cellular anoxia and compounding
cytotoxic edema.
—Wendy Elder and Robert F. Spetzler
See also–Brain Injury, Traumatic; Brain Ischemic
Edema; Cerebral Metabolism and Blood Flow;
Head Trauma, Overview; Hydrocephalus
Further Reading
Black, K. (1996). Blood–brain barrier. In Youmans’ Neurological
Surgery (J. R. Youmans, Ed.), 4th ed., pp. 482–490. Saunders,
Philadelphia.
Hariri, R. J. (1994). Cerebral edema. Neurosurg. Clin. North Am.
5, 687–706.
Liau, L. M., Bergsneider, M., and Becker, D. P. (1996). Pathology
and pathophysiology of head injury. In Youmans’ Neurological
Surgery (J. R. Youmans, Ed.), 4th ed., pp. 1549–1594.
Saunders, Philadelphia.
Steen, S. N., and Zelman, V. (1996). Neuroanesthesia. In
Youmans’ Neurological Surgery (J. R. Youmans, Ed.), 4th ed.,
pp. 709–723. Saunders, Philadelphia.
Victor, V., and Ropper, A. H. (2001). Adams and Victor’s
Principles of Neurology. McGraw-Hill, New York.
Cerebral Hemispheric
Interactions
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TWO SIDES of the brain look very much like
mirror images of one another, but they function in
surprisingly different ways. This was not widely
appreciated until the 1860s, when Paul Broca
discovered that damage to the third convolution of
the left frontal lobe, now known as Broca’s area,
disrupts speech but leaves nonspeech movements of
the articulators unaffected. Soon afterward, Carl
Wernicke discovered that damage to a region around
the juncture of the parietal, temporal, and occipital
lobes, again usually in the left hemisphere, results in
deficits in comprehension. People with damage in
this area, known as Wernicke’s area, can often speak
fluently and grammatically but what they say makes
little sense. These and other language deficits caused
by brain damage are known as aphasias. The one-
time notion of Broca’s area as concerned with the
production of speech and Wernicke’s area with the
comprehension of speech has been modified by the
discovery that damage to Broca’s area may affect
both the production and comprehension of gramma-
tical structure. Studies based on cerebral blood flow
patterns in normal people confirm that these areas
are involved in both spoken and written language but
show that other areas, notably in the temporal lobe,
are also critically involved and that there is
considerable variability between individuals. Despite
conflicting evidence, what remains clear is that
propositional language is very largely a function of
the left hemisphere.
The role of the left hemisphere in language was
confirmed in studies of people with surgical section
of the corpus callosum and in some cases of the
other forebrain commissures as well. This so-called
‘‘split-brain’’ operation is sometimes carried out for
the relief of intractable, multifocal epilepsy. If a
word or a picture of an object is flashed to the left of
where a person is looking, it is relayed via
retinocortical pathways to the right side of the brain
and split-brained people are usually unable to say
what they have seen, presumably because the
information has no access to the speech centers on
the left. If the information is flashed to the right of
fixation it is relayed to the left hemisphere, and split-
brained people then have little trouble naming it.
Similarly, split-brained people are typically unable to
name objects placed in the left hand (but out of
view) but have little difficulty with objects in the
right hand.
Curiously, split-brained people may show compre-
hension of words to the left of visual fixation,
suggesting that the right hemisphere has some
capacity for receptive language. This seems to
contradict the extreme lack of comprehension that
often follows damage to the left hemisphere. One
possibility is that split-brained people are atypical in
having developed a right-hemispheric capacity for
comprehension. Another is that the right hemisphere
does normally have some capacity to comprehend

but is inhibited by the left. This inhibition would be
disconnected in the split brain.
Besides being specialized for language, the left
hemisphere also exerts control over the right hand,
which is for most people the preferred hand for a
wide variety of activities. Damage to the left hemi-
sphere may also result in apraxia, which is a deficit in
making skilled movements that typically affects both
hands as well as other parts of the body, including
the face. Apraxia is often associated with aphasia but
may occur independently of it. Because of its role in
language, handedness, and skilled action, the left
hemisphere was long regarded as the dominant or
major hemisphere. This terminology is now consid-
ered outmoded largely because it is well documented
that the right has specialties of its own. It even
appears to contribute more than the left to some
aspects of language, notably those that might be
considered nonpropositional. Studies based on the
effects of unilateral brain lesions, the split brain, and
functional imaging of the normal brain suggest that
the right hemisphere may be more proficient in
processing prosody, which refers to the intonational
pattern of speech, such as whether the speaker is
angry or happy or whether an utterance is a question,
a command, or a statement. The right hemisphere
may also be more adept at detecting metaphor or
irony. However, the fundamental properties that
identify language as a uniquely human accomplish-
ment—namely, phonology and syntax, which to-
gether comprise grammar—are largely if not
exclusively under the control of the left hemisphere.
There are other respects in which the right
hemisphere appears to function more effectively than
the left. The most striking example is spatial
attention. People with damage to the right hemi-
sphere often exhibit left hemineglect, in which they
ignore information on the left side of space. They
may bump into things on the left, fail to eat from the
left side of the plate, refuse to talk to or acknowledge
people on the left, and fail to dress the left side of
their own bodies. In marked contrast, people with
left-hemispheric damage seldom show right-sided
hemineglect, and if they do it is usually transient.
This suggests that the right side of the brain is
responsible for directing attention to both sides of
space, whereas the left side can direct attention only
to the right side.
The right hemisphere may also be superior to the
left in spatial orientation, perception of nonverbal
sounds, and the perception and expression of
emotion. Some studies show it to be the more
CEREBRAL HEMISPHERIC INTERACTIONS 607
specialized for music, although there is also evidence
that the left hemisphere is dominant for music in
professional musicians, perhaps because they under-
stand music in more ‘‘linguistic’’ fashion. There is a
popular view that the two hemispheres are somehow
complementary, or even opposites, in their ways of
perception and thought. Thus, the left hemisphere is
often characterized as linear, analytical, and rational
and the right as divergent, holistic, intuitive, and
more creative than its supposedly rather dull partner.
Such views are grossly exaggerated. The two sides of
the brain are too similar anatomically and physiolo-
gically to give rise to opposite ways of processing,
and many supposedly right-hemispheric advantages
are small and evanescent. Even face recognition,
often considered a prototypically holistic perceptual
process, appears to depend on bilateral mechanisms,
although some studies suggest a slight right-hemi-
spheric bias. Another prototypically holistic, spatial
process is mental rotation—the ability to imagine
shapes rotating in two- or three-dimensional space.
Although some studies suggest a right-hemispheric
advantage for mental rotation, others suggest bilat-
eral processing, and some even suggest that the left
hemisphere is the more actively involved. As
discussed later, some tasks may involve cooperation
between the hemispheres.
It is also clear that the right hemisphere can ‘‘take
over’’ language functions if the left hemisphere is
incapacitated early in life. In a recent case, a boy
suffering from Sturge–Weber syndrome, a congenital
brain disorder, underwent removal of the left hemi-
sphere at age 812 and thereafter rapidly acquired
language with apparently normal syntax. This
suggests that so-called equipotentiality between the
hemispheres for language may continue at least until
middle childhood, but beyond the age of puberty
there is little evidence that the right hemisphere can
compensate in this fashion. In this case, as in others,
the right-hemispheric takeover of language occurred
at the expense of spatial abilities normally associated
with that hemisphere. Hemispheric differences are
therefore somewhat malleable, especially early in
life, and probably depend more on programmed
differences in growth rate between the two sides of
the brain than on ‘‘hard wiring.’’
Not all people show the pattern of cerebral
asymmetry outlined previously. It was once thought
that left-handers would show the reverse pattern,
with speech and prepositional language represented
in the right hemisphere. In fact, the relation to
handedness is more complex. Nearly all right-
608 CEREBRAL HEMISPHERIC INTERACTIONS
handers (probably more than 95%) do show this
pattern, but left-handers are more mixed. Approxi-
mately 70% of left-handers are left-cerebrally
dominant for speech, whereas the remaining 30%
seem to be about equally divided between those with
right-hemispheric dominance and those with bilat-
eral representation of speech. These and other facts
are largely consistent with a simple genetic model in
which both handedness and cerebral asymmetry are
influenced by a single gene locus, with one ‘‘dextral’’
allele (D) specifying right-handedness and left
cerebral speech dominance and one ‘‘chance’’ allele
(C) leaving the direction of both asymmetries to
chance. According to this model, DD homozygotes
will all be right-handed and left cerebrally dominant
for speech, CD heterozygotes have approximately a
75% chance of being right-handed and left cerebrally
dominant, whereas in CC homozygotes all combina-
tions are equally possible. This model remains just
that—a model—but nevertheless captures many of
the facts about variations in cerebral and manual
asymmetry and their inheritance.
Much of the emphasis in research on the cerebral
hemispheres has been on their different functions and
on how they function in isolation. Certainly, the
relatively normal everyday behavior of split-brained
people suggests that the two sides of the brain can
function largely independently, as though they were
separate ‘‘minds.’’ Nevertheless, they are not com-
pletely separated, even in the split brain, since
subcortical commissures, such as those connecting
the colliculi and the two sides of the cerebellum,
remain intact. Subcortical connections allow at least
some integration of the two sides of visual space. For
example, split-brained people can direct attention to
locations on one side of space depending on
information presented on the other side, they can
judge whether tilted lines on the two sides of space
are aligned or not, and if a dot appears on one side
followed by a dot on the other side they see apparent
motion across the midline. Such activities may
operate with less precision than normally, but they
do at least indicate a subcortical component inte-
grating relatively low-level aspects of vision across
the two sides of visual space. At least one split-
brained man successfully drives a vehicle. However,
with even only slightly more complex tasks, there is
virtually no integration. Split-brained people usually
cannot determine whether colors, or even simple
shapes such as letters or geometric forms, are the
same or different if they are shown on opposite sides
of space.
In normal people, cooperation between the hemi-
spheres can be examined by asking whether certain
tasks are better performed when the information is
contained within a hemisphere or spread between
hemispheres. This depends on the complexity of the
task. There is no advantage gained by spreading the
information between hemispheres if the task is
simple, but there is an advantage to sharing when
the task is complex. For example, if a person is asked
to decide whether a letter on the bottom of a screen is
exactly the same as one or the other of two letters on
the top, it makes little difference whether the
matching letter is on the same side of space or the
opposite side of space as the bottom letter. However,
if the task is made more difficult, for example, by
having the upper letters in uppercase and the lower
letter in lowercase and asking the viewer to match by
name rather than by shape, then the matching is
faster across the sides of space and thus between
hemispheres. Functional neuroimaging studies have
also shown that there is more bilateral activity when
people perform complex tasks than when they
perform simple ones.
Following Broca’s discoveries of the 1860s, there
was immense interest in hemispheric asymmetry,
leading to exaggerated theories and bizarre therapies
for the relief of disorders thought to result from
hemispheric imbalance. This eventually led to a loss
of credibility, and interest died away rapidly after the
turn of the century. History repeated itself in the
1960s following Sperry’s pioneering work on the
split brain; once again, exaggerated theories entered
into folklore, influencing therapeutic practices, edu-
cation, and even business. Today, it is hoped that we
can retain a balanced perspective on how the two
hemispheres of the brain actually work.
—Michael C. Corballis
See also–Broca’s Area; Handedness;
Hemispherectomy; Language, Overview;
Localization; Wernicke’s Area
Further Reading
Corballis, M. C. (1991). The Lopsided Ape. Oxford Univ. Press,
New York.
Corballis, M. C. (1995). Visual integration in the split brain.
Neuropsychologia 33, 937–959.
Corballis, M. C. (1999). Are we in our right minds? In Mind
Myths (S. Della Sala, Ed.), pp. 26–41. Wiley, Chichester, UK.
Gazzaniga, M. S. (Ed.) (2000). The New Cognitive Neurosciences,
pp. 949–958. MIT Press, Cambridge, MA.
Harrington, A. (1987). Medicine, Mind, and the Double Brain.
Princeton Univ. Press, Princeton, NJ.

McManus, I. C. (1999). Handedness, cerebral lateralization, and
the evolution of language. In The Descent of Mind (M. C.
Corballis and S. E. G. Lea, Eds.), pp. 194–217. Oxford Univ.
Press, Oxford.
Vallar, G. (1998). Spatial hemineglect in humans. Trends Cognitive
Sci. 2, 87–96.
Vargha-Khadem, F., Carr, L. J., Isaacs, E., et al. (1997). Onset of
speech after left hemispherectomy in a nine-year-old boy. Brain
120, 159–182.
Cerebral Metabolism and
Blood Flow
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
QUANTITATIVE determinations of cerebral blood flow
(CBF) and metabolism in man were first accom-
plished in 1948 by means of the nitrous oxide (N2O)
method of Kety and Schmidt. Although originally
designed and most frequently used for human
subjects, it has been adapted and used in animals as
well. The method, which is based on the Fick
principle, originally utilized low concentrations of
N2O as the tracer because it is a chemically inert gas
that diffuses freely across the blood–brain barrier
and can be easily measured in blood. However, there
have been modifications that use other inert gases
(e.g., hydrogen and the radioactive gases 79krypton,
85
krypton, and 133xenon). It is the N2O method and
its modifications that have provided much of our
knowledge of the circulation and metabolism of the
human brain in health and disease.
NORMAL RATES OF CEREBRAL BLOOD
FLOW AND METABOLISM IN MAN
CBF in normal, conscious, young adult men is
approximately 57 ml/100 g/min or 800 ml/min for
an average brain of 1400 g (Table 1). This high rate
of blood flow is needed to support the brain’s
comparably high rate of energy metabolism. Cere-
bral oxygen consumption (CMRO2) in these young
men is approximately 3.5 ml/100 g brain/min or
approximately 49 ml O2 per minute for the whole
brain (Table 1). This is an energy consumption
approximately equivalent to that of a 20-W bulb.
Therefore, the brain, which represents only approxi-
mately 2% of total body weight in normal young
adult men, takes approximately 15% of the total
resting cardiac output and consumes approximately
CEREBRAL METABOLISM AND BLOOD FLOW 609
Table 1 CEREBRAL BLOOD FLOW, OXYGEN CONSUMPTION,
AND GLUCOSE UTILIZATION IN NORMAL, CONSCIOUS,
YOUNG ADULT MEN
Per 100 grams Per whole
Function of brain tissue brain (1400 g)
Cerebral blood flow 57 798
(ml/min)
Cerebral O2 3.5 49
consumption (ml/min)
Cerebral glucose 31 434
utilization (mmol/min)
20% of the total resting body oxygen consumption.
In children, the brain comprises a much larger
fraction of total body weight and consumes an even
larger fraction of the total resting body O2 con-
sumption—as much as 50% in the middle of the first
decade of life. The substrate for this very high rate of
O2 consumption is normally almost exclusively
glucose. The brain has no respite from this enormous
energy demand. Cerebral energy metabolism con-
tinues unabated day and night, even during sleep.
Cerebral metabolic rate is reduced in slow wave sleep
by no more than approximately 20–30% and may
actually be increased during rapid eye movement
sleep.
Because the stores of O2 and glucose in the brain
are small compared to their rates of consumption,
brain function is absolutely dependent on a con-
tinuously uninterrupted replenishment of these sub-
strates by the circulation. Complete interruption of
the CBF results within seconds in loss of conscious-
ness and within minutes in irreversible pathological
changes in the brain. In cardiac arrest, for example,
brain damage is the critical factor in determining the
likelihood and extent of recovery. Lesser degrees of
cerebral circulatory insufficiency also lead relatively
rapidly to permanent brain damage, particularly in
vulnerable areas such as the CA1 region of the
hippocampus. Fortunately, the physiological me-
chanisms that regulate the CBF appear to have been
designed to preserve an adequate CBF, even under
conditions in which perfusion of other tissues may be
jeopardized.
SUBSTRATES OF CEREBRAL
ENERGY METABOLISM
In contrast to most other tissues, which exhibit
considerable flexibility with respect to the foodstuffs

McManus, I. C. (1999). Handedness, cerebral lateralization, and
the evolution of language. In The Descent of Mind (M. C.
Corballis and S. E. G. Lea, Eds.), pp. 194–217. Oxford Univ.
Press, Oxford.
Vallar, G. (1998). Spatial hemineglect in humans. Trends Cognitive
Sci. 2, 87–96.
Vargha-Khadem, F., Carr, L. J., Isaacs, E., et al. (1997). Onset of
speech after left hemispherectomy in a nine-year-old boy. Brain
120, 159–182.
Cerebral Metabolism and
Blood Flow
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
QUANTITATIVE determinations of cerebral blood flow
(CBF) and metabolism in man were first accom-
plished in 1948 by means of the nitrous oxide (N2O)
method of Kety and Schmidt. Although originally
designed and most frequently used for human
subjects, it has been adapted and used in animals as
well. The method, which is based on the Fick
principle, originally utilized low concentrations of
N2O as the tracer because it is a chemically inert gas
that diffuses freely across the blood–brain barrier
and can be easily measured in blood. However, there
have been modifications that use other inert gases
(e.g., hydrogen and the radioactive gases 79krypton,
85
krypton, and 133xenon). It is the N2O method and
its modifications that have provided much of our
knowledge of the circulation and metabolism of the
human brain in health and disease.
NORMAL RATES OF CEREBRAL BLOOD
FLOW AND METABOLISM IN MAN
CBF in normal, conscious, young adult men is
approximately 57 ml/100 g/min or 800 ml/min for
an average brain of 1400 g (Table 1). This high rate
of blood flow is needed to support the brain’s
comparably high rate of energy metabolism. Cere-
bral oxygen consumption (CMRO2) in these young
men is approximately 3.5 ml/100 g brain/min or
approximately 49 ml O2 per minute for the whole
brain (Table 1). This is an energy consumption
approximately equivalent to that of a 20-W bulb.
Therefore, the brain, which represents only approxi-
mately 2% of total body weight in normal young
adult men, takes approximately 15% of the total
resting cardiac output and consumes approximately
CEREBRAL METABOLISM AND BLOOD FLOW 609
Table 1 CEREBRAL BLOOD FLOW, OXYGEN CONSUMPTION,
AND GLUCOSE UTILIZATION IN NORMAL, CONSCIOUS,
YOUNG ADULT MEN
Per 100 grams Per whole
Function of brain tissue brain (1400 g)
Cerebral blood flow 57 798
(ml/min)
Cerebral O2 3.5 49
consumption (ml/min)
Cerebral glucose 31 434
utilization (mmol/min)
20% of the total resting body oxygen consumption.
In children, the brain comprises a much larger
fraction of total body weight and consumes an even
larger fraction of the total resting body O2 con-
sumption—as much as 50% in the middle of the first
decade of life. The substrate for this very high rate of
O2 consumption is normally almost exclusively
glucose. The brain has no respite from this enormous
energy demand. Cerebral energy metabolism con-
tinues unabated day and night, even during sleep.
Cerebral metabolic rate is reduced in slow wave sleep
by no more than approximately 20–30% and may
actually be increased during rapid eye movement
sleep.
Because the stores of O2 and glucose in the brain
are small compared to their rates of consumption,
brain function is absolutely dependent on a con-
tinuously uninterrupted replenishment of these sub-
strates by the circulation. Complete interruption of
the CBF results within seconds in loss of conscious-
ness and within minutes in irreversible pathological
changes in the brain. In cardiac arrest, for example,
brain damage is the critical factor in determining the
likelihood and extent of recovery. Lesser degrees of
cerebral circulatory insufficiency also lead relatively
rapidly to permanent brain damage, particularly in
vulnerable areas such as the CA1 region of the
hippocampus. Fortunately, the physiological me-
chanisms that regulate the CBF appear to have been
designed to preserve an adequate CBF, even under
conditions in which perfusion of other tissues may be
jeopardized.
SUBSTRATES OF CEREBRAL
ENERGY METABOLISM
In contrast to most other tissues, which exhibit
considerable flexibility with respect to the foodstuffs
610 CEREBRAL METABOLISM AND BLOOD FLOW
they extract and consume from the blood, the brain
is normally restricted almost exclusively to glucose
as its substrate for energy metabolism. In steady-
state conditions glucose and O2 are consumed in
near stoichiometric amounts for the complete
oxidation of glucose to CO2 and H2O (Table 2).
The normal brain in the conscious human consumes
O2 and produces CO2 at rates of approximately 156
mmol/100 g tissue/min. The cerebral respiratory
quotient (RQ) is therefore close to 1.0, indicating
that carbohydrate is the substrate for oxidative
metabolism. Inasmuch as complete oxidation of
glucose to CO2 and H2O consumes 6 mmol of O2
and produces 6 mmol of CO2 per mmole of glucose,
the brain’s rates of O2 consumption and CO2
production are equivalent to a rate of complete
oxidation of glucose of 26 mmol/100 g tissue/min.
The measured cerebral glucose utilization (CMRglc),
however, is approximately 31 mmol/100 g/min,
indicating that CMRglc is not only sufficient to
account for all of the brain’s O2 consumption and
CO2 production but also exceeds it by 5 mmol/100
g/min or approximately 20%. This excess glucose
consumption lowers the molar ratio of O2 con-
sumption to glucose utilization from one of com-
plete stoichiometry (i.e., 6.0) to 5.5. The fate of the
excess glucose is unknown, but obviously the brain
cannot continuously accumulate the excess carbon
atoms indefinitely. Some of these carbon atoms are
distributed among the many intermediates and
products of glucose metabolism, some of which
may be released from the brain into the blood in
insufficient amounts to be detected in the cerebral
arteriovenous differences. Some glucose must also
be utilized not for production of energy but for
synthesis of various chemical constituents of the
Table 2 RELATIONSHIP BETWEEN CEREBRAL OXYGEN
CONSUMPTION AND GLUCOSE UTILIZATION IN NORMAL,
CONSCIOUS, YOUNG ADULT MEN
Function
O2 consumption (mmol/100 g of tissue/min)
Glucose utilization (mmol/100 g of tissue/min)
O2/glucose ratio (mol/mol)
Glucose equivalent of O2 consumption (mmol/100 g
tissue/min), assuming 6 mol O2 per mole of
glucose
CO2 production (mmol/100 g of tissue/min)
Cerebral respiratory quotient
n
Values are means of individual ratios and not ratios of means.
brain. Also, some oxygen is utilized for the
oxidation of substances not derived from glucose
(e.g., the synthesis and metabolic degradation of
monoamine neurotransmitters), but the amount of
oxygen utilized for these processes is extremely
small and undetectable in the presence of the
enormous oxygen consumption used for carbohy-
drate oxidation.
A cerebral RQ of unity, an almost complete
stoichiometry between CMRO2 and CMRglc, and
the absence of significant cerebral arteriovenous
differences for any other energy-rich substrates
provide strong evidence that the brain normally
derives its energy from oxidative glucose metabo-
lism. This does not imply that glucose is oxidized,
like in combustion, directly to CO2 and H2O. Many
chemical transformations occur between the uptake
of the substrates, glucose and O2, and the liberation
of their end products, CO2 and H2O. Various
compounds derived from glucose are intermediates
in the process. Glucose carbon is incorporated into
other carbohydrates, amino acids, protein, lipids,
glycogen, etc., all of which are turned over and are
intermediates in the overall pathway from glucose to
CO2 and H2O. The CO2 being produced at any
moment is not derived directly from the glucose
entering the brain at that time but from the metabolic
intermediates derived from glucose taken up pre-
viously. The facts that O2 and glucose are consumed
and CO2 produced in almost stoichiometric balance
and that uptake from the blood of any other energy-
laden substrates is negligible mean that the net
energy made available to the brain must ultimately
be derived from oxidative glucose metabolism. It
should be noted that this situation holds only during
normal steady states. In non-steady states the
different time courses of the pathways of glucose
and O2 metabolism may be temporally dissociated
and the stoichiometry between CMRO2 and CMRglc
temporarily disrupted. Also, as discussed later, there
are special circumstances or abnormal states, such as
Value
ketosis, in which other substrates may partially
replace glucose as the substrate for the brain’s
156 oxidative metabolism.
31 Not only does the brain prefer glucose as it energy
5.5n source but also it is obligatorily dependent on its
26 oxidative metabolism. Most other tissues are largely
facultative in their choice of substrates and can use
them interchangeably more or less in proportion to
156
their availability. In the brain, however, except for
0.97n
some unusual and special circumstances, only the
aerobic utilization of glucose is capable of providing

sufficient energy to maintain normal cerebral func-
tion and structure. For example, hypoxemia of
sufficient degree rapidly results in aberrations of
cerebral function, even to the point of unconscious-
ness. Similarly, cerebral glucose deprivation pro-
duced by hypoglycemia or blockade of glycolysis
with pharmacological doses of 2-deoxyglucose is
associated with changes in mental state ranging from
mild, subjective sensory disturbances to coma, with
the severity depending on both the degree and the
duration of the hypoglycemia. The behavioral effects
in hypoglycemia are paralleled by abnormalities in
electroencephalograph (EEG) patterns and CMRO2.
The EEG exhibits increased prominence of slow,
high-voltage delta rhythms, and CMRO2 and
CMRglc decline. CMRglc declines more than CMRO2
so that there is no longer any stoichiometric relation-
ship between them, but the cerebral RQ remains
approximately 1.0, indicating that other carbohy-
drates, presumably derived from the brain’s endo-
genous stores, are the substrates for the brain’s
oxidative metabolism. These changes in brain func-
tion and metabolism are not due to insufficient CBF,
which is, in fact, markedly increased in hypoxemia,
hypoglycemia, and during blockade of glycolysis by
loading doses of 2-deoxyglucose.
Hypoglycemic coma provides a convenient test
condition for identifying substances that can sub-
stitute for glucose as a substrate for the brain’s
energy metabolism. An effective substrate, when
administered during hypoglycemic coma, should
restore normal consciousness and EEG without
raising the blood glucose level. Numerous potential
substrates have been tested in humans and animals,
but few have been found to restore normal brain
functions in hypoglycemia. Of those that have, all
but one did so not by serving directly as a substrate
for the brain’s energy metabolism but rather by
raising blood glucose levels. The one exception is
mannose, which can traverse the blood–brain barrier,
be phosphorylated to mannose-6-phosphate by
hexokinase, and enter the glycolytic pathway
through conversion to fructose-6-phosphate by
phosphomannose isomerase, an enzyme present in
brain tissue. However, normally there is little, if any,
mannose in blood. Maltose, epinephrine, glutamate,
arginine, glycine, r-aminobenzoate, and succinate
can occasionally restore normal behavior and EEG
activity in hypoglycemia, but they do so by raising
blood glucose levels through a variety of mechan-
isms, in some cases by mobilizing glucose from liver
glycogen secondary to stimulation of epinephrine
CEREBRAL METABOLISM AND BLOOD FLOW 611
release from the adrenal medulla. It should be noted
that failure of parenteral administration of a
substance to restore normal cerebral function in
hypoglycemia does not exclude the brain’s ability to
utilize it. Many substances tested and found to be
ineffective are compounds normally formed and/or
metabolized within the brain and may be normal
intermediates in its intermediary metabolism. For
example, lactate, pyruvate, fructose-1,6-bispho-
sphate, acetate, d-b-hydroxybutyrate, and acetoace-
tate can all be utilized by brain slices, homogenates,
or cell-free fractions, and adequate enzyme levels for
their metabolism are present in brain tissue, but they
are not available to brain tissue because of inade-
quate blood levels or restricted blood–brain barrier
transport. Glycerol and ethanol can cross the barrier
relatively freely, but the enzyme levels needed for
their metabolism are insufficient in the brain. In
summary, cerebral function in vivo depends on
substrates supplied by the blood, but no normally
available endogenous substitute for glucose has been
found. Glucose must therefore be considered essen-
tial for normal physiological behavior of the central
nervous system.
There are special circumstances in which the brain
may, at least in part, satisfy its nutritional needs with
substrates other than glucose. Normally, the blood
levels of the ketone bodies d-b-hydroxybutyrate and
acetoacetate are low, but they are elevated in ketotic
states, such as those associated with high fat
ingestion, enhanced fatty acid metabolism, diabetes,
and starvation. In such circumstances, the brain can
utilize ketone bodies in more or less direct proportion
to their blood levels. Cerebral ketone body utilization
is also normal in the neonatal period because new-
born infants tend to be hypoglycemic but become
ketotic while nursing mother’s milk with a high fat
content. When weaned onto normal diets, the ketosis
and cerebral ketone utilization disappear. It should be
noted, however, that the ketone bodies are incapable
of maintaining or restoring normal cerebral function
in hypoglycemic coma, suggesting that they can only
partially replace glucose but cannot by themselves
fully satisfy the brain’s energy needs.
REGULATION OF CEREBRAL BLOOD FLOW
AND METABOLISM
Regulation of the Cerebral Circulation
The mechanisms of regulation of CBF are well suited
to serve the brain’s unique metabolic demands. As in
612 CEREBRAL METABOLISM AND BLOOD FLOW
all vascular beds, blood flow to the brain depends on
two opposing variables: the blood pressure gradient
providing the force to drive the blood through the
blood vessels and the cerebrovascular resistance
(CVR), which is the net effect of all the factors
impeding the flow of blood through the vascular bed.
CVR is computed as the ratio of pressure gradient to
blood flow (i.e., the pressure needed to push a unit of
blood through the brain per unit time).
The cerebral blood pressure gradient equals the
difference between mean arterial blood pressure
(MABP) at the head level and the cerebral venous
pressure. Because cerebral venous pressure (normally
0.5 mmHg) is low compared to MABP, it generally
exerts negligible influence on the pressure gradient
and on CBF, except in congestive heart disease when
central venous pressure, and therefore also cerebral
venous pressure, may increase sufficiently to lower
CBF. Also, in cerebrovascular disease, when CBF
may already be marginal, abrupt increases in venous
pressure during straining or Valsalva-like maneuvers
may precipitate symptoms of cerebrovascular insuf-
Figure 1
Schema of the multiple factors regulating cerebral blood flow.
ficiency. MABP at the head level is normally
zealously guarded by intrinsic circulatory reflexes
of the baroreceptor type such as the carotid sinus
reflex, which tends to stabilize MABP at the head
level without altering CVR and thus maintains a
relatively constant CBF. However, when the capacity
of these reflexes is exceeded and MABP is altered, the
tone of the cerebral vessels and CVR are adjusted to
counteract the effects of the altered pressure gradient
and thus maintain a relatively constant CBF in the
face of fairly wide changes in MABP. This phenom-
enon is known as autoregulation. Ultimately, when
MABP decreases from its usual level of approxi-
mately 90 mmHg to a critical level between 50 and
70 mmHg, CBF tends to decrease and signs and
symptoms of cerebrovascular insufficiency appear.
When MABP declines below 35 mmHg, CBF
decreases from its normal level of 50–60 to
approximately 30 ml/100 g/min, a level inadequate
to maintain consciousness.
Over a wide range of MABP, CBF is regulated by
the cerebrovascular resistance, which encompasses

all the factors that affect the resistance to the flow of
blood through the cerebral vessels (Fig. 1), including
static physical factors and the more dynamically
regulated tone of the cerebral vessels. Many of these
are shown in Fig. 1. Much of the CVR is due to the
frictional resistance to flow of blood in the cerebral
vessels, and this is markedly influenced by size and
morphological state of the vessels (e.g., their
diameters). When they are narrowed by vascular
disease such as arteriosclerosis, CVR is increased and
CBF is reduced.
Within the limits imposed on them by their
morphological state, the cerebral vessels can alter
their size and tone and allow dynamic regulation of
CBF to meet changing needs of the brain. The
mechanisms of this regulation are not fully defined,
but many factors that influence the caliber and tone
of the cerebral vessels have been identified. It is
almost certain that the dynamic regulation of the
cerebral circulation is not mediated by a single
exclusive mechanism but is achieved by numerous
factors acting in concert (Fig. 1).
The role of neurogenic regulation of cerebrovas-
cular tone is undefined. Dural, pial, and intracerebral
vessels have nerve supplies, and myelinated and
unmyelinated fibers and perivascular adrenergic,
cholinergic, and peptidergic nerves are found on
intracerebral arterioles as small as 15–20 mm in
diameter. However, their role in the regulation of
CBF remains unclear.
Dynamic regulation of cerebrovascular tone is
probably achieved mainly by chemical factors
(Fig. 1). The respiratory gases exert greater influ-
ence on CVR and CBF than any other agents or
means of physiological significance. Increased
blood pCO2, produced by inhalation of CO2
dilates cerebral vessels and markedly increases
CBF, and reduced arterial pCO2 produced by
hyperventilation constricts the cerebral vessels
and lowers CBF. Somewhat less effective, but still
quite marked, are the effects of alteration in
arterial pO2. Reduced blood pO2 dilates cerebral
vessels and increases CBF, and increased arterial
pO2 has small opposite effects that may be indirect
and secondary to the hyperpnea and hypocapnia
often associated with breathing high-oxygen gas
mixtures. Blood and tissue pH also influence
cerebral vascular tone; acids dilate and bases
constrict cerebral vessels, and some of the effects
of CO2 may be due to effects on pH.
Increased pCO2 and reduced pO2 and pH are to
be expected in tissues when their energy metabolism
CEREBRAL METABOLISM AND BLOOD FLOW 613
is stimulated, and all these dilate the cerebral
vessels. In contrast, when altered in the opposite
direction, to be expected with decreased energy
metabolism, they constrict the cerebral vessels. This
has led to the popular hypothesis that CBF is
adjusted to meet the demands of the local cerebral
energy metabolism by chemical regulation of
cerebrovascular tone mediated by these metabolic
products. Although pCO2, pO2, and pH contribute,
they are almost certainly not the sole mediators of
the adjustment of CBF to functional activity. There
are numerous other chemical factors related to
energy metabolism and/or functional activity that
may contribute. Some of those reported to influence
CBF are shown in Fig. 1.
Regulation of Cerebral Energy Metabolism
In normal physiological conditions, when CBF and
glucose and O 2 supplies to the brain are sufficient,
steady-state rates of energy metabolism in the
adult brain are regulated mainly by neuronal
functional activity. CMRO2 and CMRglc are
increased by functional activation and decreased
by reduced functional activity. CMR glc in localized
regions of the nervous system has been shown to
vary linearly with the spike frequency in afferent
pathways to the region. Both oxygen and glucose
metabolism, however, may be altered by other
factors during development and in pathophysiolo-
gical conditions.
LOCAL CEREBRAL BLOOD FLOW
AND METABOLISM
The nitrous oxide method and its modifications
were designed to determine only average CBF and
metabolism in the brain as a whole. The brain,
however, is composed of many subunits subserving
different neural functions that often operate inde-
pendently of one another. Therefore, methods to
measure CBF or metabolism in individual regions
of the brain that are noninvasive to the brain and
can be used without the need for general anes-
thesia were developed. The first such method was
the autoradiographic [131I]trifluoroiodomethane
(CF131
3 I) technique developed by Kety and associates
to measure local CBF. CF1313 I is a relatively stable,
chemically inert, radioactive gas that diffuses freely
across the blood–brain barrier so that its uptake by
the local cerebral tissues is blood flow dependent.
The tracer, dissolved in blood or normal saline, is
infused intravenously for approximately 1 min
614 CEREBRAL METABOLISM AND BLOOD FLOW

while the arterial blood is sampled for determina- Table 3 LOCAL BLOOD FLOW IN REPRESENTATIVE
tion of the time course of arterial tracer concentra- STRUCTURES OF THE CAT BRAIN
tion. At the end of the infusion period, the animal is Blood flow, ml/g/min
decapitated to terminate the CBF, the head is rapidly (mean7SEM)
frozen in liquid N2, and local brain tissue concen-
Light
trations of tracer are determined by quantitative thiopental
autoradiography. The autoradiograms provide pic- Conscious anesthesia
torial representations of the relative concentrations Structure (n ¼ 10) (n ¼ 11)
of isotope in the various structures in the brain that
Superficial cerebral structures
reflect their rates of blood flow, but local CBF in
Cortex:
each structure of interest can be quantitatively
Sensorimotor 1.3870.12 0.6570.07n
computed from the local tracer concentrations in Auditory 1.3070.05 0.7270.07n
the tissues, determined by densitometric analysis of Visual 1.2570.06 0.7770.09n
the autoradiograms, and an equation that defines Miscellaneous-association 0.8870.04 0.6770.06n
CBF as a function of the time course of arterial Olfactory 0.7770.06 0.6270.07
White matter 0.2370.02 0.2670.04
tracer concentration, relative solubility of the tracer
in blood and brain, local concentration in the tissue
Deep cerebral structures
of interest, and the time after introduction of the
Medial geniculate nucleus 1.2270.04 0.8170.09n
tracer into the circulation. This method provided Lateral geniculate nucleus 1.2170.08 0.7970.07n
values of local CBF in conscious and thiopental- Caudate nucleus 1.1070.08 0.9170.11
anesthetized cats (Table 3) and also led to the first Thalamus 1.0370.05 0.7170.09n
demonstration of functional brain imaging in the Hypothalamus 0.8470.05 0.5570.06n
Basal ganglia and 0.7570.03 0.5870.05n
visual system of unanesthetized cats (Fig. 2). The
amygdala
tracer, CF1313 I, was subsequently replaced by Hippocampus 0.6170.03 0.5970.04
[14C]iodoantipyrine, which is nonvolatile, traverses Optic tract 0.2770.02 0.2270.08
the blood–brain barrier almost as freely as the gas,
is uniformly soluble in all structures of the brain, Midbrain and pons
and provides values for local CBF similar to those Inferior colliculus 1.8070.11 1.4170.14n
obtained with CF131 3 I but with better spatial
Superior olive 1.1770.13 1.5670.27
Superior colliculus 1.1570.07 0.8270.10n
resolution. This method has also been adapted for
Pontine gray 0.8870.04 0.6170.03n
use in humans with H15 2 O and positron emission Reticular formation 0.5970.05 0.4970.06
tomography (PET). Pontine white 0.2470.02 0.3170.04
The autoradiographic CF131 3 I method and its
derivatives are applied during uptake of tracer by Cerebellum, medulla and
the brain, but the same principles apply during spinal cord
clearance of the tracer from previously preloaded Cerebellum
Nuclei 0.7970.05 0.5670.08n
tissues. This is the basis of the frequently used
133 Cortex 0.6970.04 0.5770.05n
xenon-clearance technique, in which brain tis- White matter 0.2470.01 0.2970.06
sues are first loaded with the radioactive tracer and Medulla
local tissue CBF is then determined from the rate Vestibular nuclei 0.9170.04 0.8470.10
constant of the blood flow-dependent clearance of Cochelar nuclei 0.8770.07 0.9970.14
Pyramids 0.2670.02 0.2870.03
the tracer from the tissues measured with judi-
Spinal cord
ciously placed scintillation counters directed at Gray matter 0.6370.04 0.5370.07
regions of the brain. White matter 0.1470.02 0.1570.06
Quantitative autoradiography has also been used n
Significantly different from conscious control values
as a method for measurement of glucose consump- ðpo0:05Þ:
tion in discrete functional and structural components
of the brain in intact conscious laboratory animals.
Instead of a chemically inert tracer, this method
utilizes a radioactive analog of glucose, 2-deoxy-d- brain barrier by the glucose transporter. In the tissue,
[14C]glucose (2-[14C]DG), to trace glucose metabo- it is phosphorylated to 2-[14C]DG-6-phosphate (2-
lism. 2-[14C]DG is transported across the blood– [14C]DG-6-P) by hexokinase in competition with

Figure 2
Autoradiograms of sections of cat brains showing effects of retinal
stimulation on local cerebral blood flow measured with
[131I]trifluoroiodomethane. The darker the image, the higher the
rate of blood flow. Circular areas of uniform density represent
calibrated 131I-labeled gelatin standards autoradiographed
together with brain sections and used for quantitative
densitometric analysis. (A) Control study in the conscious cat with
eyelids shut; note the visual cortex (Vis Cx) and lateral (LG) and
medial (MG) geniculate nuclei. (B) Autoradiogram of a section of
the brain of the same cat at another level showing superior colliculi
(SCol) and visual cortex. (C) Autoradiogram of the brain section at
a level comparable to the section in A from conscious cat with both
eyes open and retinae stimulated by photoflashes at a rate of six
per second. Note the effects of the photic stimulation—that is,
marked increases in optical density in the visual cortex and lateral
geniculate nuclei relative to those of other structures, such as the
medial geniculate nucleus. (D) Autoradiogram from stimulated cat
at the same level as the section in B; note the marked increases in
optical densities in the superior colliculi and discrete areas of the
visual cortex relative to other areas.
glucose; however, in contrast to glucose-6-phos-
phate, 2-[14C]DG-6-P cannot be metabolized further
down the glycolytic pathway and remains trapped in
the tissue for an extended period. Local tissue 14C
concentrations are determined by the same quanti-
tative autoradiographic technique, and local CMRglc
is computed by an equation that defines CMRglc as a
function of local 2-[14C]DG-6-P concentration,
relative concentrations of 2-[14C]DG and glucose in
arterial plasma, rate constants for 2-[14C]DG trans-
CEREBRAL METABOLISM AND BLOOD FLOW 615
port between plasma and brain, and enzyme kinetic
constants of hexokinase for 2-deoxyglucose and
glucose. Applications of this method have shown
that local CMRglc varies as widely as CBF through-
out the brain (Table 4) and that in normal animals
the two are closely correlated. Changes in functional
activity produced by physiological stimulation,
anesthesia, or deafferentation result in corresponding
changes in blood flow and glucose consumption in
the structures involved in the functional change. This
method has also been adapted for human applica-
tions by the use of PET and the positron-emitting
analog of 2-[14C]DG, 2-[18F]fluoro-2-deoxy-d-glu-
cose.
All these regional methods are used to map
functional neural pathways and to localize the effects
of disease or pharmacological agents in the brain.
Their adaptations for human use with PET are now
widely used in functional brain imaging studies of
cognitive functions in man.
CHANGES IN CEREBRAL BLOOD FLOW AND
METABOLISM DURING THE LIFE SPAN
Cerebral energy metabolism and CBF vary consider-
ably from birth to old age. Both are low at birth,
increase and reach peak levels at different times
depending on the maturation rate of the particular
structure, and then decline to young adult levels. In
predominantly white matter structures, the peaks
coincide approximately with the times of maximal
rates of myelinization. After reaching normal young
adult levels, changes in CBF and cerebral energy
metabolism are very much influenced by health. In
normal 70- to 80-year-old subjects carefully selected
for good health and free from disease, including
vascular disease, CBF and CMRO2 were found to be
similar to values found in normal young men 50
years younger. In comparable elderly subjects with
objective evidence of even minimal arteriosclerosis,
CBF was reduced. CMRO2 remained normal
through enhanced extraction of O2 from the blood
but at the expense of a reduced cerebral venous pO2,
suggesting reduced tissue pO2 and a relative brain
tissue hypoxia. Apparently, aging per se does not
lower CBF and CMRO2, but when arteriosclerosis is
present it lowers CBF and causes a chronic relative
hypoxia in the brain that may ultimately lead to
reduced CMRO2 and pathological changes in the
tissue. Because arteriosclerosis is prevalent in the
aged, this pattern probably occurs in most aged
individuals.
616 CEREBRAL METABOLISM AND BLOOD FLOW

Table 4 REPRESENTATIVE VALUES FOR LOCAL CEREBRAL changes in global CBF (Table 5). For example,
GLUCOSE UTILIZATION IN THE NORMAL CONSCIOUS ALBINO inadequate cerebral nutrient supply depresses the
RAT AND MONKEY (MEAN7SEM) level of consciousness, ranging from confusion to
lmol/100 g/min coma. Nutrition of the brain can be limited by
hypoxemia, hypoglycemia, or reduced CBF, as seen
Albino rat Monkey
Structure (n ¼ 10) (n ¼ 7)
with increased intracranial pressure due to brain
tumors. In many conditions, the causes of depression
Gray matter of both consciousness and cerebral metabolic rate are
Visual cortex 10776 5972 unknown and are likely due to intracellular defects in
Auditory cortex 16275 7974
the brain. For example, in general anesthesia CMRO2
Parietal cortex 11275 4774
Sensori-motor cortex 12075 4473 is always reduced regardless of the anesthetic agent
Thalamus used, whereas CBF may or may not be decreased and
Lateral nucleus 11675 5472 may even increase. This reduction in energy metabo-
Ventral nucleus 10975 4372 lism during anesthesia probably results from de-
Medial geniculate nucleus 13175 6573
creased energy demand due to reduced synaptic
Lateral geniculate nucleus 9675 3971
Hypothalamus 5472 2571 transmission and neuronal firing. Also, local cerebral
Mammillary body 12175 5773 glucose utilization has, in fact, been shown to be
Hippocampus 7973 3972 directly proportional to the spike frequency in the
Amygdala 5272 2572 afferent pathways to the affected region. There are
Caudate putamen 11074 5273
also a number of systemic diseases (e.g., diabetic
Nucleus accumbens 8273 3672
Globus pallidus 5872 2672 acidosis and coma, hepatic insufficiency and ammonia
Substantia nigra 5873 2972 intoxication, and renal failure) that depress cerebral
Vestibular nucleus 12875 6673 energy metabolism independent of any effects on the
Cochlear nucleus 11377 5173
Superior olivary nucleus 13377 6374
Inferior colliculus 197710 10376
Table 5 CEREBRAL BLOOD FLOW AND METABOLIC
Superior colliculus 9575 5574
RATE IN HUMANS WITH VARIOUS DISORDERS AFFECTING
Pontine gray matter 6273 2871
MENTAL STATE
Cerebellar cortex 5772 3172
Cerebellar nuclei 10074 4572 Cerebral Cerebral O2
blood flow consumption
White matter Mental (ml/100 g/ (ml/100 g/
Corpus callosum 4072 1171 Condition state min) min)
Internal capsule 3372 1371
Normal Alert 54 3.3
Cerebellar white matter 3772 1271
Increased Coma 34n 2.5n
intracranial
Weighted average for whole brain 6873 3671 pressure (brain
tumor)
Insulin
hypoglycemia
Arterial glucose
CEREBRAL ENERGY METABOLISM IN level
PATHOLOGICAL STATES 74 mg/100 ml Alert 58 3.4
19 mg/100 ml Confused 61 2.6n
In general, disorders that alter the quality of menta- 8 mg/100 ml Coma 63 1.9n
tion but not the level of consciousness (e.g., functional Thiopental Coma 60n 2.1n
neuroses, psychoses, and psychotomimetic states) do anesthesia
not alter average CBF and CMRO2 of the brain as a Convulsive state
whole, although they undoubtedly have regional Before convulsion Alert 58 3.7
effects within the brain. However, systemic and After convulsion Confused 37n 3.1n
neurological disorders that affect the level of con- Diabetes
sciousness do have profound effects. Progressive Acidosis Confused 45n 2.7n
Coma Coma 65n 1.7n
reductions in the level of consciousness, regardless
Hepatic insufficiency Coma 33n 1.7n
of cause, are paralleled by corresponding graded
n
decreases in CMRO2 without any corresponding Significantly different from normal conscious state ðpo0:05Þ:

cerebral circulation. The mechanisms of their effects
on brain metabolism are in most cases undefined.
IMPACT OF METHODS FOR MEASURING
REGIONAL CEREBRAL BLOOD FLOW AND
ENERGY METABOLISM
The relatively recent development of methods for
measuring blood flow and glucose utilization at
regional or local levels within the brain has opened
new avenues of investigation of brain functions in
health and disease. Such methods, when combined
with PET, have provided means to localize specific
functions, including cognitive functions, within the
normal human brain. They have also proved useful
in studies of disease. For example, they can localize
and even to some extent grade brain tumors. They
can help to localize epileptogenic foci in partial
complex epilepsy. They greatly assist in evaluating
the extent and severity of an ischemic insult and the
identification of regions that may survive. One can
expect major advances from the application of these
methods.
—Louis Sokoloff
See also–Cerebral Angiography; Cerebral Blood
Flow, Measurement of; Cerebral Blood Vessels:
Arteries; Cerebral Blood Vessels: Veins and
Venous Sinuses; Cerebral Microcirculation
Further Reading
Chadwick, D. J., and Wheaton, J. (Eds.) (1991). Exploring Brain
Functional Anatomy with Positron Tomography, Ciba Founda-
tion Symposium No. 163. Wiley, Chichester, UK.
Clarke, D. D., and Sokoloff, L. (1999). Circulation and energy
metabolism of the brain. In Basic Neurochemistry: Molecular,
Cellular, and Medical Aspects (G. Siegel, B. Agranoff, R. W.
Albers, and S. Fisher, Eds.), 6th ed., pp. 637–669. Lippincott–
Raven, Philadelphia.
Edvinsson, L., MacKenzie, E. T., and McCulloch, J. (1993).
Cerebral Blood Flow and Metabolism. Raven Press, New York.
Kety, S. S. (1950). Circulation and metabolism of the human brain
in health and disease. Am. J. Med. 8, 205–217.
Kety, S. S., and Schmidt, C. F. (1948). The nitrous oxide method
for the quantitative determination of cerebral blood flow in
man: Theory, procedure, and normal values. J. Clin. Invest. 27,
476–483.
Kety, S. S., and Schmidt, C. F. (1948). Effects of altered arterial
tensions of carbon dioxide and oxygen on cerebral blood flow
and cerebral oxygen consumption of normal young men. J.
Clin. Invest. 27, 484–492.
Landau, W. M., Freygang, W. H., Rowland, L. P., et al. (1955).
The local circulation of the living brain; Values in the
unanesthetized and anesthetized cat. Trans. Am. Neurol. Assoc.
80, 125–129.
CEREBRAL MICROCIRCULATION 617
Lassen, N. A. (1959). Cerebral blood flow and oxygen consump-
tion in man. Physiol. Rev. 39, 183–238.
Lassen, N. A., Ingvar, D. H., Raichle, M. E., et al. (Eds.) (1991).
Brain Work and Mental Activity. Quantitative Studies with
Radioactive Tracers, Alfred Benzon Symposium No. 31.
Munksgaard, Copenhagen.
Phelps, M. E., Huang, S. C., Hoffman, E. J., et al. (1979).
Tomographic measurement of local cerebral glucose metabolic
rate in humans with (F-18)2-fluoro-2-deoxy-d-glucose: Valida-
tion of method. Ann. Neurol. 6, 371–388.
Reivich, M., Kuhl, D., Wolf, A., et al. (1977). Measurement of
local cerebral glucose metabolism in man with 18F-2-fluoro-2-
deoxy-d-glucose. Acta Neurol. Scand. 56, 190–191.
Sokoloff, L. (1959). The action of drugs on the cerebral
circulation. Pharmacol. Rev. 11, 1–85.
Sokoloff, L. (1981). Localization of functional activity in the
central nervous system by measurement of glucose utilization
with radioactive deoxyglucose. J. Cereb. Blood Flow Metab. 1,
7–36.
Sokoloff, L. (Ed.) (1985). Brain Imaging and Brain Function,
Proceedings of the Association for Research in Nervous and
Mental Disease., Vol. 63. Raven Press, New York.
Sokoloff, L., Reivich, M., Kennedy, C., et al. (1977). The
[14C]deoxyglucose method for the measurement of local
cerebral glucose utilization: Theory, procedure, and normal
values in the conscious and anesthetized albino rat. J.
Neurochem. 28, 897–916.
Cerebral Microcirculation
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MICROVASCULAR SYSTEMS of both gray and
white matter are formed of a few small arterioles
with luminal diameters (d) of 8–50 mm; an abundant,
complex capillary network (dp8 mm); and some
small venules (d ¼ 8–50 mm). In these systems,
small venules are three or four times more abundant
than small arterioles. Approximately 75% of micro-
vascular blood is in capillaries, 20% in small venules,
and 5% in small arterioles. Cerebral capillary
networks consist of an incredible array of branching
and joining segments that twist and turn and
are organized to provide ‘‘collateral’’ flow; they
resemble piles of pretzels. Capillary segments,
which are defined as the individual ‘‘tubes’’ running
between branching and joining points, differ
widely in diameter, length, and tortuosity. Fitting
with the great structural and functional variability
within the brain, no two capillary segments are
alike.
The purpose of cerebral microvascular systems
is to delivery metabolic substrates, such as oxygen
and glucose, and blood-borne messengers, such as

cerebral circulation. The mechanisms of their effects
on brain metabolism are in most cases undefined.
IMPACT OF METHODS FOR MEASURING
REGIONAL CEREBRAL BLOOD FLOW AND
ENERGY METABOLISM
The relatively recent development of methods for
measuring blood flow and glucose utilization at
regional or local levels within the brain has opened
new avenues of investigation of brain functions in
health and disease. Such methods, when combined
with PET, have provided means to localize specific
functions, including cognitive functions, within the
normal human brain. They have also proved useful
in studies of disease. For example, they can localize
and even to some extent grade brain tumors. They
can help to localize epileptogenic foci in partial
complex epilepsy. They greatly assist in evaluating
the extent and severity of an ischemic insult and the
identification of regions that may survive. One can
expect major advances from the application of these
methods.
—Louis Sokoloff
See also–Cerebral Angiography; Cerebral Blood
Flow, Measurement of; Cerebral Blood Vessels:
Arteries; Cerebral Blood Vessels: Veins and
Venous Sinuses; Cerebral Microcirculation
Further Reading
Chadwick, D. J., and Wheaton, J. (Eds.) (1991). Exploring Brain
Functional Anatomy with Positron Tomography, Ciba Founda-
tion Symposium No. 163. Wiley, Chichester, UK.
Clarke, D. D., and Sokoloff, L. (1999). Circulation and energy
metabolism of the brain. In Basic Neurochemistry: Molecular,
Cellular, and Medical Aspects (G. Siegel, B. Agranoff, R. W.
Albers, and S. Fisher, Eds.), 6th ed., pp. 637–669. Lippincott–
Raven, Philadelphia.
Edvinsson, L., MacKenzie, E. T., and McCulloch, J. (1993).
Cerebral Blood Flow and Metabolism. Raven Press, New York.
Kety, S. S. (1950). Circulation and metabolism of the human brain
in health and disease. Am. J. Med. 8, 205–217.
Kety, S. S., and Schmidt, C. F. (1948). The nitrous oxide method
for the quantitative determination of cerebral blood flow in
man: Theory, procedure, and normal values. J. Clin. Invest. 27,
476–483.
Kety, S. S., and Schmidt, C. F. (1948). Effects of altered arterial
tensions of carbon dioxide and oxygen on cerebral blood flow
and cerebral oxygen consumption of normal young men. J.
Clin. Invest. 27, 484–492.
Landau, W. M., Freygang, W. H., Rowland, L. P., et al. (1955).
The local circulation of the living brain; Values in the
unanesthetized and anesthetized cat. Trans. Am. Neurol. Assoc.
80, 125–129.
CEREBRAL MICROCIRCULATION 617
Lassen, N. A. (1959). Cerebral blood flow and oxygen consump-
tion in man. Physiol. Rev. 39, 183–238.
Lassen, N. A., Ingvar, D. H., Raichle, M. E., et al. (Eds.) (1991).
Brain Work and Mental Activity. Quantitative Studies with
Radioactive Tracers, Alfred Benzon Symposium No. 31.
Munksgaard, Copenhagen.
Phelps, M. E., Huang, S. C., Hoffman, E. J., et al. (1979).
Tomographic measurement of local cerebral glucose metabolic
rate in humans with (F-18)2-fluoro-2-deoxy-d-glucose: Valida-
tion of method. Ann. Neurol. 6, 371–388.
Reivich, M., Kuhl, D., Wolf, A., et al. (1977). Measurement of
local cerebral glucose metabolism in man with 18F-2-fluoro-2-
deoxy-d-glucose. Acta Neurol. Scand. 56, 190–191.
Sokoloff, L. (1959). The action of drugs on the cerebral
circulation. Pharmacol. Rev. 11, 1–85.
Sokoloff, L. (1981). Localization of functional activity in the
central nervous system by measurement of glucose utilization
with radioactive deoxyglucose. J. Cereb. Blood Flow Metab. 1,
7–36.
Sokoloff, L. (Ed.) (1985). Brain Imaging and Brain Function,
Proceedings of the Association for Research in Nervous and
Mental Disease., Vol. 63. Raven Press, New York.
Sokoloff, L., Reivich, M., Kennedy, C., et al. (1977). The
[14C]deoxyglucose method for the measurement of local
cerebral glucose utilization: Theory, procedure, and normal
values in the conscious and anesthetized albino rat. J.
Neurochem. 28, 897–916.
Cerebral Microcirculation
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MICROVASCULAR SYSTEMS of both gray and
white matter are formed of a few small arterioles
with luminal diameters (d) of 8–50 mm; an abundant,
complex capillary network (dp8 mm); and some
small venules (d ¼ 8–50 mm). In these systems,
small venules are three or four times more abundant
than small arterioles. Approximately 75% of micro-
vascular blood is in capillaries, 20% in small venules,
and 5% in small arterioles. Cerebral capillary
networks consist of an incredible array of branching
and joining segments that twist and turn and
are organized to provide ‘‘collateral’’ flow; they
resemble piles of pretzels. Capillary segments,
which are defined as the individual ‘‘tubes’’ running
between branching and joining points, differ
widely in diameter, length, and tortuosity. Fitting
with the great structural and functional variability
within the brain, no two capillary segments are
alike.
The purpose of cerebral microvascular systems
is to delivery metabolic substrates, such as oxygen
and glucose, and blood-borne messengers, such as
618 CEREBRAL MICROCIRCULATION
bioactive peptides, to brain cells and remove the
products of metabolism (e.g., CO2 and heat) and
locally secreted hormones. This is partially accom-
plished by the plasma and blood cells that flow
through capillary networks. The rates of blood flow
per unit tissue weight differ among brain areas, with
areas such as the inferior colliculus and neural lobe
of the pituitary having flow rates six to seven times
greater than those in white matter. Similarly,
capillary frequency or capillarity varies many-fold
among brain areas, with high flow areas having the
greatest capillarity (and usually the highest rate of
metabolism).
The rate of local cerebral blood flow can be quickly
and greatly altered through microvascular systems.
The greatest changes in blood flow are driven by
severe hypercapnia and hypoxia. Hypercapnia is
apparently the strongest physiological stimulator of
blood flow, in the extreme raising blood flow as much
as fourfold in many brain areas. This implies that
blood flow is very much tuned to the clearance of the
products of metabolism as hypothesized a century
ago by Sherrington. Under conditions of increased
local neural activity and metabolism such as occurs
with auditory stimulation (consider Bach, Mozart, or
Beethoven), blood flow can be increased in only the
activated areas. This physiological phenomena is now
used for noninvasive tract tracing in humans by
positron emission tomography and functional mag-
netic resonance imaging. Of relevance, blood consists
of plasma with its proteins plus blood cells (mainly
red cells). The hematocrit within cerebral microvas-
cular systems (microhematocrit) is less than the
central hematocrit. This and other observations
indicate that normally approximately 80% of capil-
lary segments contain red cells but all contain plasma.
When blood flow increases, the microhematocrit
tends to decrease, and the flows of red cells and
plasma become even more disparate.
Most of the exchange of material between blood
and brain takes place across the capillary wall, which
consists of endothelial cells, encircling basement
membrane, and astrocytic foot processes. The junc-
tions that join endothelial cells are extremely tight
and exclude or greatly restrict the diffusion of
virtually all materials including water. The flux of
material in both directions thus takes place virtually
exclusively through the endothelial cell. Accordingly,
cerebral capillaries are considered to form a barrier,
and they (as well as this function) are often referred
to as the blood–brain barrier (BBB). Because of the
lipidity of endothelial membranes, the rate of simple
diffusional flux across the BBB is set mainly by lipid
solubility, which varies 1 millionfold among physio-
logical molecules and ions. Oxygen and CO2 are
fairly lipid soluble and diffuse rapidly in both
directions across the BBB. Other materials that
readily permeate the BBB are the social drugs—
alcohol, nicotine, and caffeine.
The BBB has not only barrier but also carrier
functions. To facilitate the transendothelial passage
of relatively lipid-insoluble materials, substrate-
specific transport proteins are sited in the luminal
and abluminal membranes of cerebral endothelial
cells. Such carrier systems operate at the BBB for
hexoses (e.g., d-glucose), monocarboxylic acids (e.g.,
lactate), many groups of amino acids (e.g., the large
neutral amino acids such as phenylalanine and
tyrosine), and other polar compounds needed by
the brain. During the past 10 years, a number of
transport proteins or transporters of the BBB have
been cloned or otherwise identified. For instance,
the glucose transporter of the BBB is GLUT-1,
which also is located on astrocytic but not
neuronal membranes. These transport systems
have kinetic properties similar to those of enzyme
systems, namely substrate specificity (affinity),
competitive inhibition, and maximum transfer capa-
city. In addition, the fluxes of K þ , Na þ , and Ca2 þ
across the BBB are mediated and regulated by ion
pumps.
Finally, several brain structures do not have BBB-
like capillaries. Most, perhaps all, of these structures
have endocrine functions and seemingly communi-
cate rapidly with circulating blood and the rest of the
body via the release and uptake of compounds such
as peptides. They are referred to as the circumven-
tricular organs and include the area postrema,
median eminence, subfornical organ, and pineal
gland. The choroid plexuses are often placed in this
group because of their location and the leakiness of
their capillaries, but they seem to have a variety of
functions, notably forming cerebrospinal fluid (CSF)
and secreting various peptides and transport proteins
such as transthyretin into CSF for subsequent
delivery to brain.
—Joseph D. Fenstermacher
See also–Cerebral Angiography; Cerebral Blood
Flow, Measurement of; Cerebral Blood Vessels:
Arteries; Cerebral Blood Vessels: Veins and
Venous Sinuses; Cerebral Metabolism and Blood
Flow

Cerebral Palsy
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE TERM CEREBRAL PALSY is not a specific diagnosis
but rather used to include a group of children who
have a variety of motor abnormalities thought to be
secondary to a static or nonprogressive lesion(s) of
the central nervous system that occurred in the pre-
or perinatal periods or in early infancy. Although
manifestations of motor dysfunction comprise the
primary symptoms and signs of these disorders,
many, if not most, patients will have associated
abnormalities of cognition, behavior, and sensation.
Motor findings primarily relate to changes of
posture, muscle tone, and power, as seen in
corticospinal tract and extrapyramidal disorders,
but also include specific movement disorders and,
occasionally, ataxia.
The severity of the postural changes and abnorm-
alities of tone and power may vary during the first
few years of life, but by the age of 3 years the clinical
findings are relatively static. Very young patients
with mild disorders may improve remarkably during
the first few years of life so that neurological findings
are ultimately minimal. It must be remembered that
the term cerebral palsy is useful in only a general
sense, namely, when considering children with
relatively static or nonprogressive motor disabilities
of varying etiologies.
EPIDEMIOLOGY
The inherent vagaries of the term cerebral palsy are
reflected in the attempts to provide reliable
epidemiological studies, but recent studies have
provided better insight into the prevalence of
these disorders. The California Cerebral Palsy
Project (CCPP), a population-based study of
192 children with moderate to severe cerebral
palsy from four counties in the San Francisco
Bay area born between 1983 and 1985 who were
alive and residing in California at the age of 3
years, reported a prevalence at the age of 3 of 1.2/
1000 survivors. Of these children, 53% had a birth
weight more than 2500 g and 28% had a birth
weight less than 1500 g. No association was found
between birth weight and the severity of functional
impairment, and no consistent relationship was
demonstrated between birth weight and prevalence
of associated disabilities.
CEREBRAL PALSY 619
A Swedish study showed that 2.17/1000 live births
between 1978 and 1982 had cerebral palsy and 43%
of cases were preterm. It has been shown in the
United States, Great Britain, Ireland, and New
Zealand that there has been no decrease in the
incidence of cerebral palsy but rather an increase that
has been attributable to the notable advances in
technology and provision of intensive neonatal care,
significantly lowering the mortality rate and enabling
infants of very low birth weight to survive.
Because of the variety of disorders and multiplicity
of etiologies included in this group of patients, no
universally acceptable classification has been
adopted. However, most classifications consider the
clinical manifestations of the disorders noted in
Table 1.
Comparing rates of incidence of the different types
of cerebral palsy also shows some measure of
variability. For example, careful examination of
some children thought to have spastic diplegia may
demonstrate findings of spastic quadriplegia. Bron-
son and Crothers included in their monograph a
small number of children with monoplegia, but this
condition rarely, if ever, can unequivocally be shown
because on careful examination there are usually
findings consistent with hemiparesis. Other studies
have not included a category of ‘‘ataxic cerebral
palsy,’’ but this is sometimes unclear because some
patients with structural abnormalities may or may
not show findings consistent with truncal and/or limb
ataxia.
As noted by Bronson and Crothers, the terms
hemiparesis and hemiplegia are used interchange-
ably, and some distinguish the terms on the basis of
severity of tone increase—namely, hemiplegia is
more severe as seen in patients with an acute vascular
accident. In common parlance, however, it seems
Table 1 CLASSIFICATION OF CEREBRAL PALSY
Spastic disorders
Spastic diplegia
Spastic hemiplegia
Spastic quadriplegia
Extrapyramidal disorders
Chorea
Athetosis
Choreoathetosis
Dystonia
Hypotonic disorders
Ataxic disorders
Mixed types
620 CEREBRAL PALSY
reasonable that one should not distinguish between
the two terms.
SPASTIC DISORDERS
Spastic Diplegia
During the past several decades, there has been an
increased frequency of spastic diplegia, which is a
form of cerebral palsy characterized by an abnormal
increase of muscle tone that is greater in the legs than
in the arms. It is believed that the increased
frequency is the result of improved neonatal care,
which has resulted in the survival of low-birth-
weight infants. The CCPP study showed that spastic
diplegia occurred in 48% of infants with a birth
weight less than 1500 g, in 23% of those with a birth
weight of 1500–2499 g, and in 28% of those
weighing more than 2500 g. A Swedish study
reported that spastic diplegia occurred in 71.3% of
preterm infants and 18.7% of term infants. In the
earlier studies of Ingram, 44% of children with
spastic diplegia had a birth weight less than 2500 g.
Patients with this form of cerebral palsy have
notably increased muscle tone, greater in the legs
than in the arms, and when suspended vertically by
underarm support they will extend their legs in
adduction, or ‘‘scissoring,’’ of the hips and legs. As
patients become older, usually after several years, the
spasticity increases and patients assume an upright
posture with flexion of the hips and knees and
limited dorsiflexion of the feet. In milder cases,
patients walk with an equinovarus posturing and
‘‘toe walking.’’ Arm involvement is well demon-
strated while walking because the arms are generally
elevated and flexed at the elbow, lending a mechan-
ical quality to gait. In the upper limbs, there is
impairment of fine motor movements of the hands.
Ultimately, the contractures can become fixed, with
the hips in flexion and adduction, knees in flexion,
and plantar flexion of the ankles. The deep tendon
reflexes are increased except in cases in which they
are dampened by muscle contracture, particularly in
the ankles. Also, ankle clonus is often restricted by
contractures of the Achilles tendon. The plantar
responses are bilaterally extensor. Abnormal sensory
function is uncommon, but some patients show
vasomotor abnormalities. In some cases, there is a
decrease in the size of lower limbs.
Ingram found that approximately half of the
affected patients had an ocular convergent squint,
which occurred more often in preterm infants and
appeared to become less apparent as patients grew
older. He noted that facial weakness was common in
patients with spastic diplegia, although today authors
believe this occurs less often. The frequency of seizure
disorders, usually generalized tonic–clonic in nature,
has been reported to vary from 16 to 27% and
appears to be unrelated to the severity of the motor
deficit. Acquisition of speech and language is often
delayed, and at least one-third of patients with spastic
diplegia have impaired intelligence, which is com-
monly related to the severity of the motor deficit. With
the increased survival of infants of low birth weight,
the frequency of mental subnormality is increasing.
The neuropathological changes observed in pre-
term and term infants are varied. Preterm infants are
found to primarily have periventricular leukomalacia
with loss of white matter. The associated corticosp-
inal tract fibers are interrupted by the changes of
white matter. Term infants can have periventricular
leukomalacia, but associated malformations are
common, including porencephaly and malformations
of the gyri, as observed in polymicrogyria.
Spastic Hemiparesis
Symptoms and signs of spastic hemiparesis are
usually present in early infancy and manifested by
decreased movement of the affected side. Arm
weakness is usually apparent before one can discern
weakness of the leg, and one must be concerned
about the possibility of hemiparesis in infants who
show a hand preference before the age of 12 or
sometimes 18 months. For reasons that are not clear,
the right side is affected more often than the left.
There is variability of motor involvement, but fine
motor movements of the hand, wrist extension, and
forearm pronation are usually most apparent,
whereas lower limb involvement is commonly
manifested as weakness of foot dorsiflexion and
eversion. There is increased flexor tone in the arm
and leg, resulting in a posture characterized by
flexion of the joints of the arm and leg. The deep
tendon reflexes are increased in the affected limbs
and the plantar response is extensor. There may be
occasional involuntary movements of the affected
limb characterized by dystonic posturing and chor-
eoathetosis.
Approximately one-fourth of patients have a
homonymous hemianopsia, and ocular squint is not
uncommon. Supranuclear involvement of the cranial
nerves can occur, and approximately one-half of
patients have facial weakness on the affected side.
Occasionally, deviation of the tongue toward the

affected side is apparent. Abnormalities of sensory
perception are not uncommon, particularly stereo-
gnosis and two-point discrimination, but sensory
involvement does not correlate well with the severity
of the hemiparesis. Growth retardation can also
occur on the affected side, with distal tissues affected
more than proximal tissues. This can be well
demonstrated by comparing the size of the thumb-
nails, which are smaller on the involved side.
Although the acquisition of motor milestones is
often delayed, most children will walk before the age
of 2 years. Approximately one-half of patients with
spastic hemiparesis will have a seizure disorder,
commonly beginning as partial motor fits but later
becoming secondarily generalized. Of those patients
who had seizures in the neonatal period, the
likelihood of recurrence is 100%. Approximately
one-half of patients will have normal intelligence as
measured by standard intelligence tests, and approxi-
mately one-fifth will have IQs higher than 100.
Neuropathological examinations have shown that
cerebral infarction primarily found in the distribu-
tion of the middle cerebral artery, more often on the
left than the right, is common in patients with spastic
hemiplegia. Other causes include periventricular
leukomalacia, areas of cortical dysplasia, schizence-
phaly, and hemimegalencephaly.
Spastic Quadriplegia
Children with spastic quadriplegia have generalized
increased muscle tone, commonly manifested as
rigidity of flexion and extension in the arms and
legs. The quality and distribution of the spasticity are
consistent with the classic description by Little in
1861. In the CCPP study, 22% of children were
thought to have spastic quadriplegia, and Hagberg
reported similar findings in 10% of children with
cerebral palsy who were born at term and in 4% of
prematures.
In patients with severe spastic quadriplegia, rigidity
of the limbs is notable, and some patients have
intermittent and sometimes continuous opisthoto-
nous. Deep tendon reflexes are greatly increased
unless dampened by spasticity and joint contractures,
and occasionally subluxation of the hips can occur.
Ankle clonus is present unless inhibited by contrac-
tures of the Achilles tendon, and the plantar responses
are bilaterally extensor. Affected patients commonly
have pseudobulbar signs, and because of dysphagia
and incoordination of muscles of glutition, aspiration
is an ever-present danger. More than half of patients
have seizures and virtually all are notably retarded.
CEREBRAL PALSY 621
Neuropathological studies have shown a wide
variety of abnormalities, particularly cystic encepha-
lomalacia, but other structural malformations occur,
such as polymicrogyria and schizencephaly. Changes
observed in term infants who sustained perinatal
hypoxia include parasagittal cortical lesions, polycys-
tic encephalomalacia, and lesions of the basal ganglia.
EXTRAPYRAMIDAL DISORDERS
The extrapyamidal type of cerebral palsy is char-
acterized by abnormalities of posture and tone and
incoordination of voluntary as well as involuntary
movements. Spasticity is a commonly associated
feature of the disorder. In the CCPP study, 7% of
patients with dyskinesia/ataxia (extrapyramidal cer-
ebral palsy) had a birth weight less than 1500 g and
93% had a birth weight more than 2500 g. In a
Swedish report, Kyllerman noted that patients with
this cerebral palsy should be considered to have one
of two types—a hyperkinetic type, characterized by
purposeless involuntary movements, and a dystonic
type manifested by abnormal muscle tone induced by
emotional or postural stimuli, intentional move-
ments, persistence of primitive reflexes, and a
tendency to repeatedly assume and maintain abnor-
mal posture in the same stereotypic pattern. Patients
with the dystonic type also showed some involuntary
movements. Patients in the hyperkinetic group were
primarily premature infants who sustained asphyxia
and hyperbilirubinemia, whereas those in the dys-
tonic group were infants small for gestational age
who also experienced hypoxia during the last
trimester or the perinatal period. Currently, the
occurrence of hyperbilirubinemia is uncommon due
to improved prenatal care.
The extrapyramidal form of cerebral palsy is
initially manifested by hypotonia and brisk deep
tendon reflexes, and it is usually not until 2 or 3 years
of age that disorders of movement become apparent.
More severely affected patients tend to be hypotonic
for longer periods of time. A transient form of
dystonia has also been described. The disorders of
movement vary but have been generally considered
as choreoathetosis.
Acquisition of motor milestones is delayed. Ingram
reported that an average age for walking was 2.5
years, but most children can walk, albeit with some
assistance, by the age of 4 years. All motor move-
ments can be affected. This is particularly apparent
in movements of the fingers, hands, and limbs as
well as incoordination of the movements of the
622 CEREBRAL PALSY
oral–buccal–lingual muscles, which commonly re-
sults in dysarthria, dysphagie, and drooling.
Cranial nerve involvement is less often seen in this
type of cerebral palsy, although approximately one-
third of patients have strabismus. Kyllerman re-
ported that 34% of patients had a sensorineural
hearing defect. The intelligence of children with this
form of cerebral palsy associated with dysarthria and
incoordinated movement can be misinterpreted.
Bronson and Crothers reported that 65% had an
IQ higher than 70 and 45% had an IQ higher than
90. Kyllerman found that 78% of patients with
choreoathetosis had an IQ higher than 90.
As one would expect, the neuropathological
changes in this form of posthypoxic cerebral palsy
primarily involve the basal ganglia, particularly the
thalamus and putamen. The findings of gliosis are
consistent with those found in patients who experi-
enced perinatal asphyxia.
HYPOTONIC DISORDERS
Hypotonic cerebral palsy is a relatively uncommon
condition characterized by generalized hypotonia
that persists for at least several years and is
associated with normal to hyperactive deep tendon
reflexes. There is generally no associated weakness of
limbs, but due to the wide range of differential
diagnoses, one must pay particular attention to
ruling out any primary disease of the spinal cord
(e.g., progressive spinal muscular atrophy), periph-
eral nerve, myoneural junction or muscle, as well as
other metabolic or degenerative diseases.
In some cases of early persistent hypotonia,
patients will later show signs of incoordination or
ataxia. Moreover, extrapyramidal cerebral palsy is
initially manifested by hypotonia in the presence of
normal to brisk deep tendon reflexes, and patients
manifest disorders of movement when they reach the
age of 2 or 3 years. The acquisition of motor
milestones is commonly delayed, and although there
is improvement of tone with maturation, some
patients will remain hypotonic into the adult years.
ATAXIC DISORDERS
A small group of patients primarily have a nonpro-
gressive ataxia from early life that is sometimes
associated with other less prominent motor disabil-
ities. Early manifestations include hypotonia and
ataxia. Motor development is commonly delayed,
and some may not walk without assistance until 3 or
4 years of age. Although some patients may be
intellectually impaired, significant retardation is
uncommon. Because the differential diagnosis of
ataxia in childhood is so vast, much attention must
be directed at ruling out the possibility of other
metabolic and degenerative diseases. Neuroimaging
may or may not demonstrate any structural abnorm-
ality of the cerebellum.
MIXED FORMS
It is not uncommon for patients with one predomi-
nant type of cerebral palsy to have manifestations of
another type as well. For example, those who
primarily have spastic cerebral palsy may also have
choreoathetosis or dystonic posturing. This is also
true for patients with the extrapyramidal type of
cerebral palsy who not uncommonly will show signs
of corticospinal tract involvement. Patients are
categorized according to the predominant type of
their motor disability.
TREATMENT
Multiple forms of therapy are available for patients
with cerebral palsy. Although it is difficult to obtain
reliable statistical data regarding the prevalence and
types of static motor disabilities, it is probably more
difficult to obtain reliable information regarding the
results of different treatment methods. It must be
understood that therapy does not just involve the
child but, rather, the entire family, which must
understand the nature of the problem and accom-
modate the range of disabilities of the patient,
particularly the specific primary motor problems.
The types of therapy available to patients with
cerebral palsy include physical and occupational
therapy, management of muscle tone, orthopedic
surgical procedures including the use of orthoses,
and, potentially, the use of botulinum toxin. Equally
important to this multifaceted therapeutic approach
are specialists, including psychologists, speech
pathologists, education specialists, and social work-
ers, who are not only skilled in the assessment and
management of children but also have expertise in
the management of children with many special needs.
Most important, the patient with cerebral palsy
must have one physician who understands the nature
of these disabilities, is supportive of the patient and
the family, and is in charge of the many specialists
involved in the care and management of the patient.
—Bruce Berg

See also–Ataxia; Dysarthria; Dyskinesias;
Hereditary Spastic Paraplegia; Hypotonic Infant;
Progressive Supranuclear Palsy; Spasticity
Further Reading
Cohen, M. E., and Duffner, P. K. (1981). Prognostic indicators in
hemiparetic cerebral palsy. Ann. Neurol. 9, 353–357.
Crothers, B., and Paine, R. S. (1959). The Natural History of
Cerebral Palsy. Harvard Univ. Press, Cambridge, MA.
Grether, J. K., Cummins, S. K., and Nelson, K. B. (1992). The
California Cerebral Palsy Project. Paediatr. Perinatal Epide-
miol. 6, 339–351.
Hagberg, B., Hagberg, G., and Olow, I. (1975). The changing
panorama of cerebral palsy in Sweden 1954–1970. I. Analysis
of the general changes. Acta Paediatr. Scand. 64, 187–192.
Hagberg, B., Hagberg, G., and Olow, I. (1975). The changing
panorama of cerebral palsy in Sweden. 1954–1970. II. Analysis
of the various syndromes. Acta Paediatr. Scand. 64, 193–200.
Hagberg, B., Hagberg, G., Olow, I., et al. (1996). The changing
pattern of cerebral palsy in Sweden. V. The birth year period
1979. Acta Pediatr. Scand. 78, 283–290.
Hayashi, M., Satoh, J., Sakamoto, K., et al. (1991). Clinical and
neuropathological findings in severe athetoid cerebral palsy: A
comparative study of globo-Luysian and thalamo-putaminal
groups. Brain Dev. 13, 47–51.
Ingram, T. T. S. (1964). Paediatric Aspects of Cerebral Palsy.
Livingstone, Edinburgh, UK.
Krageloh-Mann, I., Petersen, D., Hagberg, G., et al. (1995).
Bilateral spastic cerebral palsy—MRI pathology and origin.
Analysis from a representative series of 56 cases. Dev. Med.
Child Neurol. 37, 379–397.
Kyllerman, M. (1981). Dyskinetic Cerebral Palsy. Lundgren
Tryckeri AB Partille, Göteborg, Sweden.
Little, W. J. (1843). Course of lectures on deformities of human
frame. Lancet 1, 318–322.
Little, W. J. (1861). On the influence of abnormal parturition,
difficult labours, premature birth, and asphyxia neonatorum on
the mental and physical condition of the child, especially in
relation to deformities. Trans. Obstet. Soc. London 3, 293.
McDonald, A. D. (1963). Cerebral palsy in children of very low
birth weight. Arch. Dis. Child. 38, 579–588.
Veelken, N., Hagberg, B., Hagberg, G., et al. (1983). Diplegic
cerebral palsy in Swedish term and preterm children; Differ-
ences in reduced optimality, relations to neurology and
pathogenetic factors. Neuropaediatrics 14, 20–28.
Cerebral Protection
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ISCHEMIC STROKE affects more than 500,000 people
in the United States annually and is the third leading
cause of death. Until recently, the treatment of stroke
primarily involved supportive medical care. How-
ever, with advances in molecular and cellular biology
CEREBRAL PROTECTION 623
and improvements in clinical triage, a new concept of
stroke has emerged. An acute ischemic stroke is now
regarded as a ‘‘brain attack.’’ In many medical
centers, acute stroke patients receive rapid diagnostic
imaging and intravenous thrombolytics, and in some
centers they undergo endovascular revascularization
techniques.
Cerebral protection can be achieved through
reperfusion therapy and neuronal protection therapy.
Cerebral angiography demonstrates that arterial
occlusion is responsible for more than 80% of acute
ischemic stroke. Therefore, reperfusion using throm-
bolytics can restore blood flow to the brain before
the process of infarction can be completed. Tissue
plasminogen activator (t-PA) for cerebral arterial
thrombolysis is effective within 3 hr of acute
ischemic stroke. t-PA is one of only a few drugs
approved by the Federal Drug Administration for the
treatment of acute ischemic stroke. Neuronal protec-
tion therapy encompasses the cellular, biochemical,
and metabolic aspects of acute ischemic stroke. An
increased understanding of the complexity of brain
ischemia has fostered the development of new
strategies to alter the ischemic process. Many
neuronal protection agents are now being tested in
animal models. Neuronal protection therapy may
slow or even halt the actual process of cell death in
the presence of ongoing ischemia.
THE ISCHEMIC PENUMBRA
With the onset of focal ischemia, blood flow within
the central region of the affected vascular territory is
minimal or absent. Moving peripherally, cerebral
blood flow (CBF) gradually increases until the brain
is perfused normally. The area between this ischemic
core and normal brain tissue is called the ischemic
penumbra (Fig. 1). The name is an analogy to the
partly illuminated area around the complete shadow
of the moon during a solar eclipse. Cellular injury in
the penumbra is considered reversible, and these cells
are most likely to benefit from neuronal protection
and augmentation of blood flow. As time elapses, the
ischemic core expands outward to obliterate the
penumbra, and the opportunity for cerebral protec-
tion is lost.
THE TIME WINDOW
It seems inherent that a specified time window exists
during which cerebral protection is effective. Outside
this time window, cells die throughout the vascular

See also–Ataxia; Dysarthria; Dyskinesias;
Hereditary Spastic Paraplegia; Hypotonic Infant;
Progressive Supranuclear Palsy; Spasticity
Further Reading
Cohen, M. E., and Duffner, P. K. (1981). Prognostic indicators in
hemiparetic cerebral palsy. Ann. Neurol. 9, 353–357.
Crothers, B., and Paine, R. S. (1959). The Natural History of
Cerebral Palsy. Harvard Univ. Press, Cambridge, MA.
Grether, J. K., Cummins, S. K., and Nelson, K. B. (1992). The
California Cerebral Palsy Project. Paediatr. Perinatal Epide-
miol. 6, 339–351.
Hagberg, B., Hagberg, G., and Olow, I. (1975). The changing
panorama of cerebral palsy in Sweden 1954–1970. I. Analysis
of the general changes. Acta Paediatr. Scand. 64, 187–192.
Hagberg, B., Hagberg, G., and Olow, I. (1975). The changing
panorama of cerebral palsy in Sweden. 1954–1970. II. Analysis
of the various syndromes. Acta Paediatr. Scand. 64, 193–200.
Hagberg, B., Hagberg, G., Olow, I., et al. (1996). The changing
pattern of cerebral palsy in Sweden. V. The birth year period
1979. Acta Pediatr. Scand. 78, 283–290.
Hayashi, M., Satoh, J., Sakamoto, K., et al. (1991). Clinical and
neuropathological findings in severe athetoid cerebral palsy: A
comparative study of globo-Luysian and thalamo-putaminal
groups. Brain Dev. 13, 47–51.
Ingram, T. T. S. (1964). Paediatric Aspects of Cerebral Palsy.
Livingstone, Edinburgh, UK.
Krageloh-Mann, I., Petersen, D., Hagberg, G., et al. (1995).
Bilateral spastic cerebral palsy—MRI pathology and origin.
Analysis from a representative series of 56 cases. Dev. Med.
Child Neurol. 37, 379–397.
Kyllerman, M. (1981). Dyskinetic Cerebral Palsy. Lundgren
Tryckeri AB Partille, Göteborg, Sweden.
Little, W. J. (1843). Course of lectures on deformities of human
frame. Lancet 1, 318–322.
Little, W. J. (1861). On the influence of abnormal parturition,
difficult labours, premature birth, and asphyxia neonatorum on
the mental and physical condition of the child, especially in
relation to deformities. Trans. Obstet. Soc. London 3, 293.
McDonald, A. D. (1963). Cerebral palsy in children of very low
birth weight. Arch. Dis. Child. 38, 579–588.
Veelken, N., Hagberg, B., Hagberg, G., et al. (1983). Diplegic
cerebral palsy in Swedish term and preterm children; Differ-
ences in reduced optimality, relations to neurology and
pathogenetic factors. Neuropaediatrics 14, 20–28.
Cerebral Protection
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
ISCHEMIC STROKE affects more than 500,000 people
in the United States annually and is the third leading
cause of death. Until recently, the treatment of stroke
primarily involved supportive medical care. How-
ever, with advances in molecular and cellular biology
CEREBRAL PROTECTION 623
and improvements in clinical triage, a new concept of
stroke has emerged. An acute ischemic stroke is now
regarded as a ‘‘brain attack.’’ In many medical
centers, acute stroke patients receive rapid diagnostic
imaging and intravenous thrombolytics, and in some
centers they undergo endovascular revascularization
techniques.
Cerebral protection can be achieved through
reperfusion therapy and neuronal protection therapy.
Cerebral angiography demonstrates that arterial
occlusion is responsible for more than 80% of acute
ischemic stroke. Therefore, reperfusion using throm-
bolytics can restore blood flow to the brain before
the process of infarction can be completed. Tissue
plasminogen activator (t-PA) for cerebral arterial
thrombolysis is effective within 3 hr of acute
ischemic stroke. t-PA is one of only a few drugs
approved by the Federal Drug Administration for the
treatment of acute ischemic stroke. Neuronal protec-
tion therapy encompasses the cellular, biochemical,
and metabolic aspects of acute ischemic stroke. An
increased understanding of the complexity of brain
ischemia has fostered the development of new
strategies to alter the ischemic process. Many
neuronal protection agents are now being tested in
animal models. Neuronal protection therapy may
slow or even halt the actual process of cell death in
the presence of ongoing ischemia.
THE ISCHEMIC PENUMBRA
With the onset of focal ischemia, blood flow within
the central region of the affected vascular territory is
minimal or absent. Moving peripherally, cerebral
blood flow (CBF) gradually increases until the brain
is perfused normally. The area between this ischemic
core and normal brain tissue is called the ischemic
penumbra (Fig. 1). The name is an analogy to the
partly illuminated area around the complete shadow
of the moon during a solar eclipse. Cellular injury in
the penumbra is considered reversible, and these cells
are most likely to benefit from neuronal protection
and augmentation of blood flow. As time elapses, the
ischemic core expands outward to obliterate the
penumbra, and the opportunity for cerebral protec-
tion is lost.
THE TIME WINDOW
It seems inherent that a specified time window exists
during which cerebral protection is effective. Outside
this time window, cells die throughout the vascular
624 CEREBRAL PROTECTION
Figure 1
Schematic depiction of a middle cerebral artery (MCA) occlusion.
In the ischemic core, cerebral blood flow (CBF) is minimal or
absent. Moving peripherally, CBF increases in the ischemic
penumbra until the brain is perfused normally. The process is
dynamic. As the duration of occlusion increases, the ischemic core
gradually expands into the penumbra zone. Once the ischemic
penumbra is obliterated, the opportunity for cerebral protection is
lost.
territory. In a rat model of temporary middle cerebral
artery (MCA) occlusion, the size of an infarct
increases as ischemia is prolonged. At 3 hr, the size
of the infarction is the same as that achieved after
permanent MCA occlusion. The time window in
human clinical trials is less concrete. In the National
Institutes of Neurological Disorders and Stroke
(NINDS) trial, patients treated with intravenous t-
PA within 3 hr of onset of acute ischemic stroke were
at least 30% more likely to have minimal or no
disability after 3 months compared with those
treated with placebo. In this clinical trial, the time
window was set at 3 hr. Other studies have pushed
the time window to 6–8 hr. Stroke outcomes can be
improved in a select group of patients who receive
intra-arterial thrombolytics (delivered during cere-
bral angiography) within 6 hr of the time of stroke
onset. Several positive emission tomography studies
have even documented that ischemic but ultimately
viable tissue can be detected 18–24 hr after stroke
onset in the ultimately infarcted zone. Therefore, the
precise limit of the time window for safe and
effective reperfusion or neuronal protection has yet
to be fully established.
THE ISCHEMIC CASCADE
The major cellular events involved in the ischemic
cascade are outlined in Figures 2 and 3.
Excitotoxicity and Calcium
Although the brain represents only 2% of body
weight, it uses an astonishing 20% of the body’s
oxygen in adults. The innumerable cells of the brain
require an almost continuous flow of oxygen and
glucose, making them exquisitely sensitive to any
interruption in energy supply. Energy depletion and
reduced levels of adenosine triphosphate initiate a
series of events that cause cells to die.
Glutamate, the main excitatory neurotransmitter
of the central nervous system, is the trigger of
neuronal loss during stroke. During ischemia, an
excess of glutamate is released into the extracellular
space. The mechanism to clear glutamate is energy
dependent; glutamate quickly builds to toxic levels
when energy is depleted. Glutamate causes ionic
shifts; Na þ enters the cell and K þ exits. Water
NUCLEUS
TNFa
GFs Hsps H2O2
IEGs IL-1
(FGF)
SOD
-
VGCC
O2• } ROS
CYTOSOL Calcium
NMDA
MITOCHONDRION nNOS M
Bcl-2 Bax NO AMPA/
Kainate
_ +
cytochrome c
Caspases Glutamate
Apaf-1
Figure 2
The ischemic cascade. The binding of glutamate to its receptors
and the activation of voltage-gated Ca2 þ channels (VGCC) causes
calcium to influx into the cell. Calcium is among the mediators
that initiate the genomic response to cerebral ischemia. The
superoxide dismutase (SOD) gene is upregulated to neutralize the
reactive oxygen species (ROS). The generation of nitrous oxide
(NO) in the neuron is cytotoxic. The interaction between anti-
apoptotic genes, such as Bcl-2, and proapoptotic genes, such as
Bax, determines whether cytochrome c will be translocated from
the mitochondria to the cytosol. In the cytosol, cytochrome c
combines with Apaf-1 to activate the caspases. Proinflammatory
cytokines, such as interleukin-1 (IL-1) and tumor neurotic factor-a
(TNF-a), are generated. Survival pathways involving growth
factors (GFs), immediate early genes (IEGs), and heat shock
proteins (Hsps) are also stimulated. Ultimately, the activation of
these genetic pathways determines the fate of the ischemic cell
[adapted from Savitz et al. (1999). Neuroscientist 5, 238–253.
Copyright 1999. Reprinted with permission of Sage Publications,
Inc.].

Excitotoxicity
Peri-infarct
depolarizations Inflammation
Apoptosis
Minutes Hours Days
Time
Figure 3
Timing of events in focal cerebral ischemia. Initially, glutamate
excess leads to excitotoxicity and peri-infarct depolarizations.
Soon thereafter, the inflammatory response and apoptosis begin
[adapted from Dirnagl et al. (1999). Trends Neurosci. 22, 391–
397. Copyright 1999. Reprinted with permission from Elsevier
Science].
passively follows the influx of Na þ leading to
cellular swelling and edema. The membrane poten-
tial is lost and the cell deporalizes. In the ischemic
core, cells undergo anoxic depolarization and never
repolarize. However, cells in the penumbra initially
retain the ability to repolarize so that they may
depolarize again. As cells in the penumbra undergo
these peri-infarct depolarizations the energy supply
and ionic homeostasis are further compromised,
resulting in an increase in the size of the ischemic
lesion.
Glutamate also activates three main families of
receptors: N-methyl-d-aspartate (NMDA), a-amino-
3-hydroxy-5-methylisoxazole/kainate, and metabo-
tropic glutamate receptors. Activation of these
receptors leads to a buildup of Ca2 þ within the cell.
Ischemia therefore triggers glutamate receptor-
mediated excitotoxicity and Ca2 þ overload within
the cell. The administration of glutamate receptor
antagonists has provided neuronal protection in
animal models.
Originally, neuronal death from excitotoxicity was
believed to result from depletion of cellular energy
stores from overexcited neurons. However, the influx
of Ca2 þ seems to be the major pathogenic event
contributing to cell death. This translocation of
Ca2 þ is accomplished through glutamate, particu-
larly through the NMDA receptor, as well as through
voltage-gated Ca2 þ channels that open after cell
CEREBRAL PROTECTION 625
depolarization. Calcium channel antagonists have
displayed neural protection in animal models but
have shown benefit in clinical trials partially because
they were administered too late after stroke onset or
in insufficient quantity. However, it appears that
Ca2 þ influx into the cell is only the initial step in a
complex biochemical cascade.
Free Radicals
Reactive oxygen species are produced after the
induction of ischemia and upon reperfusion. The
oxidative stress produced by the reactive oxygen
species destroys the cell through lipid peroxidation,
protein oxidation, and DNA damage. Certain
endogenous antioxidants scavenge and neutralize
the reactive oxygen species. In particular, the anti-
oxidant superoxide dismutase detoxifies the super-
oxide (O
2 ) free radical by converting it to hydrogen
peroxide (H2O2). Glutathione peroxidase can then
convert H2O2 into oxygen and water. During times
of oxidative stress, the superoxide dismutase gene is
upregulated. Neural protection strategies have in-
cluded both the administration of exogenous super-
oxide dismutase and manipulation of the superoxide
dismutase gene family.
Nitric oxide (NO) is another free radical that is
increased during ischemia due to an increase in
intracellular Ca2 þ . The formation of NO is cata-
lyzed by the enzyme NO synthase (NOS). NOS has
several isoforms—a neuronal type (nNOS) located in
neurons and an endothelial type (eNOS) in the
vascular endothelium. NO is also generated in
microglia, astrocytes, and invading macrophages
after the induction of an inducible isoform (iNOS).
Initially after ischemia, the formation of NO in the
vascular endothelium by eNOS may improve CBF
through vasodilatation offering neuroprotection.
However, synthesis of NO by nNOS and iNOS is
cytotoxic, leading to an inhibition of mitochondrial
respiration, glycolysis, and DNA synthesis. Because
of the dual role of NO in cerebral ischemia, neuronal
protection strategies need to target the specific
isoform of NOS. For instance, deletion of the nNOS
or iNOS gene in animal models has provided
neuronal protection.
Apoptosis
After an ischemic event, cells in the penumbra may
initiate a program of autodestruction known as
apoptosis. Apoptosis occurs in the developing
brain. More than half of progenitor neurons
undergo this process of programmed cell death
626 CEREBRAL PROTECTION
while forming neural circuits. During ischemia,
cells in the ischemic core undergo necrosis while
cells in the ischemic penumbra may actually self-
destruct through this process of apoptosis. The
mitochondria is regarded as the apoptotic head-
quarters of the cell. One of the key events in
apoptosis is the translocation of cytochrome c from
the intermembrane of the mitochondria into
the cytosol. In the cytosol, cytochrome c then
combines with apoptotic activating factor (Apaf-1)
to activate a set of proteases known as caspases.
These caspases actually dismantle the cell during
apoptosis.
A family of death-promoting genes, known as the
Bcl-2 family, determines whether a cell will undergo
apoptosis. The Bcl-2 gene is antiapoptotic and
prevents the translocation of cytochrome c and
activation of caspases. However, the Bax gene (one
of the members of the Bcl-2 family) is proapoptotic,
facilitating the translocation of cytochrome c and
apoptosis. During ischemia, proapoptotic genes such
as Bax are activated, resulting in the autodestruction
of the cell. Thus, neuronal protection may be gained
through blocking these death-promoting genes.
Other strategies include giving caspase antagonists
or preventing the translocation of cytochrome c from
the mitochondria. Preventing apoptosis in the pe-
numbra is another effective technique in animal
models for neuronal protection.
Inflammation
The inflammatory response may be an important
part of the ischemic cascade. Soon after the onset of
stroke, leukocytes invade the ischemic zone. The
mechanisms by which these inflammatory cells
contribute to the evolution of ischemia include
microvascular occlusion by adherence to the en-
dothelium, producing cytotoxic enzymes and gener-
ating injurious free radicals. Cytokines are
intracellular messengers that mediate the recruitment
of the leukocytes and the induction of adhesion
molecules. The two main proinflammatory cytokines
are interleukin-1 (IL-1) and tumor necrosis factor-a
(TNF-a). The adhesion molecules that facilitate the
movement of leukocytes along the surface of the
endothelium are the E and P selectins, whereas
intracellular adhesion molecules attach the leuko-
cytes to the endothelium so that they may leave the
vascular space and enter the site of injury. Research
has focused on the manipulation of these proin-
flammatory cytokines and adhesion molecules to
provide neuronal protection.
Survival Pathways
The cytokines that are activated during ischemia
also include growth factors that actually promote
neuronal survival and, in some cases, neuronal
outgrowth and synapse formation. Fibroblast
growth factor is the most extensively studied
growth factor. Although the exact mechanism of
neuroprotection of fibroblast growth factor is not
fully understood, it includes upregulation of free
radical scavenging enzymes and Ca2 þ binding
proteins, downregulation of the NMDA receptor,
and vasodilatation. The administration of growth
factors has provided cerebral protection in animal
models. Because they exert both protective and
trophic influences on neurons, growth factors
remain an exciting prospect in drug development
for stroke.
Other gene families and proteins are activated
during ischemia. Immediate early genes, such as
those of the Fos and Jun families, are activated
soon after ischemia. It is believed that Ca2 þ and
reactive oxygen species are involved in the expres-
sion of immediate early genes. Although the exact
role of each of the immediate early genes in
ischemia is not yet understood, they are known to
participate in apoptosis. Some immediate early
genes may even afford neuronal protection. Ische-
mia also induces the expression of molecular
chaperones known as heat shock proteins, which
maintain protein function and assist in protein
transport in response to injury. Increasing the
expression of heat shock proteins to combat
ischemia has been attempted.
HYPOTHERMIA
Hypothermia confers protection against the devas-
tating effects of prolonged ischemia. In animal
models, hypothermia profoundly decreases the
release of glutamate, free radical activity, and
enzymes responsible for transducing intracellular
Ca2 þ signals. Therefore, lowering the body tem-
perature during ischemia offers strong neuronal
protection. However, animal studies of postischemic
hypothermia suggest that cooling applied after an
ischemic period delays rather than prevents ischemic
injury. Hypothermia is used during cardiac and
complicated neurovascular procedures. Risks such
as ventricular fibrillation, acidosis, and bleeding
dyscrasias are associated with hypothermic manip-
ulation, and its role in stroke patients has yet to be
determined.

CONCLUSION
Cell death from ischemia involves a complex biological
cascade. Initially, energy failure is followed by
glutamate overload and Ca2 þ influx into the cell.
These processed initiate a series of events, including the
generation of free radicals, apoptosis in the penumbra,
an inflammatory response, and generation of growth
factors. Many of these processes are the direct result of
the up- or downregulation of specific gene families.
The administration of exogenous agents or the
manipulation of specific genes can lead to effective
neuronal protection by altering these cellular events.
Despite the encouraging results associated with
direct neuronal protection therapy in animal models,
there have been no unequivocally positive results
with the use of these agents in clinical trials. The only
effective techniques in human trials have involved
reperfusion. Intravenously and interventionally de-
livered arterial thrombolytic therapy improves out-
come after acute ischemic stroke because cells in the
ischemic penumbra remain viable for some time after
stroke onset. Future strategies will most likely
employ neuronal protection agents to prevent further
cell loss in the penumbra before reperfusion through
thrombolytic therapy is reestablished.
—Graham Mouw, Warren R. Selman, W. David Lust,
and Robert A. Ratcheson
See also–Cell Death; Ischemic Cell Death,
Mechanisms; Cerebral Metabolism and Blood
Flow; Hypothermia; Hypothermic Circulatory
Arrest; Stroke Units
Further Reading
Hossmann, K. (1994). Viability thresholds and the penumbra of
focal ischemia. Ann. Neurol. 36, 557–565.
The National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group (1995). Tissue plasminogen activator for
acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587.
Suarez, J., Sunshine, J., Tarr, R., et al. (1999). Predictors of clinical
improvement, angiographic recanalization, and intercranial
hemorrhage after intra-arterial thrombolysis for acute ischemic
stroke. Stroke 30, 2094–2100.
Cerebral Vasospasm
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL VASOSPASM is transient vasoconstriction
of one or more cerebral arteries. It most commonly
CEREBRAL VASOSPASM 627
describes the arterial narrowing that occurs after
subarachnoid hemorrhage. If vasospasm is severe
enough, it will reduce blood flow to the brain
supplied by the spastic artery and this part of the
brain will infarct or die. The patient will usually
develop a neurological deficit called a delayed
ischemic neurological deficit because vasospasm
does not develop until several days after the
hemorrhage. The vasospasm is said to be sympto-
matic. Vasospasm visible on an angiogram is angio-
graphic vasospasm.
CONDITIONS ASSOCIATED WITH
CEREBRAL VASOSPASM
Vasospasm can occur whenever blood surrounds one
or more cerebral arteries in the subarachnoid space.
The most common and important cause is a ruptured
cerebral aneurysm since these are located in the
subarachnoid space and tend to cause the most
severe bleeding into this space. Vasospasm can occur
after subarachnoid bleeding from tumors, vascular
malformations, head injury, and intracranial surgery
for tumors or unruptured aneurysms. Vasospasm has
been reported in patients who had no obvious
bleeding into the subarachnoid space. There is
controversy regarding whether these produce the
same pathological condition as vasospasm after
subarachnoid hemorrhage. Arterial narrowing has
been observed in meningitis, eclampsia, migraine
headache, and noninfectious vasculitis.
EPIDEMIOLOGY AND CLINICAL FEATURES
The cerebral arteries slowly and progressively narrow
after subarachnoid hemorrhage, with the peak reduc-
tion in diameter occurring 7 days after the hemor-
rhage. The arteries return to normal diameter by
approximately 14 days. Symptoms and signs most
commonly develop 8 days after the hemorrhage and
include hemiparesis, hemihypesthesia, dysphasia,
paraparesis, and decreased consciousness. Increasing
headache, low-grade fever, and meningism may occur.
Approximately two-thirds of patients with aneurysmal
subarachnoid hemorrhage have angiographic vaso-
spasm. This is symptomatic in one-third and death or
permanent deficits occur in one-sixth of patients.
Whether a patient with subarachnoid hemorrhage
will develop vasospasm can be predicted by the
amount and location of subarachnoid blood visible
on a computed tomography (CT) scan done within 1
or 2 days of the hemorrhage (Fig. 1). Symptomatic

CONCLUSION
Cell death from ischemia involves a complex biological
cascade. Initially, energy failure is followed by
glutamate overload and Ca2 þ influx into the cell.
These processed initiate a series of events, including the
generation of free radicals, apoptosis in the penumbra,
an inflammatory response, and generation of growth
factors. Many of these processes are the direct result of
the up- or downregulation of specific gene families.
The administration of exogenous agents or the
manipulation of specific genes can lead to effective
neuronal protection by altering these cellular events.
Despite the encouraging results associated with
direct neuronal protection therapy in animal models,
there have been no unequivocally positive results
with the use of these agents in clinical trials. The only
effective techniques in human trials have involved
reperfusion. Intravenously and interventionally de-
livered arterial thrombolytic therapy improves out-
come after acute ischemic stroke because cells in the
ischemic penumbra remain viable for some time after
stroke onset. Future strategies will most likely
employ neuronal protection agents to prevent further
cell loss in the penumbra before reperfusion through
thrombolytic therapy is reestablished.
—Graham Mouw, Warren R. Selman, W. David Lust,
and Robert A. Ratcheson
See also–Cell Death; Ischemic Cell Death,
Mechanisms; Cerebral Metabolism and Blood
Flow; Hypothermia; Hypothermic Circulatory
Arrest; Stroke Units
Further Reading
Hossmann, K. (1994). Viability thresholds and the penumbra of
focal ischemia. Ann. Neurol. 36, 557–565.
The National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group (1995). Tissue plasminogen activator for
acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587.
Suarez, J., Sunshine, J., Tarr, R., et al. (1999). Predictors of clinical
improvement, angiographic recanalization, and intercranial
hemorrhage after intra-arterial thrombolysis for acute ischemic
stroke. Stroke 30, 2094–2100.
Cerebral Vasospasm
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL VASOSPASM is transient vasoconstriction
of one or more cerebral arteries. It most commonly
CEREBRAL VASOSPASM 627
describes the arterial narrowing that occurs after
subarachnoid hemorrhage. If vasospasm is severe
enough, it will reduce blood flow to the brain
supplied by the spastic artery and this part of the
brain will infarct or die. The patient will usually
develop a neurological deficit called a delayed
ischemic neurological deficit because vasospasm
does not develop until several days after the
hemorrhage. The vasospasm is said to be sympto-
matic. Vasospasm visible on an angiogram is angio-
graphic vasospasm.
CONDITIONS ASSOCIATED WITH
CEREBRAL VASOSPASM
Vasospasm can occur whenever blood surrounds one
or more cerebral arteries in the subarachnoid space.
The most common and important cause is a ruptured
cerebral aneurysm since these are located in the
subarachnoid space and tend to cause the most
severe bleeding into this space. Vasospasm can occur
after subarachnoid bleeding from tumors, vascular
malformations, head injury, and intracranial surgery
for tumors or unruptured aneurysms. Vasospasm has
been reported in patients who had no obvious
bleeding into the subarachnoid space. There is
controversy regarding whether these produce the
same pathological condition as vasospasm after
subarachnoid hemorrhage. Arterial narrowing has
been observed in meningitis, eclampsia, migraine
headache, and noninfectious vasculitis.
EPIDEMIOLOGY AND CLINICAL FEATURES
The cerebral arteries slowly and progressively narrow
after subarachnoid hemorrhage, with the peak reduc-
tion in diameter occurring 7 days after the hemor-
rhage. The arteries return to normal diameter by
approximately 14 days. Symptoms and signs most
commonly develop 8 days after the hemorrhage and
include hemiparesis, hemihypesthesia, dysphasia,
paraparesis, and decreased consciousness. Increasing
headache, low-grade fever, and meningism may occur.
Approximately two-thirds of patients with aneurysmal
subarachnoid hemorrhage have angiographic vaso-
spasm. This is symptomatic in one-third and death or
permanent deficits occur in one-sixth of patients.
Whether a patient with subarachnoid hemorrhage
will develop vasospasm can be predicted by the
amount and location of subarachnoid blood visible
on a computed tomography (CT) scan done within 1
or 2 days of the hemorrhage (Fig. 1). Symptomatic
628 CEREBRAL VASOSPASM
Figure 1
Axial computed tomography (CT) scans showing the four grades
of subarachnoid hemorrhage according to Fisher et al. Group 1
showed no blood on the CT scan. (A) Group 2 showed thin layers
of subarachnoid blood that appear as white densities in the
anterior interhemispheric (arrows) and Sylvian fissures
(arrowheads). Group 3 showed localized or diffuse thick layers of
subarachnoid blood (B), and group 4 showed diffuse or no
subarachnoid blood but intracerebral (C, arrows show
intracerebral hematoma) or intraventricular clots (D, arrows show
intraventricular blood).
vasospasm usually only develops in arteries that are
encased in thick blood clots.
PATHOPHYSIOLOGY AND PATHOLOGY
OF VASOSPASM
Vasospasm per se is not harmful: It exerts its
deleterious effects by reducing the blood flow to the
brain enough to cause cerebral ischemia and/or
infarction. Whether or not angiographic vasospasm
becomes symptomatic depends on factors, in addi-
tion to vasospasm, that affect how much blood flows
through the artery (Table 1).
Vasospastic arteries have a thickened wall. There is
folding of the internal elastic lamina with bunching
up of the endothelial cells and occasional endothelial
cell desquamation, vacuolation, and necrosis. The
smooth muscle cells of the tunica media are
contracted and occasionally vacuolated and necrotic.
The adventitia is thickened and may contain
scattered inflammatory cells. These changes develop
over the days after subarachnoid hemorrhage, and as
the artery relaxes there may be some fibrosis in the
tunica media and varying degrees of intimal pro-
liferation.
ETIOLOGY AND PATHOGENESIS
The etiology of vasospasm is subarachnoid blood
clot. Most theories of pathogenesis implicate a
compound or compounds released from the subar-
achnoid clot. A prime candidate is hemoglobin.
The delayed time of onset of vasospasm is attributed
to the time it takes for the erythrocytes to lyse
and release the hemoglobin. Hemoglobin may
constrict arteries by binding and destroying the
vasodilator nitric oxide, increasing the release of
vasoconstricting endothelins, generation of vasoac-
tive eicosanoids and other lipid peroxidation pro-
ducts, inhibition of the perivascular nerves, and
possibly by a direct effect on smooth muscle cells.
Another process suggested to be important in
vasospasm is inflammation.
The mechanism of arterial narrowing early in
vasospasm is smooth muscle contraction. Studies in
animal models show that in the first days of
vasospasm, most of the narrowing is reversible with
high doses of vasodilators such as papaverine. With
time, the arteries become stiffer and less able to
contract than normal. This is manifest by decreased
ability of papaverine to relax the spasm. Studies
Table 1 FACTORS THAT MAY REDUCE CEREBRAL BLOOD
FLOW AFTER SUBARACHNOID HEMORRHAGE
Vasospasm
Greater length and more severe narrowing
Inadequate collateral circulation to the brain due to preexisting
atherosclerotic or other stenosis, congenital hypoplasias, or
variation in the Circle of Willis
Systemic factors
Low blood pressure
Increased intracranial pressure
Decreased hematocrit
Decreased blood volume
Decreased cardiac output
Decreased substrate delivery to the brain
Decreased oxygen and glucose content of the blood
Increased metabolic demand of the brain
Hyperthermia
Seizures

Figure 2
(A) Axial CT scan showing diffuse, thick subarachnoid
hemorrhage on the day of the hemorrhage. (B) A left internal
carotid artery angiogram shows normal caliber of the internal
carotid, middle cerebral, and anterior cerebral (arrows) arteries.
An aneurysm is seen at the anterior communicating artery (double
arrow). (C) Seven days later, the same angiographic view shows
severe vasospasm of the anterior cerebral artery (arrows) with
focal areas of vasospasm in the internal carotid (arrowhead) and
middle cerebral (arrowhead) arteries. The aneurysm (double
arrow) is visible. (D) A CT scan 10 days after the hemorrhage
shows a low-density area consistent with an infarction in the brain
at the border zone between the anterior and middle cerebral
arteries (arrows).
suggest that the same processes occur in humans.
Less is known about the intracellular pathways of
contraction that produce the spasm, but they
probably involve alterations in multiple contractile
and relaxant pathways.
DIAGNOSIS
The diagnosis of vasospasm is made on a cerebral
angiogram that shows that the diameter of an artery
is narrower than it was previously (Fig. 2). Symp-
toms generally do not develop unless the diameter
reduction is more than 50%. The velocity of blood
flowing in the intracranial arteries can be measured
using transcranial Doppler ultrasound. Blood flow
velocity is related directly to the overall blood flow
through the artery and inversely to the square of the
radius of the artery. Therefore, the velocity increases
as the artery develops vasospasm as long as there are
CEREBRAL VASOSPASM 629
no major changes in cerebral blood flow. Vasospasm
may be diagnosed if the mean middle cerebral artery
flow velocity is more than 200 cm/sec or the ratio of
the flow velocity in the middle cerebral artery to the
velocity in the internal carotid artery in the neck is
greater than 4:6.
TREATMENT
Since vasospasm is caused in some way by the
subarachnoid blood and since it takes days to
develop, removal of the blood clots either surgically
or by administering fibrinolytic drugs into the
subarachnoid space within days of the hemorrhage
can prevent vasospasm. This has been shown
definitively in animals, although the evidence in
humans is less convincing. The mainstays of manage-
ment are to avoid factors that decrease cerebral
blood flow or increase the metabolic demand of the
brain (Table 1).
No drug prevents vasospasm. Nimodipine blocks
voltage-gated calcium channels, and it has been
administered to patients with subarachnoid hemor-
rhage because the calcium influx through this type of
channel contributes in part to contraction of cerebral
arteries. Most patients with aneurysmal subarach-
noid hemorrhage are treated with nimodipine. Since
there is no firm evidence that it reduces the frequency
or severity of vasospasm, the mechanism of benefit is
unknown.
If a patient develops symptomatic vasospasm
despite the previously discussed measures, attempts
are made to further increase cerebral blood flow by
increasing blood pressure or cardiac output and
perhaps by increasing circulating blood volume
(only if the patient’s aneurysm has been clipped
and there are no other aneurysms) and decreasing
hematocrit. If improvement does not occur rapidly,
then infarction may ensue. If the patient does not
improve and tests have excluded other causes of
neurological deterioration, an angiogram is usually
done to confirm the diagnosis. A small catheter with
a balloon on the end can be navigated into the
vasospastic artery, inflated to dilate the artery, and
then removed. This is called angioplasty, and it
results in reversal of the vasospasm. If angioplasty
cannot be done, drugs such as papaverine can be
infused through the catheter into the vasospastic
artery. This may dilate the artery, although the
effects are less durable and the spasm may recur
after 24 hr.
—R. Loch Macdonald
630 CEREBRAL VASOSPASM, TREATMENT OF
See also–Aneurysms; Cerebral Blood Vessels:
Arteries; Cerebral Metabolism and Blood Flow;
Cerebral Vasospasm, Treatment of; Cerebral
Venous Thrombosis; Subarachnoid Hemorrhage
Further Reading
Barker, F. G., and Ogilvy, C. S. (1996). Efficacy of prophylactic
nimodipine for delayed ischemic deficit after subarachnoid
hemorrhage: A metaanalysis. J. Neurosurg. 84, 405–414.
Cook, D. A. (1995). Mechanisms of cerebral vasospasm in
subarachnoid haemorrhage. Pharmacol. Ther. 66, 259–284.
Faraci, F. M., and Heistad, D. D. (1998). Regulation of the
cerebral circulation: Role of endothelium and potassium
channels. Physiol. Rev. 78, 53–97.
Findlay, J. M., Weir, B. K., Kanamaru, K., et al. (1989). Arterial
wall changes in cerebral vasospasm. Neurosurgery 25,
736–745.
Findlay, J. M., Kassell, N. F., Weir, B. K., et al. (1995). A
randomized trial of intraoperative, intracisternal tissue plasmi-
nogen activator for the prevention of vasospasm. Neurosurgery
37, 168–176.
Fisher, C. M., Kistler, J. P., and Davis, J. M. (1980). Relation of
cerebral vasospasm to subarachnoid hemorrhage visualized by
computerized tomographic scanning. Neurosurgery 6, 1–9.
Kassell, N. F., Torner, J. C., Haley, E. C. J., et al. (1990). The
international cooperative study on the timing of aneurysm
surgery. Part 1: Overall management results. J. Neurosurg. 73,
18–36.
Lindegaard, K. F., Sorteberg, W., and Nornes, H. (1993).
Transcranial Doppler in neurosurgery. Adv. Tech. Standards
Neurosurg. 20, 39–80.
Macdonald, R. L. (1995). Cerebral vasospasm. Neurosurg. Q. 5,
73–97.
Vorkapic, P., Bevan, R. D., and Bevan, J. A. (1991). Longitudinal
time course of reversible and irreversible components of chronic
cerebrovasospasm of the rabbit basilar artery. J. Neurosurg. 74,
951–955.
Weir, B., and Macdonald, R. L. (2000). Cerebral Vasospasm.
Academic Press, San Diego.
Cerebral Vasospasm,
Treatment of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL VASOSPASM, a contraction of the major
arterial branches of the circle of Willis, is the leading
cause of death and complications among patients
admitted to hospitals with aneurysmal subarachnoid
hemorrhage (SAH). Angiographic evidence of vasos-
pasm is detectable in as many as 90% of such
patients, whereas clinically symptomatic disease is
seen in only 30% of this group. Symptoms are
variable, ranging from a depression in mental status
to a frank, acute neurological deficit. Typically, the
clinical scenario develops between days 4 and 14
after SAH. Thick collections of subarachnoid blood
in the basal cisterns are often predictive of vaso-
spasm. The diagnosis, however, can only be con-
firmed angiographically.
The standard medical treatment of vasospasm
consists of a triad of therapies—induced hyperten-
sion, hypervolemia, and hemodilution. This ‘‘triple
H’’ therapy has been studied extensively in both
humans and animal models. Although the physiolog-
ical mechanisms are debatable, each component of
this treatment has proven effective in the manage-
ment of vasospasm.
HYPERTENSION
This part of the triple H protocol has the soundest
scientific basis. Both vasospasm and SAH are
associated with impaired cerebral autoregulation.
The induction of hypertension directly augments
cerebral blood flow (CBF) by enhancing collateral
circulation and increasing the perfusion pressure in
dysautoregulated areas. This result has been sub-
stantiated both clinically and experimentally. Never-
theless, experimental evidence has also confirmed
that the ability of induced hypertension to improve
perfusion depends on the extent of collateral blood
supply and on the duration of ischemia. The use of
this therapy in patients with irreversible cellular
damage may promote focal cerebral edema, impede
microcirculatory flow, and lead to the formation of
reperfusion hemorrhages.
A number of different pharmacological inotropes,
including dopamine, neosynephrine, epinephrine,
and dobutamine, have been used to induce hyperten-
sion in patients with vasospasm. The induction of
hypervolemic therapy, however, may suffice in
raising the systemic blood pressure and thereby
obviate the need for pressor support. Typically,
blood pressure must be between 150 and 160 mmHg
to manage vasospasm effectively. This ceiling can
be pushed to approximately 200 mmHg in sympto-
matic patients with secured aneurysms. If an
aneurysm has yet to be clipped or coiled, the lower
range is preferable to reduce the likelihood of
rerupture. Although one may surmise that such
therapy could worsen cerebral arterial constriction
and produce edema, neither scenario has been
proven experimentally or clinically in patients who
have not yet reached the point of irreversible cellular
damage.
630 CEREBRAL VASOSPASM, TREATMENT OF
See also–Aneurysms; Cerebral Blood Vessels:
Arteries; Cerebral Metabolism and Blood Flow;
Cerebral Vasospasm, Treatment of; Cerebral
Venous Thrombosis; Subarachnoid Hemorrhage
Further Reading
Barker, F. G., and Ogilvy, C. S. (1996). Efficacy of prophylactic
nimodipine for delayed ischemic deficit after subarachnoid
hemorrhage: A metaanalysis. J. Neurosurg. 84, 405–414.
Cook, D. A. (1995). Mechanisms of cerebral vasospasm in
subarachnoid haemorrhage. Pharmacol. Ther. 66, 259–284.
Faraci, F. M., and Heistad, D. D. (1998). Regulation of the
cerebral circulation: Role of endothelium and potassium
channels. Physiol. Rev. 78, 53–97.
Findlay, J. M., Weir, B. K., Kanamaru, K., et al. (1989). Arterial
wall changes in cerebral vasospasm. Neurosurgery 25,
736–745.
Findlay, J. M., Kassell, N. F., Weir, B. K., et al. (1995). A
randomized trial of intraoperative, intracisternal tissue plasmi-
nogen activator for the prevention of vasospasm. Neurosurgery
37, 168–176.
Fisher, C. M., Kistler, J. P., and Davis, J. M. (1980). Relation of
cerebral vasospasm to subarachnoid hemorrhage visualized by
computerized tomographic scanning. Neurosurgery 6, 1–9.
Kassell, N. F., Torner, J. C., Haley, E. C. J., et al. (1990). The
international cooperative study on the timing of aneurysm
surgery. Part 1: Overall management results. J. Neurosurg. 73,
18–36.
Lindegaard, K. F., Sorteberg, W., and Nornes, H. (1993).
Transcranial Doppler in neurosurgery. Adv. Tech. Standards
Neurosurg. 20, 39–80.
Macdonald, R. L. (1995). Cerebral vasospasm. Neurosurg. Q. 5,
73–97.
Vorkapic, P., Bevan, R. D., and Bevan, J. A. (1991). Longitudinal
time course of reversible and irreversible components of chronic
cerebrovasospasm of the rabbit basilar artery. J. Neurosurg. 74,
951–955.
Weir, B., and Macdonald, R. L. (2000). Cerebral Vasospasm.
Academic Press, San Diego.
Cerebral Vasospasm,
Treatment of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBRAL VASOSPASM, a contraction of the major
arterial branches of the circle of Willis, is the leading
cause of death and complications among patients
admitted to hospitals with aneurysmal subarachnoid
hemorrhage (SAH). Angiographic evidence of vasos-
pasm is detectable in as many as 90% of such
patients, whereas clinically symptomatic disease is
seen in only 30% of this group. Symptoms are
variable, ranging from a depression in mental status
to a frank, acute neurological deficit. Typically, the
clinical scenario develops between days 4 and 14
after SAH. Thick collections of subarachnoid blood
in the basal cisterns are often predictive of vaso-
spasm. The diagnosis, however, can only be con-
firmed angiographically.
The standard medical treatment of vasospasm
consists of a triad of therapies—induced hyperten-
sion, hypervolemia, and hemodilution. This ‘‘triple
H’’ therapy has been studied extensively in both
humans and animal models. Although the physiolog-
ical mechanisms are debatable, each component of
this treatment has proven effective in the manage-
ment of vasospasm.
HYPERTENSION
This part of the triple H protocol has the soundest
scientific basis. Both vasospasm and SAH are
associated with impaired cerebral autoregulation.
The induction of hypertension directly augments
cerebral blood flow (CBF) by enhancing collateral
circulation and increasing the perfusion pressure in
dysautoregulated areas. This result has been sub-
stantiated both clinically and experimentally. Never-
theless, experimental evidence has also confirmed
that the ability of induced hypertension to improve
perfusion depends on the extent of collateral blood
supply and on the duration of ischemia. The use of
this therapy in patients with irreversible cellular
damage may promote focal cerebral edema, impede
microcirculatory flow, and lead to the formation of
reperfusion hemorrhages.
A number of different pharmacological inotropes,
including dopamine, neosynephrine, epinephrine,
and dobutamine, have been used to induce hyperten-
sion in patients with vasospasm. The induction of
hypervolemic therapy, however, may suffice in
raising the systemic blood pressure and thereby
obviate the need for pressor support. Typically,
blood pressure must be between 150 and 160 mmHg
to manage vasospasm effectively. This ceiling can
be pushed to approximately 200 mmHg in sympto-
matic patients with secured aneurysms. If an
aneurysm has yet to be clipped or coiled, the lower
range is preferable to reduce the likelihood of
rerupture. Although one may surmise that such
therapy could worsen cerebral arterial constriction
and produce edema, neither scenario has been
proven experimentally or clinically in patients who
have not yet reached the point of irreversible cellular
damage.
 CEREBRAL VASOSPASM, TREATMENT OF 631

HYPERVOLEMIA dilates, shear rates are low. The influence of

hematocrit is greatest at these low levels, when
Typically, patients suffering SAH demonstrate a
elevations can directly increase blood viscosity and
reduced intravascular volume and red cell mass.
impair the delivery of oxygen and nutrients to
Numerous clinical studies have shown that vaso-
ischemic regions. Although patients with elevated
spasm often occurs in this setting. Volume expansion
hematocrits and increased viscosity demonstrate a
has a beneficial therapeutic effect. However, it is
higher incidence of stroke, the opposite is true of
difficult to discern whether this result is the product
patients with anemia and low blood viscosity.
of concomitantly elevated blood pressure or the
Like hypervolemic therapy, the physiological
secondary hemodilution that typically follows the
mechanism underlying the beneficial effect of hemo-
administration of large amounts of fluids. Most
dilution has yet to be elucidated. Certainly, hemodi-
studies supporting the use of this therapeutic
lution produces two contrary effects. Although
modality fail to distinguish its role independent from
decreasing the hematocrit lowers blood viscosity
the other interventions.
and thereby improves CBF, it also reduces the
Nevertheless, most experimental evidence supports
delivery of oxygen to normal and ischemic tissues.
the effect of hypervolemia on bolstering cardiac
Like the reduction in viscosity, this latter effect can
output as the primary means of improving CBF.
also explain the improvement in CBF. As the brain
Volume expansion augments left ventricular end
receives less oxygen, blood flow is augmented to
diastolic pressure, stroke volume, and cardiac out-
counteract ischemia. Clinical and experimental
put. These hemodynamic factors improve CBF,
evidence suggests that the reduction in oxygen
although the underlying physiological mechanism is
delivery in humans is likely more influential in
unknown. Experimental evidence reveals that im-
triggering improvement in CBF than is the decrease
proved cardiac performance increases CBF to
in the hematocrit.
ischemic regions but has little effect on normally
A combination of factors probably produces the
perfused areas. Like the effect of hypertensive
beneficial effects of hemodilution. Experimental and
therapy, this phenomenon suggests that regions of
clinical studies demonstrate that oxygen transport is
dysautoregulation are uniquely susceptible to
maximized at hematocrit values ranging from 30 to
changes in CBF.
35%. At lower levels, the relative delivery of oxygen
Both isotonic and hypertonic crystalloid solutions
declines precipitously. Despite these results, the
as well as albumin, plasma, and packed erythrocytes
overall efficacy of hemodilution in the management
may be used to induce hypervolemia. Optimally,
of acute cerebral ischemia and in the treatment of
central venous pressure is elevated to 10–12 mmHg,
vasospasm remains controversial. Many studies
and the pulmonary capillary wedge pressure is raised
neglect to delineate the concomitant effects of
to 15–18 mmHg. The latter is determined through
hypervolemia, and reports on isovolemic hemodilu-
use of a pulmonary artery Swan–Ganz catheter,
tion are also conflicting.
which serves the additional role of delineating
cardiac output and guiding the use of inotropic
support. Pulmonary edema, cerebral edema, dilu- CONCLUSION
tional hyponatremia, and the assorted complications
SAH from aneurysmal rupture can produce devastat-
of central venous catheterization represent the risks
ing consequences. Cerebral vasospasm is the leading
of this therapy. Typically, however, these complica-
cause of death and of major complications in patients
tions can be avoided with judicious use of hypervo-
who survive the initial rupture. Vasospasm is
lemia and knowledge of the patient’s underlying
produced by a multifactorial cascade of events that
medical conditions.
is not fully understood. Vasospasm typically affects
the major vessels at the skull base. The ensuing
arterial contraction relegates CBF to dependence on
HEMODILUTION
the influences of blood pressure and viscosity.
Experimental and clinical evidence suggests that Hemodynamic manipulation through hypertensive,
lowering the hematocrit has a protective effect hypervolemic, and hemodilutional therapy has
against stroke. This result likely reflects the effect proven beneficial in reversing this deleterious
of the hematocrit on blood viscosity and shear rate. sequence of events.
When CBF decreases and the cerebrovasculature —Felipe C. Albuquerque and Robert F. Spetzler
632 CEREBRAL VENOUS THROMBOSIS

See also–Cerebral Metabolism and Blood Flow; ANATOMY OF THE CEREBRAL

Cerebral Vasospasm; Circle of Willis; Intracranial
Hypertension; Subarachnoid Hemorrhage
Further Reading
Awad, I. A., Carter, L. P., Spetzler, R. F., et al. (1987). Clinical
vasospasm after subarachnoid hemorrhage: Response to hyper-
volemic hemodilution and arterial hypertension. Stroke 18,
365–372.
Doberstein, C., and Martin, N. A. (1995). Cerebral blood flow
in clinical neurosurgery. In Youmans Neurological Surgery
(J. R. Youmans, Ed.), 4th ed., pp. 519–569. Saunders,
Philadelphia.
Friedman, A. H. (1996). Pre- and postoperative management of a
patient with a ruptured aneurysm. In Neurosurgery (H. H.
Wilkins and S. S. Rengachary, Eds.), pp. 2261–2270. McGraw-
Hill, New York.
Giannotta, S. L., McGillicuddy, J. E., and Kindt, G. W. (1977).
Diagnosis and treatment of postoperative cerebral vasospasm.
Surg. Neurol. 8, 286–290.
Kassell, N. F., Peerless, S. J., Durward, Q. J., et al. (1982).
Treatment of ischemic deficits from vasospasm with intravas-
cular volume expansion and induced arterial hypertension.
Neurosurgery 11, 337–343.
Levy, M. L., Rabb, C. H., Zelman, V., et al. (1993). Cardiac
performance enhancement from dobutamine in patients
refractory to hypervolemic therapy for cerebral vasospasm.
J. Neurosurg. 79, 494–499.
MacDonald, R. L., and Weir, B. (1996). Cerebral vasospasm:
Prevention and treatment. In Cerebrovascular Disease (H. H.
Batjer, L. R. Caplan, L. Friberg, R. G. Greenlee, Jr., T. A.
Kopitnik, Jr., and W. L. Young, Eds.), pp. 1111–1121.
Lippincott Williams & Wilkins, Philadelphia.
VENOUS SYSTEM
The cerebral venous system consists of the cerebral
veins, the posterior fossa veins, and the dural venous
sinuses. All cerebral veins drain into the dural venous
sinuses and ultimately into the jugular veins. There is
also a collection of emissary veins, connecting
extracranial veins with dural sinuses, and a basilar
venous plexus around the base of the brain that
communicates with the epidural venous plexus of the
spinal cord.
Major portions of the cerebral hemispheres are
drained by the superior sagittal sinus (SSS) and its
tributaries. The deep hemispheric structures are
drained by the inferior sagittal sinus, the straight
sinus, and their tributaries. Both systems converge
toward the confluence of sinuses (torcular Herophi-
li). There, the SSS is often continuous with right
lateral sinus, and the straight sinus is continuous
with the left lateral sinus.
The dural venous sinuses (Fig. 1) consist of (i) the
SSS, a midline structure between the inner table of
the skull superiorly and the two leaves of the falx
cerebri laterally, which runs from the crista galli to

Cerebral Venous Thrombosis

Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

CEREBRAL VENOUS THROMBOSIS (CVT) is a term

used to describe thrombosis of the cortical and deep
veins of the brain as well as the dural venous sinuses
into which they drain. CVT affects all ages from the
neonate to the very old, although young women are
disproportionately affected, especially during preg-
nancy and the puerperium. CVT is considerably
rarer than arterial stroke, partly due to the wide
diversity of clinical presentations and the need for
considerably more extensive diagnostic investiga-
tions. The potential for recovery is considerable,
especially with appropriate therapeutic measures Figure 1
early in the course of the disease. Therefore, early Cerebral angiography—venous phase. A, Superior sagittal sinus; B,
cortical vein; C, inferior sagittal sinus; D, straight sinus; E, torcular
diagnosis is essential, and neurologists should Herophili; F, vein of Galen; G, internal cerebral vein; H, lateral
include CVT in the differential diagnosis of a wide sinus, transverse segment; I, lateral sinus, sigmoid segment; J,
variety of conditions. jugular vein.
632 CEREBRAL VENOUS THROMBOSIS

See also–Cerebral Metabolism and Blood Flow; ANATOMY OF THE CEREBRAL

Cerebral Vasospasm; Circle of Willis; Intracranial
Hypertension; Subarachnoid Hemorrhage
Further Reading
Awad, I. A., Carter, L. P., Spetzler, R. F., et al. (1987). Clinical
vasospasm after subarachnoid hemorrhage: Response to hyper-
volemic hemodilution and arterial hypertension. Stroke 18,
365–372.
Doberstein, C., and Martin, N. A. (1995). Cerebral blood flow
in clinical neurosurgery. In Youmans Neurological Surgery
(J. R. Youmans, Ed.), 4th ed., pp. 519–569. Saunders,
Philadelphia.
Friedman, A. H. (1996). Pre- and postoperative management of a
patient with a ruptured aneurysm. In Neurosurgery (H. H.
Wilkins and S. S. Rengachary, Eds.), pp. 2261–2270. McGraw-
Hill, New York.
Giannotta, S. L., McGillicuddy, J. E., and Kindt, G. W. (1977).
Diagnosis and treatment of postoperative cerebral vasospasm.
Surg. Neurol. 8, 286–290.
Kassell, N. F., Peerless, S. J., Durward, Q. J., et al. (1982).
Treatment of ischemic deficits from vasospasm with intravas-
cular volume expansion and induced arterial hypertension.
Neurosurgery 11, 337–343.
Levy, M. L., Rabb, C. H., Zelman, V., et al. (1993). Cardiac
performance enhancement from dobutamine in patients
refractory to hypervolemic therapy for cerebral vasospasm.
J. Neurosurg. 79, 494–499.
MacDonald, R. L., and Weir, B. (1996). Cerebral vasospasm:
Prevention and treatment. In Cerebrovascular Disease (H. H.
Batjer, L. R. Caplan, L. Friberg, R. G. Greenlee, Jr., T. A.
Kopitnik, Jr., and W. L. Young, Eds.), pp. 1111–1121.
Lippincott Williams & Wilkins, Philadelphia.
VENOUS SYSTEM
The cerebral venous system consists of the cerebral
veins, the posterior fossa veins, and the dural venous
sinuses. All cerebral veins drain into the dural venous
sinuses and ultimately into the jugular veins. There is
also a collection of emissary veins, connecting
extracranial veins with dural sinuses, and a basilar
venous plexus around the base of the brain that
communicates with the epidural venous plexus of the
spinal cord.
Major portions of the cerebral hemispheres are
drained by the superior sagittal sinus (SSS) and its
tributaries. The deep hemispheric structures are
drained by the inferior sagittal sinus, the straight
sinus, and their tributaries. Both systems converge
toward the confluence of sinuses (torcular Herophi-
li). There, the SSS is often continuous with right
lateral sinus, and the straight sinus is continuous
with the left lateral sinus.
The dural venous sinuses (Fig. 1) consist of (i) the
SSS, a midline structure between the inner table of
the skull superiorly and the two leaves of the falx
cerebri laterally, which runs from the crista galli to

Cerebral Venous Thrombosis

Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

CEREBRAL VENOUS THROMBOSIS (CVT) is a term

used to describe thrombosis of the cortical and deep
veins of the brain as well as the dural venous sinuses
into which they drain. CVT affects all ages from the
neonate to the very old, although young women are
disproportionately affected, especially during preg-
nancy and the puerperium. CVT is considerably
rarer than arterial stroke, partly due to the wide
diversity of clinical presentations and the need for
considerably more extensive diagnostic investiga-
tions. The potential for recovery is considerable,
especially with appropriate therapeutic measures Figure 1
early in the course of the disease. Therefore, early Cerebral angiography—venous phase. A, Superior sagittal sinus; B,
cortical vein; C, inferior sagittal sinus; D, straight sinus; E, torcular
diagnosis is essential, and neurologists should Herophili; F, vein of Galen; G, internal cerebral vein; H, lateral
include CVT in the differential diagnosis of a wide sinus, transverse segment; I, lateral sinus, sigmoid segment; J,
variety of conditions. jugular vein.
 CEREBRAL VENOUS THROMBOSIS 633

the confluence of sinuses; (ii) the inferior sagittal symptoms secondary to localized edema and cerebral
sinus, located in the inferior free margin of the falx infarction with extravasation of blood and plasma. A
cerebri, which joins the vein of Galen to form the clot in the cerebral veins and sinuses may eventually
straight sinus; (iii) the straight sinus, between the falx become fibrotic and recanalize.
cerebri and tentorium cerebelli, which courses back-
wards to join the SSS at the confluence of sinuses; (iv)
ETIOLOGY AND PATHOGENESIS
the transverse sinuses, originating at the torcular and
coursing laterally; (v) the sigmoid sinuses, the There is a long and ever-increasing list of conditions
continuations of the transverse sinuses, which empty that have been defined as either causing or predis-
into the jugular bulb at the base of the skull; and (vi) posing to CVT (Table 1). However, the proportion of
the cavernous sinuses, a collection of venous cases of unknown etiology remains high, ranging
channels, which contain the internal carotid artery from 20 to 35%. Infections are still the single
and cranial nerves III, IV, V1, V2, and VI and most common identifiable cause of CVT, although
communicate superolaterally with the sigmoid sinus due to modern treatments they account for a
via the superior petrosal sinus and inferiorly with the
jugular bulb via the inferior petrosal sinuses.
The cerebral veins (Fig. 1) divide into superficial
Table 1 CEREBRAL VENOUS THROMBOSIS CAUSES AND
and deep veins. They do not have valves and they are PREDISPOSING CONDITIONS
much more variable than the cerebral arterial system.
Idiopathic infective causes
The superficial venous system is formed by two
Local
groups of veins—the superior group, which empties Regional infections: mastoiditis, sinusitis, otitis, cellulitis,
into the superior and inferior sagittal sinuses, and the dental infection
inferior group, which empties into the transverse and Intracranial infections: meningitis, empyema, abscess
cavernous sinuses. Important superficial veins are the Direct septic injury
Systemic
superficial middle cerebral vein, the superior anasto-
Viral (herpes, hepatitis, cytomegalovirus, HIV)
motic vein (of Trolard), and the inferior anastomotic Bacterial (septicemia, endocarditis)
vein (of Labbé). The deep venous system consists of Fungal (cryptococcus, aspergillosis)
the internal cerebral veins (formed by the septal and Parasitic (trichinosis, malaria)
the thalamostriate veins near the foramen of Monro), Noninfective causes
the great cerebral vein of Galen (formed by the two Local
Penetrating and nonpenetrating trauma
internal cerebral veins), and the deep middle cerebral
Neurosurgical procedures
vein, which drains the insula and forms in each side Foreign body (cardiac pacemaker, jugular venous catheter)
the basal vein (of Rosenthal) that empties into the Solid brain tumors
great vein. Systemic
Hemodynamic
Dehydration, congestive heart failure, fever
PATHOPHYSIOLOGY Hypercoagulable states
Polycythemia vera, sickle cell disease, thrombocythemia,
In the acute stage, thrombosis of the cerebral veins leukemia
and venous sinuses leads to the development of a Disseminated intravascular coagulation, thrombotic
predominantly red clot (consisting of red blood cells thrombocytopenic purpura
Antithrombin III, protein C, and protein S deficiencies
and fibrin). Within the dural venous sinuses, the clot
Anti-phospholipid antibodies
or its products may activate pain receptors, disrupt Inflammatory disorders
the absorption of the cerebrospinal fluid through the Inflammatory bowel disease
arachnoid granulations, and distend the superficial Behcet’s disease
and deep veins that drain into the venous sinuses. Systemic lupus erythematosus
Obstetrical–gynecological
These distended cerebral veins may rupture into the
Puerperium and pregnancy
brain parenchyma or into the subarachnoid space Oral contraceptives
and cause intracerebral or subarachnoid hemor- Hereditary
rhage. In infectious cases, either purulent meningitis Factor V Leiden mutation
or brain abscess may result. If the thrombotic process G20210A mutation in the prothrombin (factor II) gene
Homozygous C677 T mutation in the methylene
extends from the sinus into the superficial or deep
tetrahydrofolate reductase gene
cerebral veins, it could cause focal signs and
634 CEREBRAL VENOUS THROMBOSIS
proportionally smaller number of cases. Regional
infections, such as otitis, mastoiditis, sinusitis, dental
abscesses, osteomyelitis, and epidermal infections,
most commonly precipitate thrombosis of the caver-
nous sinuses, the lateral sinuses, and the SSS
either hematogenously or via contiguous spread.
Intracranial infections, meningitis, and brain ab-
scesses also predispose to CVT. Systemic infections
with bacterial, viral, parasitic, and fungal pathogens
are also associated with thrombotic states, most
often of the SSS.
Noninfectious causes of CVT also include either
local or general systemic disorders. Local precipi-
tants include penetrating and nonpenetrating head
injuries, neurosurgical operations, and placement of
cardiac pacemakers or jugular venous catheters.
Solid malignant tumors can also precipitate CVT
by obstructing the venous sinus or the jugular
outflow tract, thus creating stasis. Obstruction of a
sinus from within can occur in cases of hematological
malignancies, such as leukemia.
The general medical conditions associated with
CVT are numerous and include those that cause
alteration in the hemodynamic status, such as
congestive heart failure and dehydration; a hyper-
coagulable state, such as malignancy, polycythemia
vera, disseminated intravascular coagulation, and
sickle cell anemia; and inflammatory changes within
the venous sinuses and channels, such as Behcet’s
disease, inflammatory bowel disease, and systemic
lupus erythematosus.
The mean age of approximately 40 years for those
diagnosed with CVT is partially explained by the
large number of young women who develop CVT in
their reproductive years. In developing countries,
CVT occurs in young women mostly during the
puerperium and pregnancy, whereas in developed
countries oral contraceptives play a more important
role than the natural reproductive events and are
associated with approximately 10% of cases. The
role of contraceptives is likely more complex because
there is interaction between contraceptives and other
predisposing or etiological factors, such as collagen
vascular disease, malignancy or Behcet’s disease, or
hereditary thrombophilias.
The hereditary thrombophilic states, such as the
factor V Leiden mutation (causing resistance to
activated protein C) and the 20210 G-to-A pro-
thrombin gene mutation, are among the most
common noninfective causes of CVT. They are
known to increase the risk of venous thrombosis by
4–10 and 2–4 times, respectively, and have been
identified as contributing factors in large series of
CVT. Hereditary thrombophilias should be the
object of careful and systematic investigation in
CVT because they increase the risk of CVT
associated with other conditions, such as oral
contraceptives, anti-phospholipid antibodies, puer-
perium, or head trauma, and because their detection
is important for the long-term prevention of venous
thrombosis in high-risk situations in patients and
their family members. In general, the search for a
cause remains one of the most difficult problems in
CVT, often requiring extensive initial diagnostic
investigations and long periods of follow-up.
CLINICAL PRESENTATION
The spectrum of symptoms and signs of CVT is
remarkably wide, and it reflects the site and rate of
thrombosis and the nature of the causing or
predisposing disorder. Headache, papilledema, focal
neurological deficits, and progressive depression in
the level of consciousness are features of classic
description of CVT, which with early diagnosis is not
necessarily the most common one.
Headache, the most frequent symptom of CVT in
all series, is present in at least 75% of patients in the
largest series. This headache has no specific features
or pattern, is likely due to irritation of pain-sensitive
structures by the evolving thrombotic process, and is
often associated with other neurological signs.
Papilledema is found in approximately half of
patients and is mostly observed in young patients.
This results when the venous clot prevents resorption
of the cerebrospinal fluid (CSF) through the ara-
chnoid granulations. Transient visual obscurations
may occur in association with papilledema. The
combination of headache and papilledema is a
common presentation of thrombosis of the superior
sagittal or the lateral sinuses and mimics pseudotu-
mor cerebri. In these cases, magnetic resonance
imaging of the brain should be performed to rule
out the existence of a mass lesion and to search for
the presence of CVT.
Seizures are more frequent with CVT than with
arterial stroke, and they are present at some time
during its course in approximately 40% of patients.
They signify the presence of an irritative cortical
lesion, such as a hemorrhagic venous infarction
occurring as a result of extension of the thrombotic
process into a cortical vein. They are typically of a
focal nature. Depressed level of consciousness is
rarely an initial symptom, but it is present during the

course of CVT in approximately half of patients. It is
noted early mostly in patients with extensive
involvement of the deep venous system, likely as a
result of extensive bilateral thalamic dysfunction.
Deep unconsciousness is uncommon and suggests
either a postictal state or extensive and rapid deep
venous system thrombosis. Sudden, severe headache
in combination with altered mental status may also
signify rupture of a distended cerebral vein into the
subarachnoid space or thalamic infarctions.
Focal neurological deficits occur during the course
of the disease in approximately 60% of patients. The
type and severity of the deficit depend on the location
and extent of the thrombosis. They may occur with
isolated thrombosis of the deep or superficial
cerebral veins or because of extension of the clot
from a dural sinus into a cortical vein. Sudden onset
of a focal neurological deficit, such as hemiparesis or
aphasia, may mimic an arterial stroke. In CVT,
however, the neurological deficits are often preceded
by headache and may be accompanied by a focal
seizure. When the focal neurological deficits are
transient, a migraine equivalent or a transient
ischemic attack of arterial origin may be considered
in the differential diagnosis. With subacute or
chronic progression of the deficits, the clinical picture
may mimic a brain abscess or tumor.
Although rare, thrombosis of the cavernous sinus
results in the most distinct clinical presentation.
Unilateral proptosis, chemosis, and ophthalmoplegia
from venous congestion and inflammation of the
oculomotor nerves may be associated with facial
sensory symptoms in the first two divisions of the
trigeminal nerve. Involvement of the opposite caver-
nous sinus often follows, and this spread helps
distinguish this constellation of symptoms from other
causes, such as thyroid ophthalmopathy, superior
orbital or orbital apex syndromes, orbital cellulitis,
and Tolosa–Hunt syndrome.
There are many other uncommon presentations of
CVT, including psychiatric disturbances, akinetic
mutism, ataxia and vertigo, and isolated cortical
blindness. CVT has also been reported as an
incidental finding on autopsy studies—not clinically
apparent during life and not related to the cause of
death.
DIAGNOSIS
In the early stages of CVT, the diagnosis is often
elusive. The temperature is higher than 37.51C in
half of the patients, the laboratory values are often
CEREBRAL VENOUS THROMBOSIS 635
normal or nondiagnostic, and leukocytosis and an
elevated erythrocyte sedimentation rate may occur,
especially when the underlying cause is inflamma-
tory, infectious, or neoplastic. The diagnostic evalua-
tion is focused first on establishing the diagnosis of
CVT and second on defining the underlying etiology.
Cerebrospinal Fluid
The pressure may be elevated. CSF abnormalities
occur in most patients. Protein elevation is most
common, whereas pleocytosis, xanthochromia, or
subarachnoid blood are less common. Obviously,
CSF analysis plays a major role in suspected septic
CVT, but even in these patients the CSF cultures are
often sterile.
Electroencephalography
Normal and abnormal electroencephalograms
(EEGs) are encountered equally frequently. The most
common abnormality is diffuse slow-wave activity,
even in patients with focal signs. Epileptiform
activity is found in fewer than 20% of patients.
Bilateral frontal continuous or paroxysmal delta
activity and slow spike-and-wave formations are
characteristically seen in thrombosis of the superior
sagittal sinus.
Neuroimaging
The diagnosis of CVT is primarily based on the
findings of neuroradiological studies. Computed
tomography (CT) of the head is usually the first
emergent investigation. It may be normal, especially
when CVT presents as pseudotumor cerebri. CT scan
reveals direct signs of CVT in approximately one-
third of cases. Signs include the empty delta sign
(Fig. 2), visible after contrast injection, usually in the
first month in cases of thrombosis of the SSS; the
cord sign, an irregular high-density lesion in super-
ficial aspects of the cerebral hemisphere thought to
represent a thrombosed cortical vein; and the delta
(dense triangle) sign, an abnormally high density in
relation to the SSS or straight sinus. Other changes
seen on nonenhanced CT include diffuse cerebral
swelling, small ventricles, and unilateral or bilateral
hemorrhage and hemorrhagic infarctions. On en-
hanced CT scans, intense tentorial enhancement,
diffuse gyral enhancement, and the absence of the
normal enhancement of the cavernous sinus may be
encountered. Spiral CT venous angiography has also
been developed and may eventually be accepted as an
excellent tool to detect CVT.
636 CEREBRAL VENOUS THROMBOSIS
Figure 2
Enhanced CT scan demonstrating (A) hemorrhagic infarct, (B)
empty delta sign, and (C) enhancement of the falx cerebri.
Magnetic resonance imaging (MRI) offers major
advantages for the evaluation of CVT because of its
sensitivity in detecting blood flow, its ability to
visualize the thrombus, and its noninvasive nature.
The MRI scan often demonstrates dural sinus
thrombosis while the CT scan remains normal. The
appearance of the thrombus changes over time as a
result of conversion of intracellular oxyhemoglobin
to extracellular oxyhemoglobin to methemoglobin.
In the first few days, the MRI diagnosis is often more
difficult. There may be an absence of flow void
within the affected venous sinus (Fig. 3a), and the
clot is isointense on T1-weighted imaging and
hypointense on T2-weighted imaging. The use of
gradient echo T2-weighted imaging may allow easier
interpretation of the findings in the acute phase. A
few days later, the diagnosis becomes more obvious
because there is increased signal of the clot on both
T1-weighted imaging (Fig. 3b) and T2-weighted
imaging. After the first 2–4 weeks, the diagnosis
may become more difficult because the clot acquires
a variable signal and the flow void returns due to
recanalization of the clot. The MRI diagnosis of CVT
is more straightforward with thrombosis of the SSS
and the lateral and straight sinuses. Cortical vein
thrombosis is much more difficult to demonstrate.
MRI also allows definition of the parenchymal
lesions induced by CVT, such as brain swelling,
infarction, and hemorrhage. Recently, diffusion-
weighted imaging has revealed a combination of
vasogenic and cytotoxic edema in patients with CVT.
Venous MR angiography is an excellent tool for the
detection of dural sinus thrombosis and subsequent
follow-up (Fig. 4).
Catheter cerebral angiography is performed
mostly when the diagnosis is uncertain after MRI,
when MRI cannot be done, or when there is need for
assessment of specific sequelae of CVT, namely dural
arteriovenous fistula. An effective technique in-
volves four-vessel angiography with visualization
of the entire venous phase on at least two, preferably
three, projections, with obtainment of delayed films
(up to 12 sec after dye is injected). Partial or
complete lack of filling of veins or sinuses are typical
signs of CVT, but these findings are mostly
recognized when either the posterior part or the
entire SSS, both lateral sinuses, or the deep venous
system are affected. Interpreting the angiographic
findings in the anterior segment of the SSS, the left
lateral sinus, or the cortical veins is difficult due to
wide anatomical variations. The diagnosis of cor-
tical vein thrombosis is extremely difficult in
isolated vein thrombosis. Other angiographic find-
ings include increased arteriovenous circulation
time, dilation or tortuosity of the collateral veins,
reversal of flow away from the obstructed area, and
nonspecific mass effect.
OUTCOME
The outcome of CVT is extremely diverse. Originally
thought to carry a high mortality because the
diagnosis was made at autopsy, mortality rates in
recent series are less than 30%. In the placebo-
treated arm of a recent therapeutic trial, bad
outcome (death or severe disability) a few months
after the diagnosis was observed in 25% of the
patients. Clinical indicators of poor prognosis
include coma, extremes of age, focal neurological
signs, and rapid development of increased intracra-
nial pressure. Septic CVT is associated with
poor rates of recovery, with mortality rates approxi-
mately 80% in cases of septic SSS thrombosis. Deep
cerebral and cerebellar vein involvement is a poorer

Figure 3
(a) Sagittal T1-weighted MRI showing lack of flow and isointense signal in the superior sagittal sinus (arrows). (b) Sagittal T1-weighted MRI
revealing high signal in the vein of Galen compatible with thrombus.
prognostic factor than thrombosis of the superficial
veins and sinuses.
When a patient with CVT survives, the chance for
recovery without neurological sequelae is approxi-
mately 85%. The clinical improvement is mostly
related to the adequacy of collateral channels rather
than recanalization of the occluded lumen. In
patients with residual neurological impairment, optic
atrophy, seizures, and hemiparesis are the most
common sequelae. Seizures are observed in approxi-
mately 15% of patients, usually in those who had
seizures and focal signs in the acute stage. Formation
of a dural arteriovenous fistula will predispose the
patient to later hemorrhage. The overall risk of
recurrence of the thrombotic event is related to the
underlying systemic disorder(s) that induced the
original thrombotic event and in one series was
approximately 20% during the next several years
despite antithrombotic therapy.
TREATMENT
The therapeutic approach has three aims: to arrest
the progression of CVT and improve neurological
outcome; to treat the consequences of CVT, such as
CEREBRAL VENOUS THROMBOSIS 637
epilepsy and increased intracranial pressure; and to
treat the disorder(s) predisposing to development of
CVT in an attempt to prevent recurrence.
Anticoagulation
Intravenous heparin is being increasingly used
because there is strong evidence indicating both its
safety and effectiveness, even in the presence of
hemorrhagic lesions. The effectiveness of heparin
was suspected because of the dramatic improvement
some patients experienced shortly after the initiation
of heparin treatment and the good prognosis of
heparin-treated patients in a large retrospective and
prospective series. The efficacy and safety of heparin
were confirmed by the first prospective randomized
trial, which was stopped after enrollment of 20
patients because of a dramatic difference in favor of
heparin treatment between the heparin-treated and
the placebo-treated groups. In the same study,
patients with CVT and intracerebral hemorrhage
had a much lower mortality when treated with
heparin compared to placebo-treated patients (4 vs
69%), indicating that heparin is an effective therapy
for CVT and that the presence of an intracerebral
hemorrhage is not a contraindication for its use.
638 CEREBRAL VENOUS THROMBOSIS
Figure 4
Magnetic resonance venography demonstrating lack of flow in a
portion of the left lateral sinus.
Another prospective trial, in which patients with
CVT were randomized to either subcutaneous
nadroparin (low-molecular-weight heparin) or pla-
cebo groups (the nadroparin-treated group was
subsequently treated with oral warfarin for 10
weeks), revealed that treatment with heparin was
safe but not as effective as in previous studies, and
that there was no worsening attributable to new or
enlarging hematoma in the heparin-treated patients.
A meta-analysis of these two prospective trials
concluded that with heparin treatment there is 14%
risk reduction in mortality and 15% risk reduction in
death and dependency, which combined with the
proven safety of heparin establish the use of heparin
as first-line treatment for CVT.
Thrombolysis
There have been no controlled trials to prove the
efficacy of thrombolytic therapy in CVT. Small
uncontrolled series have reported the safety of
treatment with intravenous urokinase and heparin.
In the largest series of local thrombolysis to date, 13
patients with extensive thrombosis of several sinuses
were treated with local urokinase, resulting in good
sinus patency and good recovery in 12 patients and
no worsening in any patient despite the presence of
hemorrhagic infarctions. In two recent series, rt-PA
was used because of its theoretical advantage of
lower hemorrhagic risk. In one study, treatment of 12
patients with combined intraclot rt-PA and intrave-
nous heparin resulted in improvement in 9, hemor-
rhagic worsening in 2, and no improvement in 1
patient. In the other study, complete restoration of
flow and recovery was achieved in all 9 treated
patients. Flow restoration is obviously faster with rt-
PA and heparin than with heparin alone, but the
correlation between flow restoration and clinical
recovery is not very strong. Local rt-PA carries the
risk of hemorrhage, whether at the puncture site, in
internal organs, or in the brain, in contrast with the
absence of deterioration even in patients with
hemorrhagic lesions treated with heparin.
There is no evidence that treatment with throm-
bolytics results in better outcome, despite the more
rapid restoration of flow, and thrombolytics carry a
higher risk of intracerebral hemorrhage. Therefore,
there is no good scientific evidence to recommend
local thrombolysis as first-line treatment, but cer-
tainly this can be considered if there is progressive
deterioration despite adequate anticoagulation with
heparin.
Surgery
Surgery plays a major role in septic CVT, especially
regarding the lateral sinus, in which drainage or
debridement of an infective focus, with dual diag-
nostic and therapeutic purpose, can be done. In
aseptic CVT, the role of surgery is limited to specific
clinical scenarios, such as the management of trauma
or laceration of a venous sinus, resection of a
cerebral tumor compressing the sinus, or evacuation
of an expanding intracerebral hematoma in patients
with deteriorating neurological status. Surgical
thrombectomy has been performed with poor results,
and the vast majority of specialists oppose this form
of treatment, which may be harmful to a swollen or
hemorrhagic brain.
Symptomatic Treatment
Symptomatic treatment focuses primarily on seizure
control and reduction of intracranial pressure. Antic-
onvulsants are required in patients with seizures. The
duration of treatment beyond the acute phase
depends on the presence or absence of a focal lesion,
the normal or abnormal neurological exam, and the
findings from the EEG. In general, anticonvulsants
can be stopped after 2 years if the patient is
neurologically normal and the EEG reveals no focal
lesions.

Several measures have been employed for reduc-
tion of elevated intracranial pressure. Lumbar
puncture can rapidly reduce the intracranial pres-
sure, especially if there is visual impairment. Man-
nitol, steroids, and acetazolamide have also been
used for this purpose. Steroids may aggravate the
thrombotic process and are usually undesirable.
Barbiturate coma and surgical decompression of
hematoma have been reported to improve the out-
come in small series of patients with extensive CVT
and intracerebral hemorrhage related to venous
infarction.
Etiological Treatment
When possible, the underlying cause should be
treated in conjunction with the anticoagulants and
other symptomatic measures. Behcet’s disease should
be treated aggressively with steroids and immuno-
suppression. Similarly, systemic lupus erythematosus
or other collagen vascular diseases should be treated
with steroids or immunosuppressants to decrease
disease activity. The treatment for septic CVT
includes antibiotics, possibly in association with
surgical debridement of the primary site of the
infection (mastoiditis, sinusitis, etc.). Oral contra-
ceptives should be discontinued. An underlying
prothrombotic state should be investigated and, if
identified, appropriate antithrombotic therapy, in-
cluding long-term anticoagulation, should be con-
sidered.
—Panayiotis D. Mitsias and Jorge Burneo
See also–Anticoagulant Treatment; Arterial
Thrombosis, Cerebral; Cerebral Blood Vessels:
Veins and Venous Sinuses; Coagulopathies and
Stroke; Stroke, Thrombolytic Treatment of;
Venous Malformations
Further Reading
Ameri, A., and Bousser, M. G. (1992). Cerebral venous thrombo-
sis. Neurol. Clin. 10, 87–111.
Bousser, M. G., Chiras, J., Bories, J., et al. (1985). Cerebral venous
thrombosis. A review of 38 cases. Stroke 16, 199–213.
Crawford, S. C., Digre, K. B., Palmer, C. A., et al. (1995).
Thrombosis of the deep venous drainage of the brain in adults.
Analysis of seven cases with review of the literature. Arch.
Neurol. 52, 1101–1108.
Daif, A., Awada, A., Al-Rajeh, S., et al. (1995). Cerebral venous
thrombosis in adults. A study of 40 cases from Saudi Arabia.
Stroke 26, 1193–1195.
De Bruijn, S. F. T. M., and Stam, J., for the cerebral venous sinus
thrombosis study group (1999). Randomized, placebo-con-
CEREBROSPINAL FLUID RHINORRHEA 639
trolled trial of anticoagulant treatment with low-molecular-
weight heparin for cerebral sinus thrombosis. Stroke 30, 484–
488.
Deschiens, M.-A., Conard, J., Horellou, M. H., et al. (1996).
Coagulation studies, factor V Leiden, and anticardiolipin
antibodies in 40 cases of cerebral venous thrombosis. Stroke
27, 1724–1730.
Einhaupl, K. M., Villringer, A., Meister, W., et al. (1991).
Heparin treatment in sinus venous thrombosis. Lancet 338,
597–600.
Frey, J. L., Muro, G. J., McDougall, C. G., et al. (1999). Cerebral
venous thrombosis. Combined intrathrombus rtPA and intra-
venous heparin. Stroke 30, 489–494.
Horowitz, M., Purdy, P., Unwin, H., et al. (1995). Treatment of
dural sinus thrombosis using selective catheterization and
urokinase. Ann. Neurol. 38, 58–67.
Isensee, Ch., Reul, J., and Thron, A. (1994). Magnetic
resonance imaging of thrombosed dural sinuses. Stroke 25,
29–34.
Kim, S. Y., and Suh, J. H. (1997). Direct endovascular
thrombolytic therapy for dural sinus thrombosis: Infusion of
alteplase. Am. J. Neuroradiol. 18, 639–645.
Preter, M., Tzourio, C., Ameri, A., et al. (1996). Long term
prognosis in cerebral venous thrombosis. Follow-up of 77
patients. Stroke 27, 243–246.
Tsai, F. Y., Wang, A. M., Matovich, V. B., et al. (1995).
MR staging of acute dural sinus thrombosis: Correlation
with venous pressure measurements and implications for
treatment and prognosis. Am. J. Neuroradiol. 16, 1021
–1029.
Vandenbroucke, J. P., Koster, T., Briet, E., et al. (1994). Increased
risk of venous thrombosis in oral-contraceptive users who
are carriers of factor V Leiden mutation. Lancet 344, 1453–
1457.
Vogl, T. J., Bergman, C., Villringer, A., et al. (1994). Dural sinus
thrombosis: Value of venous MR angiography for diagnosis and
follow-up. Am. J. Roentgenol. 162, 1191–1198.
Cerebrospinal Fluid
Rhinorrhea
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBROSPINAL FLUID (CSF) is an extracellular fluid
secreted by the choroid plexus located in the walls of
the lateral ventricles of the brain and ependymal cells
lining the remainder of the ventricular system and the
central spinal canal. CSF flows from the lateral
ventricles through the interventricular foramen (fora-
men of Monro) into the third ventricle and then
through the cerebral aqueduct (of Sylvius) into the
fourth ventricle and through the foramina of
Magendie and Luschka to reach the subarachnoid
space contained between the delicate arachnoid and

Several measures have been employed for reduc-
tion of elevated intracranial pressure. Lumbar
puncture can rapidly reduce the intracranial pres-
sure, especially if there is visual impairment. Man-
nitol, steroids, and acetazolamide have also been
used for this purpose. Steroids may aggravate the
thrombotic process and are usually undesirable.
Barbiturate coma and surgical decompression of
hematoma have been reported to improve the out-
come in small series of patients with extensive CVT
and intracerebral hemorrhage related to venous
infarction.
Etiological Treatment
When possible, the underlying cause should be
treated in conjunction with the anticoagulants and
other symptomatic measures. Behcet’s disease should
be treated aggressively with steroids and immuno-
suppression. Similarly, systemic lupus erythematosus
or other collagen vascular diseases should be treated
with steroids or immunosuppressants to decrease
disease activity. The treatment for septic CVT
includes antibiotics, possibly in association with
surgical debridement of the primary site of the
infection (mastoiditis, sinusitis, etc.). Oral contra-
ceptives should be discontinued. An underlying
prothrombotic state should be investigated and, if
identified, appropriate antithrombotic therapy, in-
cluding long-term anticoagulation, should be con-
sidered.
—Panayiotis D. Mitsias and Jorge Burneo
See also–Anticoagulant Treatment; Arterial
Thrombosis, Cerebral; Cerebral Blood Vessels:
Veins and Venous Sinuses; Coagulopathies and
Stroke; Stroke, Thrombolytic Treatment of;
Venous Malformations
Further Reading
Ameri, A., and Bousser, M. G. (1992). Cerebral venous thrombo-
sis. Neurol. Clin. 10, 87–111.
Bousser, M. G., Chiras, J., Bories, J., et al. (1985). Cerebral venous
thrombosis. A review of 38 cases. Stroke 16, 199–213.
Crawford, S. C., Digre, K. B., Palmer, C. A., et al. (1995).
Thrombosis of the deep venous drainage of the brain in adults.
Analysis of seven cases with review of the literature. Arch.
Neurol. 52, 1101–1108.
Daif, A., Awada, A., Al-Rajeh, S., et al. (1995). Cerebral venous
thrombosis in adults. A study of 40 cases from Saudi Arabia.
Stroke 26, 1193–1195.
De Bruijn, S. F. T. M., and Stam, J., for the cerebral venous sinus
thrombosis study group (1999). Randomized, placebo-con-
CEREBROSPINAL FLUID RHINORRHEA 639
trolled trial of anticoagulant treatment with low-molecular-
weight heparin for cerebral sinus thrombosis. Stroke 30, 484–
488.
Deschiens, M.-A., Conard, J., Horellou, M. H., et al. (1996).
Coagulation studies, factor V Leiden, and anticardiolipin
antibodies in 40 cases of cerebral venous thrombosis. Stroke
27, 1724–1730.
Einhaupl, K. M., Villringer, A., Meister, W., et al. (1991).
Heparin treatment in sinus venous thrombosis. Lancet 338,
597–600.
Frey, J. L., Muro, G. J., McDougall, C. G., et al. (1999). Cerebral
venous thrombosis. Combined intrathrombus rtPA and intra-
venous heparin. Stroke 30, 489–494.
Horowitz, M., Purdy, P., Unwin, H., et al. (1995). Treatment of
dural sinus thrombosis using selective catheterization and
urokinase. Ann. Neurol. 38, 58–67.
Isensee, Ch., Reul, J., and Thron, A. (1994). Magnetic
resonance imaging of thrombosed dural sinuses. Stroke 25,
29–34.
Kim, S. Y., and Suh, J. H. (1997). Direct endovascular
thrombolytic therapy for dural sinus thrombosis: Infusion of
alteplase. Am. J. Neuroradiol. 18, 639–645.
Preter, M., Tzourio, C., Ameri, A., et al. (1996). Long term
prognosis in cerebral venous thrombosis. Follow-up of 77
patients. Stroke 27, 243–246.
Tsai, F. Y., Wang, A. M., Matovich, V. B., et al. (1995).
MR staging of acute dural sinus thrombosis: Correlation
with venous pressure measurements and implications for
treatment and prognosis. Am. J. Neuroradiol. 16, 1021
–1029.
Vandenbroucke, J. P., Koster, T., Briet, E., et al. (1994). Increased
risk of venous thrombosis in oral-contraceptive users who
are carriers of factor V Leiden mutation. Lancet 344, 1453–
1457.
Vogl, T. J., Bergman, C., Villringer, A., et al. (1994). Dural sinus
thrombosis: Value of venous MR angiography for diagnosis and
follow-up. Am. J. Roentgenol. 162, 1191–1198.
Cerebrospinal Fluid
Rhinorrhea
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBROSPINAL FLUID (CSF) is an extracellular fluid
secreted by the choroid plexus located in the walls of
the lateral ventricles of the brain and ependymal cells
lining the remainder of the ventricular system and the
central spinal canal. CSF flows from the lateral
ventricles through the interventricular foramen (fora-
men of Monro) into the third ventricle and then
through the cerebral aqueduct (of Sylvius) into the
fourth ventricle and through the foramina of
Magendie and Luschka to reach the subarachnoid
space contained between the delicate arachnoid and
640 CEREBROSPINAL FLUID RHINORRHEA
pia mater. CSF travels down the spinal canal and also
over the surface of the brain. Absorption of CSF
occurs through arachnoid villi, which communicate
from the subarachnoid space through the dura into
the superior sagittal sinus and other venous net-
works.
CSF plays a crucial role in central nervous system
(CNS) homeostasis. By providing a steady external
environment, CSF allows neurons and glial cells to
optimally function. The pH of CSF has effects on
cerebral blood flow and pulmonary ventilation. The
one-way directional flow of CSF may help the brain
and spinal cord eliminate potentially harmful meta-
bolites and may serve as a lymphatic system for the
CNS. By serving as a common medium, CSF allows
distant parts of the brain to communicate by
releasing peptides and substrates into this extracel-
lular fluid. CSF also has a vital role in cushioning the
brain against trauma from the inner calvarium. The
CSF also provides physical support for the brain and
a cushion for changes in central venous and arterial
pressure.
A breach in the integrity of the dura mater, which
is tougher than the arachnoid and pia mater, may
cause a communication between the subarachnoid
space, containing CSF, and the extradural space. The
egress of CSF will occur if the pressure gradient
within the CNS is greater than that of the extradural
tissue adjacent to the dural dehiscence. Since the
adult brain produces approximately 500 ml of CSF a
day, which is enough to completely recycle the entire
CSF volume three or four times a day, the primary
concern with CSF leakage is usually not related to
the actual loss of fluid, except in extreme circum-
stances in which the loss of CSF is rapid and
extensive. The principal issue with CSF leakage is
the possibility of ascending infection through the
communicating tract. With the proximity of the
upper nasopharynx tract, including the paranasal
sinuses and mastoid/temporal bone cavities, there is
an abundance of local flora that can easily infect the
meninges.
Once CSF has exited the intracranial compart-
ment, it will commonly manifest as rhinorrhea or
otorrhea. For the purposes of this entry, we focus on
CSF rhinorrhea. Clinically, patients present with a
clear fluid discharge from one or both nasal cavities.
The rhinorrhea will often increase in magnitude
when the patient increases intracranial pressure by
bending over, lifting heavy objects, or performing the
valsalva maneuver. The nasal discharge often mimics
the drip of a leaky faucet.
The anatomical location of the dural tear present-
ing as CSF rhinorrhea can be quite varied. The
anterior skull base, which forms the floor of the
anterior cranial fossa and the roof of the nose,
paranasal sinuses, and orbits, is a common site of
origin for the drainage of CSF. Olfactory nerves
penetrate the cribiform plate to enter the base of the
brain, and these tiny holes can serve as a conduit for
the extravasation of CSF. The bone of the cribiform
plate is extremely thin and the dura is closely
adherent to it. Just lateral to the cribiform plate is
the attachment of the middle turbinate to the skull
base. This region of the anterior skull base is notably
weaker than the surrounding bone and thus is also a
possible spot of injury. Continuing laterally, the
fovea ethmoidalis, the roof of the ethmoid air cells, is
another site of possible communication between the
intracranial and extracranial compartments. The
posterior table of the frontal sinus, which is much
thinner and weaker than the anterior wall, is another
anterior skull base site of possible CSF extravasation.
From any of these possible sites, CSF will enter
the nose through the involved sinus or directly
through the cribiform/olfactory area superiorly in
the nasal vault.
The slope of the skull base slants inferiorly as it
extends posteriorly. The roof of the posterior
ethmoid region is lower than the anterior ethmoid.
Posterior to the ethmoid complex (and slightly
inferior) is the sphenoid sinus. The sella turcica and
the pituitary gland lie above the sphenoid sinus. CSF
leakage through the sella/sphenoid region can pre-
sent as CSF rhinorrhea, or the CSF may descend
posteriorly from the nasal cavity into the nasophar-
ynx and present as a persistent postnasal drip.
Lateral to the sphenoid sinus on either side is the
petrous apex of the temporal bone. The temporal
bone houses the cochleovestibular system of the
inner ear as well as the mastoid and the middle ear.
The eustachian tube connects the middle ear to the
nasopharynx. The anterior/superior portion of the
temporal bone forms the floor of the middle cranial
fossa, and the posterior wall of the temporal bone
forms a portion of the floor of the posterior fossa. On
all its sides, the temporal bone is in intimate contact
with dura. A communication at any of these
locations causes flow of CSF into the cell system of
the temporal bone. Once in the temporal bone, CSF
can exit via the ear (CSF otorrhea) or by traveling
down the eustachian tube and exiting via the nose as
rhinorrhea or causing a persistent postnasal drip.
This complex anatomy is crucial to understanding

that it is possible for a dural tear along the anterior,
middle, or posterior cranial fossae to present as CSF
rhinorrhea.
More than 2000 years ago, Galen was the first to
document CSF rhinorrhea. Since then, many phys-
icians have argued the various causes of this
condition. In recent times, classification schemes
have been devised to help organize our thoughts
regarding the etiological factors leading to CSF
rhinorrhea. Although it is possible to classify this
clinical entity based on the location of the leak, using
the etiology as the discriminating factor yields a
better understanding of the disease process leading to
the rhinorrhea and helps in the initiation of a more
focused treatment plan.
All causes of CSF rhinorrhea can be classified as
either traumatic or nontraumatic in origin. Trauma is
the most common cause of CSF rhinorrhea. Trau-
matic episodes can be further subdivided into
surgical and nonsurgical. Blunt or penetrating
trauma can lead to CSF rhinorrhea because a dural
tear can accompany fractures located throughout the
skull base, sinuses, and temporal bone. The rhinor-
rhea associated with these events may occur im-
mediately following the events or it may not manifest
for days, weeks, months, or even years after the
initial injury. Scar tissue at the site of the dural
dehiscence may weaken over time due to the constant
pulsations of the CSF or due to an increase in
intracranial pressure. These types of CSF leaks are
referred to as delayed.
In recent times, the incidence of surgical CSF
rhinorrhea has increased largely due to an increase in
the number of patients undergoing neurosurgical,
skull base, paranasal sinus, and otological proce-
dures. Often, a CSF leak can be appreciated at the
time of surgery and treatment initiated immediately.
Many procedures are performed with the knowledge
that an intracranial communication will be created
by the procedure, and the reconstruction can be
planned to accompany the original surgical event.
For a CSF leak that occurs after an operation, the
surgeon will have an intimate knowledge of the
surgical site and thus be able to more easily identify
the location of a leak. As with nonsurgical traumatic
CSF leaks, the surgical variety also may present in a
delayed fashion weeks, months, or years after the
original surgical event.
Nontraumatic CSF rhinorrhea can be divided into
two categories based on the intracranial pressure,
which is either elevated or normal. In high-pressure
situations, the increased intracranial CSF pressure
CEREBROSPINAL FLUID RHINORRHEA 641
puts added stress on the dura, which eventually leads
to a break in the dural membrane at a weak point.
Tumors may cause increased CSF pressure via a
number of different mechanisms. Intracranial tumors
may prevent the proper flow of CSF via an
anatomical obstruction along the course of the CSF
route. This leads to an increase in the back pressure
behind the obstruction. Intracranial tumors are often
treated with chemotherapy and radiation therapy,
which can impair the outflow tract of CSF secondary
to edema and/or scarring causing increased pressure.
Primary and acquired hydrocephalus and benign
intracranial hypertension (pseudotumor cerebri) are
other possible etiologies within the category of
nontraumatic, high-pressure CSF rhinorrhea. It is
important to note that prior to repairing the dural
dehiscence associated with these leaks, the primary
cause of the increased intracranial pressure needs to
be treated. Failure to restore a normal intracranial
pressure may lead to failure of the repair and
recurrence of the CSF rhinorrhea.
CSF rhinorrhea associated with a nontraumatic,
normal pressure etiology presents a diverse group.
Tumors again appear in this group because they can
erode the dura and skull base. Treatment (chemo-
therapy or radiation therapy) modalities may also
weaken or necrose the dura or bone. Infections are
another etiology to be considered under this
category. Chronic ear disease (cholesteatoma) or
temporal bone osteomyelitis (often related to pro-
longed external ear canal disease) can erode the dura
causing CSF drainage. Ear disease, systemic infec-
tions, paranasal sinus disease, orbital infections, and
septic emboli are all possible causes of brain abscess
that may result in normal pressure, nontraumatic
CSF rhinorrhea. Empty sella describes an outpouch-
ing of the CSF-filled arachnoid membrane into the
sella. Pulsations of this CSF ‘‘balloon’’ against the
floor of the sella may cause bone erosion and
ultimately CSF rhinorrhea. This condition may
occur after tumor removal in the sella turcica (e.g.,
pituitary adenoma) or may be a congenital/primary
phenomenon.
The final two subdivisions in the normal pressure,
nontraumatic category are the congenital and idio-
pathic varieties of CSF rhinorrhea. Both of these
groups as general categories serve to encompass all
the diagnoses that do not immediately conform to
another group. Congenital problems include primary
empty sella syndrome, meningocele, encephalocele,
meningoencephalocele, primary bony and dural
defects without herniation, and leakage through
642 CEREBROSPINAL FLUID RHINORRHEA
preformed pathways, including the round window,
oval window, cochlear or vestibular aqueduct,
olfactory nerve, and Hyrtle’s fissure. The link
between idiopathic and congenital etiologies is that
many congenital sources of CSF leaks may only be
recognized after a thorough workup and may be
thought initially to be idiopathic in origin.
Idiopathic CSF rhinorrhea is a diagnosis that has
spurred much debate. Some experts deny its true
existence, noting that idiopathic cases are always
found to have an identifiable etiology after a
thorough workup. Others believe that idiopathic
CSF rhinorrhea does exist, albeit rarely. A source of
resolution to describe idiopathic CSF rhinorrhea is
the concept of arachnoid granulations. Normally, the
arachnoid membrane perforates the dura in path-
ways referred to as granulations to empty CSF into
venous sinuses. When arachnoid granulations occur
at the skull base, they may not connect to venous
sinuses and thus serve as ‘‘miniherniations’’ of
arachnoid through the dura against the inner surface
of the skull base. These pockets of CSF may exert
pulsatile pressure on the skull base, ultimately
leading to erosion of the bone and CSF leak.
Although this may explain many idiopathic CSF
leaks, others will be reconciled into any of the other
categories as unrecognized trauma or unrecognized
congenital causes.
The evaluation of the patient with CSF rhinorrhea
begins with a thorough history and physical exam-
ination. Recent or remote traumatic events, including
surgeries, must be clearly delineated. Concurrent
symptoms, such as visual changes, headaches, or
otologic symptoms, may aid in developing a diag-
nosis. The physical examination may confirm the
rhinorrhea. Tumors of the nose, sinuses, orbits, ears,
and skull base may be identified through nasal, oral,
ear, and pharyngeal examinations.
Following the physical examination, the evalua-
tion of the patient with CSF rhinorrhea can be
divided into two phases: It is first necessary to
confirm the leak and then to try to localize the site of
dehiscence. If a patient’s rhinorrhea is present during
examination and can be sampled, the glucose level
can be obtained from the fluid. A glucose level of
430 in a clear fluid from the nose is suggestive of
CSF. Fluid analysis of the rhinorrhea with a b2
transferrin test can confirm the presence of CSF
because b2 transferrins are unique to CSF. Another
test available to confirm the presence of a leak
involves placing a marker in the intrathecal space via
a lumbar tap and collecting the substance in the nasal
vault. Radioactive tracers are ideal for this purpose.
Twenty-four hours after placing nasal packing in the
nose, a Geiger counter can measure the presence or
absence of radioactive material on the nasal packs.
Fluoroscein may be used in a similar manner, and
the dye can be detected on the nasal packing or
in nasal secretions. However, because of rare
reports of reaction to the dye, some clinicians
recommend against its use. Fluoroscein is not
approved by the Food and Drug Administration for
intrathecal use.
Once the presence of a leak is confirmed, the
clinician must try to localize the site of the CSF
drainage. In the postoperative patient, this may be
accomplished by reviewing operative notes and
preoperative scans. In the remainder of CSF rhinor-
rhea patients, localization of a leak will require one
or more imaging studies of the head and skull base. A
thin-cut coronal computed tomography (CT) scan
provides a comprehensive assessment of the skull
base. A magnetic resonance imaging (MRI) scan
provides better soft tissue contrast than the CT scan
and is often the first test ordered in cases of CSF
rhinorrhea. Contrast enhancement will often high-
light the area of dural involvement, but it may be
misleading if other intracranial processes or dural
inflammatory conditions exist. A third scan that can
help delineate the leak is CT cisternography. Dye is
injected intrathecally prior to obtaining a CT scan.
The contrast dye will fill the CSF cisterns and
ventricles and may drain through the site of CSF
leakage. This invasive study may provide the most
information if the leak is active because it localizes
the site of the leak by visualizing flow through the
dehiscence.
Once the diagnosis of CSF rhinorrhea is con-
firmed, treatment, conservative or surgical, is in-
itiated. Conservative treatment is useful for
nonrecurrent leaks as a primary treatment modality.
Patients are maintained on bed rest and many
clinicians place a lumbar drain to decrease the CSF
outflow pressure at the site of the leak. The drain is
allowed to siphon a predetermined amount of CSF
every hour for the first few days, and then the drain
is closed for a period of time prior to its removal to
confirm that the rhinorrhea has stopped. Patients
undergoing this therapy are given stool softeners and
antitussives and advised to not blow their nose in an
effort to maintain CSF pressure at a low level. If
conservative treatment fails, or in the case of
recurrent CSF rhinorrhea, surgical management
may be considered.

Surgery for CSF rhinorrhea can be approached
transnasally, transtemporally, extracranially, and in-
tracranially. Surgery through the nose is ideal for
dehiscence of the anterior skull base at the cribiform/
ethmoid region and in the sphenoid region. These
leaks can often be repaired endoscopically, which
offers the patient minimal morbidity and quicker
recovery. Transtemporal repairs are done through the
ear and mastoid or via a lateral temporal fossa
procedure. Other extracranial approaches may be
accomplished through the transpalatal, transeptal,
midfacial degloving, or external sinus techniques.
Intracranial procedures are done via a craniotomy and
may require retraction of the cerebral cortex to gain
adequate exposure. Intracranial approaches have the
distinct advantage of patching the dural tear from the
inside and can be tailored to expose CSF leaks in any
intracranial compartment. Once exposed using any
approach, the dural tear can be repaired using
harvested fat, fascia, muscle, cartilage, or bone. Bone
and pedicled flaps or free tissue transfer may be used
to reconstruct large surgical defects. Cadaveric dura,
fascia, allogenic dermis, and local mucosal flaps
within the nose have been used to close small leaks.
During the immediate postoperative period, pa-
tients remain on bed rest with a lumbar drain in place
until the repair has a chance to begin healing and
scarring. It is paramount to keep the patient from
sustaining any further head trauma and to minimize
increases in CSF pressure as much as possible because
the resultant scar will always be a weak point in the
dural membrane. The first attempt at closing a CSF
leak is regarded as having the best chance for success.
Once a CSF leak recurs, the chance of repairing the
defect successfully decreases and it continues to
decrease with each sequential attempt.
The patient with CSF rhinorrhea poses a challenge
to the clinician. Complications of CSF rhinorrhea
can be devastating, and accurate and efficient
diagnosis and management are crucial. The anatomy
of the skull base is complex and the possible
etiologies are numerous. A thorough evaluation is
necessary and will often identify the site of dural
dehiscence. Management of CSF rhinorrhea can be
conservative or surgical, depending on the etiology
and the anatomy of the leak. Long-term follow-up
with CSF rhinorrhea patients is important to observe
for recurrent leaks. CSF rhinorrhea presents a multi-
faceted condition requiring the clinician to have a
genuine understanding of the nature of the problem
and its treatment.
—Andrew C. Goldman and Gady Har-El
CEREBROVASCULAR MALFORMATIONS 643
See also–Cerebral Edema; Hydrocephalus
Further Reading
Applebaum, E. L., and Chow, J. M. (1998). Cerebrospinal fluid
leaks. In Otolaryngology—Head and Neck Surgery (C. W.
Cummings, J. M. Fredrickson, L. A. Harker, C. J. Krause, M. A.
Richardson, and D. E. Schuller, Eds.), 3rd ed., Vol. 2. Mosby,
St. Louis.
Burkey, B. B., Gerek, M., and Day, T. (1999). Repair of the
persistent cerebrospinal fluid leak with the radial forearm free
fascial flap. Laryngoscope 109, 1003–1006.
Fliss, D. M., Zucker, G., Cohen, A., et al. (1999). Early outcome
and complications of the extended subcranial approach to the
anterior skull base. Laryngoscope 109, 153–160.
Garcia-Uria, J., Ley, L., Parajon, A., et al. (1999). Spontaneous
cerebrospinal fluid fistulae associated with empty sellae:
Surgical treatment and long term results. Neurosurgery 45,
766–774.
Gassner, H. G., Ponikau, J. U., Sherris, D. A., et al. (1999).
CSF rhinorrhea: 95 consecutive surgical cases with long
term follow-up at the Mayo Clinic. Am. J. Rhinol. 13,
439–447.
Har-El, G. (1999). What is ‘‘spontaneous’’ cerebrospinal fluid
rhinorrhea? Classification of cerebrospinal fluid leaks. Ann.
Otol. Rhinol. Laryngol. 108, 323–326.
Nachtigal, D., Frenkiel, S., Yoskovitch, A., et al. (1999). Endo-
scopic repair of cerebrospinal fluid rhinorrhea: Is it the
treatment of choice? J. Otolaryngol. 28, 129–133.
Ng, M., Maceri, D. R., Levy, M. M., et al. (1998). Extracranial
repair of pediatric traumatic cerebrospinal fluid rhinorrhea.
Arch. Otolaryngol. Head Neck Surg. 124, 1125–1130.
Rowland, L. P., Fink, M. E., and Rubin, L. (1991). Cerebrospinal
fluid: Blood–brain barrier, brain edema, and hydrocephalus. In
Principles of Neuroscience (E. R. Kandel, J. H. Schwartz, and T.
M. Jessell, Eds.), 3rd ed. Elsevier, New York.
Schick, B., Draf, W., Kahle, G., et al. (1997). Occult malforma-
tions of the skull base. Arch. Otolaryngol. Head Neck Surg.
123, 77–80.
Shetty, P. G., Shroff, M. M., Sahani, D. V., et al. (1998). Evaluation
of high-resolution CT and MR cisternography in the
diagnosis of cerebrospinal fluid fistula. Am. J. Neuroradiol.
19, 633–639.
Cerebrovascular
Malformations (Angiomas)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBROVASCULAR MALFORMATIONS affect 4 to 5%
of the population. Based on the nature of the
component vessels, McCormick’s classification
scheme organizes these lesions into the following
subgroups based on the composition of the interven-
ing neural parenchyma, the distinct clinical behavior,
and characteristic radiographic appearance: arterio-

Surgery for CSF rhinorrhea can be approached
transnasally, transtemporally, extracranially, and in-
tracranially. Surgery through the nose is ideal for
dehiscence of the anterior skull base at the cribiform/
ethmoid region and in the sphenoid region. These
leaks can often be repaired endoscopically, which
offers the patient minimal morbidity and quicker
recovery. Transtemporal repairs are done through the
ear and mastoid or via a lateral temporal fossa
procedure. Other extracranial approaches may be
accomplished through the transpalatal, transeptal,
midfacial degloving, or external sinus techniques.
Intracranial procedures are done via a craniotomy and
may require retraction of the cerebral cortex to gain
adequate exposure. Intracranial approaches have the
distinct advantage of patching the dural tear from the
inside and can be tailored to expose CSF leaks in any
intracranial compartment. Once exposed using any
approach, the dural tear can be repaired using
harvested fat, fascia, muscle, cartilage, or bone. Bone
and pedicled flaps or free tissue transfer may be used
to reconstruct large surgical defects. Cadaveric dura,
fascia, allogenic dermis, and local mucosal flaps
within the nose have been used to close small leaks.
During the immediate postoperative period, pa-
tients remain on bed rest with a lumbar drain in place
until the repair has a chance to begin healing and
scarring. It is paramount to keep the patient from
sustaining any further head trauma and to minimize
increases in CSF pressure as much as possible because
the resultant scar will always be a weak point in the
dural membrane. The first attempt at closing a CSF
leak is regarded as having the best chance for success.
Once a CSF leak recurs, the chance of repairing the
defect successfully decreases and it continues to
decrease with each sequential attempt.
The patient with CSF rhinorrhea poses a challenge
to the clinician. Complications of CSF rhinorrhea
can be devastating, and accurate and efficient
diagnosis and management are crucial. The anatomy
of the skull base is complex and the possible
etiologies are numerous. A thorough evaluation is
necessary and will often identify the site of dural
dehiscence. Management of CSF rhinorrhea can be
conservative or surgical, depending on the etiology
and the anatomy of the leak. Long-term follow-up
with CSF rhinorrhea patients is important to observe
for recurrent leaks. CSF rhinorrhea presents a multi-
faceted condition requiring the clinician to have a
genuine understanding of the nature of the problem
and its treatment.
—Andrew C. Goldman and Gady Har-El
CEREBROVASCULAR MALFORMATIONS 643
See also–Cerebral Edema; Hydrocephalus
Further Reading
Applebaum, E. L., and Chow, J. M. (1998). Cerebrospinal fluid
leaks. In Otolaryngology—Head and Neck Surgery (C. W.
Cummings, J. M. Fredrickson, L. A. Harker, C. J. Krause, M. A.
Richardson, and D. E. Schuller, Eds.), 3rd ed., Vol. 2. Mosby,
St. Louis.
Burkey, B. B., Gerek, M., and Day, T. (1999). Repair of the
persistent cerebrospinal fluid leak with the radial forearm free
fascial flap. Laryngoscope 109, 1003–1006.
Fliss, D. M., Zucker, G., Cohen, A., et al. (1999). Early outcome
and complications of the extended subcranial approach to the
anterior skull base. Laryngoscope 109, 153–160.
Garcia-Uria, J., Ley, L., Parajon, A., et al. (1999). Spontaneous
cerebrospinal fluid fistulae associated with empty sellae:
Surgical treatment and long term results. Neurosurgery 45,
766–774.
Gassner, H. G., Ponikau, J. U., Sherris, D. A., et al. (1999).
CSF rhinorrhea: 95 consecutive surgical cases with long
term follow-up at the Mayo Clinic. Am. J. Rhinol. 13,
439–447.
Har-El, G. (1999). What is ‘‘spontaneous’’ cerebrospinal fluid
rhinorrhea? Classification of cerebrospinal fluid leaks. Ann.
Otol. Rhinol. Laryngol. 108, 323–326.
Nachtigal, D., Frenkiel, S., Yoskovitch, A., et al. (1999). Endo-
scopic repair of cerebrospinal fluid rhinorrhea: Is it the
treatment of choice? J. Otolaryngol. 28, 129–133.
Ng, M., Maceri, D. R., Levy, M. M., et al. (1998). Extracranial
repair of pediatric traumatic cerebrospinal fluid rhinorrhea.
Arch. Otolaryngol. Head Neck Surg. 124, 1125–1130.
Rowland, L. P., Fink, M. E., and Rubin, L. (1991). Cerebrospinal
fluid: Blood–brain barrier, brain edema, and hydrocephalus. In
Principles of Neuroscience (E. R. Kandel, J. H. Schwartz, and T.
M. Jessell, Eds.), 3rd ed. Elsevier, New York.
Schick, B., Draf, W., Kahle, G., et al. (1997). Occult malforma-
tions of the skull base. Arch. Otolaryngol. Head Neck Surg.
123, 77–80.
Shetty, P. G., Shroff, M. M., Sahani, D. V., et al. (1998). Evaluation
of high-resolution CT and MR cisternography in the
diagnosis of cerebrospinal fluid fistula. Am. J. Neuroradiol.
19, 633–639.
Cerebrovascular
Malformations (Angiomas)
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CEREBROVASCULAR MALFORMATIONS affect 4 to 5%
of the population. Based on the nature of the
component vessels, McCormick’s classification
scheme organizes these lesions into the following
subgroups based on the composition of the interven-
ing neural parenchyma, the distinct clinical behavior,
and characteristic radiographic appearance: arterio-
644 CEREBROVASCULAR MALFORMATIONS
venous malformations (AVMs), cavernous malfor-
mations, developmental venous anomalies (DVAs),
or venous malformations and capillary telangiecta-
sias. Of the four categories, only AVMs and
cavernous malformations are considered to be
relevant surgical lesions secondary to their risk of
hemorrhage. This entry focuses on intracranial
AVMs and briefly reviews cavernous malformations,
DVAs, and venous malformations and capillary
telangiectasias.
The prevalence of AVMs is best estimated from
large autopsy series. McCormick found 272 cere-
brovascular malformations in a consecutive autopsy
series of 5754 patients. Venous malformations were
the most common, occurring in 3% of the popula-
tion. Capillary telangiectasias represented 0.9%,
cavernous malformations 0.3%, and AVMs 0.5%.
The estimated annual incidence of AVMs is approxi-
mately 3 per 100,000. The incidence of hemorrhage
from an AVM is approximately 1 per 100,000.
Cushing and Bailey described AVMs as a snarl of
tangled vessels. AVMs are characterized by the direct
connection of one or more feeding arteries to one or
more draining veins without an intervening capillary
bed. This high-flow arterial shunting of blood into
the low-resistance venous network produces venous
distention, tortuosity, and reactive changes in the
affected arteries and veins that predispose these
Figure 1
AP and lateral right vertebral angiography demonstrate a very dilated right vertebrobasilar junction, basilar artery, and the right posterior
cerebral artery supplying a large AVM of the right posterior parietal lobe.
lesions to hemorrhage. Typically, pial AVMs are
wedge-shaped lesions, with the base oriented parallel
to the cortical surface and the apex or hilum directed
toward the ventricle or deep brain (Fig. 1). However,
they can be found in all areas of the central nervous
system and can be in various shapes and sizes.
AVMs consist of three fundamental components:
the vascular core or nidus, the feeding arteries, and
the draining veins. The nidus contains the inter-
woven network of dysplastic vascular channels. The
vessels within the nidus have markedly attenuated
walls with focal areas of dilatation. Generally, the
nidus is quite compact, with only dysplastic and
nonfunctional intervening neural tissue. The feeding
arteries may be from the deep or superficial arterial
system, the anterior or posterior circulation, dural
arteries, or branches from the external carotid artery.
A terminal feeder is defined as an artery that may
supply normal brain before terminating exclusively
in the AVM nidus. A feeding artery en passage is an
artery that contributes to the nidus but continues on
to supply other normal brain regions. A transit artery
without participation is defined as a normal vessel in
close approximation to the nidus but does not supply
the AVM. Finally, the AVM nidus may derive or steal
arterial supply indirectly from pial collaterals. The
feeding arteries may display certain pathological
features, including smooth muscle hyperplasia and

10–12% frank arterial aneurysm formation. The
venous drainage may be superficial or deep. The
draining veins can also exhibit pathological features,
such as hyperplasia, strictures, and aneurysmal
dilatation or varices (Fig. 2).
The etiology and pathogenesis of AVMs have not
been determined. Cerebral AVMs are generally
believed to be congenital lesions resulting from
incomplete or abnormal resolution of the anastomo-
tic vascular plexus that normally occurs between
week 7 of gestation and the end of the first trimester
during early embryogenesis. Certain cerebral AVMs
occur in association with well-defined genetic dis-
orders, such as ataxia telangiectasia, Wyburn–Mason
syndrome, Osler–Weber–Rendu disease, and Sturge–
Weber syndrome. Alternatively, it has been postu-
lated that some AVMs, especially dural AVMs, are
acquired lesions. The development of AVMs in
laboratory animals by induced venous hypertension
indicates that the pathogenesis of AVMs may occur
well beyond the period of embryogenesis. Recent
studies have demonstrated that abnormal autoregu-
lation found in AVMs is secondary to repression of
the gene that produces endothelin-1. Immunohisto-
chemical studies also demonstrate a paucity of
Figure 2
Right vertebral artery angiography (lateral projection, venous
phase) shows the dilated venous channels associated with
numerous AV fistulas, large venous aneurysmal pouches, and
retrograde cortical venous drainage over the right parietal and
temporal lobes in a patient with a right posterior parietal AVM.
CEREBROVASCULAR MALFORMATIONS 645
immunostaining for transforming growth factor-b
in AVM nidus vessels compared to controls. In
addition, endothelial cell-specific tyrosine kinase and
vascular endothelial growth factor have been im-
plicated in the pathogenesis of AVMs.
AVMs are the most clinically relevant cerebrovas-
cular malformation. They are the second leading
cause of spontaneous subarachnoid hemorrhage,
following intracranial aneurysms. However, with
the advent of magnetic resonance imaging (MRI)
an increasing number of asymptomatic lesions are
discovered. Approximately 50–75% of AVMs pre-
sent with hemorrhage, 25% with seizures, and 25%
with other manifestations that include headaches and
progressive neurological deficits. The frequency of
hemorrhagic presentation is significantly higher in
patients younger than age 20 and those older than
age 60. The location of the AVM nidus and draining
veins often determines the clinical presentation. The
mortality and morbidity from an AVM hemorrhage
are 10–15% and 20–30%, respectively.
The diagnosis of AVMs is dependent on both
traditional radiographic and newer advanced ima-
ging techniques. Cerebral angiography is the main-
stay of radiographic evaluation. It can be utilized to
document the presence of the nidus, its arterial
supply, and venous drainage. Computed tomography
(CT) scans of the head are useful to demonstrate
acute hemorrhage from AVMs. They may also show
serpiginous isodense or slightly hyperdense vessels
that may enhance strongly following contrast admin-
istration. Calcifications can be identified in 25–30%
of cases. MRI can be used to clearly demonstrate the
anatomical location of the nidus in relation to
important surgical landmarks. On standard spin-
echo images, the typical unruptured AVM appears as
a tightly packed ‘‘honeycomb of flow voids’’ caused
by high-velocity signal loss.
The natural history of AVMs is only reasonably
understood. If left untreated, 2–4% of AVMs bleed
each year. The rate of rebleeding is thought to be 6%
during the first year, with a subsequent decline to 2–
4%. In addition to the annual risk of hemorrhage,
certain features of a given AVM, such as associated
arterial aneurysms, single draining vein, deep venous
drainage, venous aneurysms, or venous outflow
obstructions, have been identified as characteristics
that may increase the chance of hemorrhage.
The goal in treating AVMs is to completely remove
the lesion with preservation of neurological function
and to prevent possible future devastating hemor-
rhage. If any residual lesion remains, the risk of
646 CEREBROVASCULAR MALFORMATIONS

hemorrhage is not eliminated. Surgical extirpation is
the time-honored gold standard treatment for AVMs.
Open craniotomy and microsurgical resection, if
successful, is the only therapy that results in
obliteration of the AVM with no further chance of
bleeding in the short and long term; however, surgery
in deep and eloquent regions can be difficult and
complicated.
Magnetic source imaging (MSI) and functional
magnetic resonance imaging (fMRI) are recent
adjuncts to facilitate the localization of functional
areas and can be utilized to assess the resectability of
AVMs. MSI is based on magnetoencephalographic
(MEG) mapping of the extracranial magnetic fields
resulting from evoked functional brain activity. The
MEG localizations can then be projected onto
standard MRI slices or computer-generated render-
ings of the cortical surface. This imaging technique
provides a noninvasive preoperative localization of
the functional somatosensory areas in relation to
both the AVM and anatomical landmarks seen at the
time of surgery. In addition, blood oxygen level-
dependent contrast fMRI can be used in the
presurgical planning to determine language-domi-
nant brain regions.
Several grading schemes have been devised to
estimate the surgical risk. The classification system of
Spetzler and Martin is simple and the most com-
monly used. The following are key variables:
recommended for patients with grade IV and V
AVMs only when significant or repetitive intracer-
ebral hemorrhage has occurred or the patient is
experiencing progressive neurological disability. Cer-
tain contraindications to surgery include devastating
neurological sequelae from initial hemorrhage; a
nidus located on or near the midline supplied by
bilateral perforating arteries, the removal of which
would probably involve bilateral damage to the
fornices, ascending reticular tracts, or descending
motor tracts; and a preexisting medical condition
that precludes general anesthesia or limits long-term
survival to less than 5 years.
In addition to open microsurgical techniques,
endovascular embolization and radiosurgery have
been proposed. Endovascular embolization is an
adjunct to surgery or radiosurgery. Only 5–10% of
AVMs can be cured with endovascular embolization
alone. The goal of embolization is to reduce the size
and anomalous flow of the AVM in an effort to
reduce the risk of hemorrhage and facilitate treat-
ment via microsurgical or radiosurgical techniques
(Fig. 3). Various embolic materials can be delivered
by microcatheter technology to the AVM. These
embolic materials include particulate agents such as

*
Size: small (o3 cm) ¼ 1, medium (3–6 cm) ¼ 2,
and large (46 cm) ¼ 3
* Location: noneloquent ¼ 0, and eloquent ¼ 1
* Venous drainage: superficial ¼ 0, and deep ¼ 1

The AVMs are graded I–VI. A grade VI AVM is

considered inoperable. A prospective analysis of 120
AVMs using this grading system demonstrated a
negligible rate of permanent neurological deficits for
grades I–III and 16.7–21.9% permanent neurological
morbidity for grades IV and V. Although each AVM
must be evaluated individually, taking into consid-
eration the nature and extent of arterial input, the
specific vagaries in venous drainage, the degree of
cortical representation, and the geometry and com-
pactness of the AVM nidus, certain treatment
generalizations were derived from this experience.
Complete microsurgical resection is recommended
Figure 3
for grade I and II AVMs regardless of symptoms.
Fastracker 18 microcatheter can be seen in the distal inferior
Grade III AVMs are evaluated on an individual basis, division of the right middle cerebral artery poised for polyvinyl
incorporating an analysis of the presenting clinical alcohol particle embolization of this posterior temporal/parietal/
symptoms and AVM grade components. Surgery is occipital AVM.

polyvinyl alcohol, coils, balloons, silk threads, and
liquid agents such as N-butyl-2-cyanoacrylates.
Radiosurgery for the treatment of cerebrovascular
malformations involves the delivery of a single, high
dose of radiation (either gamma rays from the decay
of the radioactive isotope cobalt-60 or high-energy x-
rays produced by a linear accelerator LINAC) to a
stereotactically localized target. Current AVM radio-
surgical studies report obliteration rates of 64–81%
for AVMs smaller than 3 cm in average diameter
after radiosurgery. Complete obliteration generally
occurs over a latency interval of 1–3 years. The
primary drawbacks of AVM radiosurgery are that
patients remain at risk for bleeding until the AVM is
obliterated and treatment of larger lesions is less
successful.
Pollock et al. defined factors associated with
successful arteriovenous malformation radiosurgery
from their series of 220 AVMs, 32% of which were
located in the thalamus, basal ganglia, corpus
callosum, or brainstem. Success was defined as
complete nidus obliteration without interval hemor-
rhage, neurological morbidity, or radiation-induced
complications. Multivariate linear regression analy-
sis revealed that younger patient age, hemispheric
location, smaller AVM volume, single draining vein,
and no previous embolization were factors asso-
ciated with successful treatment.
Similarly, Harbaugh et al. analyzed a prospective
series of 72 consecutive patients who were treated
with microsurgery. They concluded that microsur-
gery is superior to stereotactic radiosurgery in the
treatment of smaller, surgically accessible AVMs
when obliterating the AVM, reducing the risk of
hemorrhage, reducing permanent neurological mor-
bidity, and reducing mortality are the desired out-
comes.
DURAL ARTERIOVENOUS
MALFORMATIONS
Dural arteriovenous malformations (DAVMs) or
dural arteriovenous fistulas (DAVFs) consist of
pathological vascular channels located within the
leaflets of the dura mater. They are fed by dural and
pachymeningeal branches and drained by dural
venous routes and often leptomeningeal veins. The
nidus of arteriovenous shunting is solely contained
within the leaflets of the dura mater, the wall of a
dural sinus, the falx, or the tentorium. This feature
distinguishes DAVMs from pial AVMs and other
cerebrovascular malformations. Intracranial DAVMs
CEREBROVASCULAR MALFORMATIONS 647
are estimated to occur only one-tenth as frequently as
pial or intraparenchymal AVMs. Although a small
number of DAVMs may be congenital, most are
thought to be acquired lesions associated with dural
sinus thrombosis, a prior trauma, postsurgery,
middle ear infections, or a febrile illness. However,
the vast majority of DAVMs occur in adulthood and
cannot be shown to be caused by any specific
precipitating factor. Dural sinus thrombosis and
consequent venous hypertension may induce the
opening of previously dormant arteriovenous shunts
in the dura mater. These lesions can present with
benign or aggressive clinical behavior ranging from
pulsatile tinnitus to catastrophic intracranial hemor-
rhage and cerebral ischemia. Progressive arterializa-
tion of the pathological dural leaflets may result in
retrograde leptomeningeal venous drainage or pial
venous drainage and the development of tortuous,
variceal, or aneurysmal venous dilatation. The most
important factor determining the propensity for an
aggressive clinical course is the presence of leptome-
ningeal venous drainage. In the absence of leptome-
ningeal venous drainage or venous hypertension with
associated stenosis or occlusion of the dural sinuses,
incidental DAVMs should be followed expectantly.
Open surgical treatment with or without preparatory
embolization remains the most effective therapeutic
option for definitively treating DAVMs with aggres-
sive characteristics (Fig. 4). Surgical objectives in-
clude the isolation, coagulation, and resection of the
pathological dural leaflets and the disconnection of
the arterialized leptomeningeal drainage.
SPINAL DURAL ARTERIOVENOUS FISTULAS
Dural arteriovenous fistulas can exist between the
radiculomedullary arteries and veins at the junction
of the root sleeve and the thecal sac. These spinal
dural arteriovenous fistulas (AVFs) comprise the
majority of spinal vascular malformations and have
a distinct clinical presentation. Neurological mani-
festations are generally due to venous hypertension.
The increased pressure in the valveless medullary
veins and the coronal venous plexus is transmitted
directly to the intrinsic veins of the spinal cord,
reducing perfusion pressure. Patients exhibit pro-
gressive neurological decline, including myelopathy,
loss of pain and temperature sensation, neurogenic
claudication, and bowel and bladder disturbances.
Subarachnoid hemorrhage is the presenting event in
approximately one-third of patients with spinal
AVMs, but it is rare with spinal dural AVFs. MRI
648 CEREBROVASCULAR MALFORMATIONS
Figure 4
AP and lateral selective occipital angiography demonstrate dural AVM with tortuous leptomeningeal drainage.
often provides the initial diagnosis of an AVM and
distinguishes intramedullary spinal AVMs from
perimedullary spinal AVFs and spinal dural AVFs.
MRI abnormalities may be produced by abnormal
vessels in the subarachnoid space, by the nidus of an
intramedullary AVM in the spinal cord, or by
changes in the spinal cord produced by venous
congestion, myelomalacia, cord infarction, or he-
morrhage. Often, these findings can be subtle for
spinal dural AVFs and the MRI may be unrevealing.
Due to the progressive nature of this disease entity,
patients with spinal dural AVFs should be treated.
Successful treatment involves the interruption of the
fistula on the arterial or venous side.
CAVERNOUS MALFORMATIONS
Cavernous malformations are well-circumscribed
multilobulated masses that consist of closely packed
sinusoidal vascular channels lined by a single layer of
endothelium with no intervening neural parenchyma.
These lesions have been likened to a mulberry due to
their dark red or purple color. The surrounding brain
parenchyma is often gliotic and pigmented by old
hemorrhage and hemosiderin. Cavernous malforma-
tions occur throughout the brain and spinal cord as
well as the meninges. Most are found in the
subcortical white matter, external capsule, and the
pons. Of these lesions, 80% are supratentorial, 15%
are infratentorial, and 5% are in the spinal cord.
Cavernous malformations represent 8–15% of all
intracranial cerebrovascular malformations and are
reported to occur in 0.3% of the general population.
They exist in two forms: familial and sporadic. The
familial form occurs in up to 30% of patients and is
characterized by the presence of multiple lesions with
an autosomal dominant inheritance pattern, particu-
larly in families of Hispanic descent. Using linkage
analysis and short tandem repeat polymorphisms, a
gene possibly responsible for familial cavernous
malformations has been localized to chromosome 7q.
Patients with the familial or sporadic form of the
disease can present with seizure, headache, progres-
sive neurological deficit, or hemorrhage. Overall,
seizures are the most common presenting complaint,
occurring in 25–50% of patients. The rate of
hemorrhage for cavernous malformations is lower
than that for AVMs. The annual risk of hemorrhage
per lesion is approximately 1%. Cavernous mal-
formations of the brainstem and pons present with
unique symptoms and neurological signs due to their
exquisitely eloquent location. Nausea, vomiting,
vertigo, cranial nerve neuropathies, facial pain or
hypesthesia, hemisensory deficits, ataxia, hemipar-
esis, and spasticity have been reported.
Most cavernous malformations are angiographi-
cally occult lesions. If the lesion has hemorrhaged, an
avascular area with mass effect can sometimes be
identified. CT scans of the head can often demon-
strate calcifications, but MRI is best for diagnosing

cavernous malformations. MRI scans usually show a
‘‘popcorn-like’’ lesion with a well-delineated com-
plex reticulated core of mixed signal intensities
representing hemorrhage in different stages of
evolution. A low-signal hemosiderin rim typically
surrounds the lesion (Fig. 5).
The treatment of cavernous malformations de-
pends on the location of the lesion and the mode of
presentation. Most lesions discovered incidentally
require no urgent therapy. Sometimes, cavernous
malformations cannot be differentiated from tumors
and a biopsy is indicated. Surgical intervention is
recommended for symptomatic lesions in accessible
locations by standard microsurgical techniques.
Cavernous malformations that are entirely sur-
rounded by functionally eloquent brainstem par-
enchyma are best treated by close observation. Deep
cavernous malformations located in critical areas
have been treated with radiosurgery, but the fre-
quency of complications, presumably due to delayed
radiation injury, limits its widespread application.
DEVELOPMENTAL VENOUS ANOMALIES
DVAs of the brain are vascular malformations
characterized by the absence of an associated arterial
component and consist of anomalous medullary
Figure 5
(a) Sagittal T1-weighted MRI demonstrates a popcorn-like lesion in the pons. (b) Axial T2-weighted MRI reveals the cavernous
malformation with its typical hemosiderin rim.
CEREBROVASCULAR MALFORMATIONS 649
veins that converge into a centrally located, dilated
trunk. These malformations are considered normal
anatomical variants of the venous drainage of the
periependymal zones. DVAs are the most common
vascular malformation of the brain, comprising 42–
63% of all cerebral vascular malformations. Essen-
tially, these lesions consist of large, competent,
transparenchymal veins draining into large subepen-
dymal or subarachnoid vessels. The transparenchy-
mal or medullary veins form in a radial fashion with
intervening neural parenchyma and drain into either
the deep or superficial systems.
DVAs are often diagnosed serendipitously on
gadolinium-enhanced MRI and cerebral angiogra-
phy. They are characterized angiographically by a
tuft or feather-like structure called a caput medusae
(Fig. 6). Other descriptions include a hydra, a
spoked-wheel, a spider, an umbrella, or a sunburst.
The most common locations for these anomalies
include the white matter of the frontal and parietal
lobes as well as the cerebellum.
Although these lesions are most often clinically
asymptomatic, seizures and headache can occur.
DVAs are also rarely associated with vascular
insufficiency and hemorrhage. Hemorrhage from a
DVA generally indicates the coexistence of an
associated cavernous malformation.
650 CEREBROVASCULAR MALFORMATIONS
Figure 6
Lateral left vertebral artery injection in the venous phase clearly
depicts a caput medusae of a DVA draining into the vein of Galen
and subsequently into the straight sinus. The internal cerebral vein
does not opacify in this injection.
The management of an incidental DVA is
characterized by therapeutic nihilism. This can be
attributed to the low rate of hemorrhage and the
associated risk of venous infarction with the
elimination of a functional draining vein that
appears to be abnormal. Garner et al. reviewed
the natural history of 100 DVAs during a 14-year
period and concluded that it is relatively benign,
and therefore surgical resection of these venous
anomalies is rarely indicated. However, previous
reports have recommended aggressive treatment for
DVAs that are surgically accessible and associated
with hemorrhage. The primary goal of surgical
treatment is complete elimination of the DVA. The
wide distribution of the DVA in the brain parench-
yma and the indiscrete borders with the normal
tissue make radical excision difficult without
destroying eloquent tissue. Likewise, the dilated
cortical or deep veins in these DVAs may represent
the functional venous drainage to the surrounding
parenchyma.
Conceptually, radiosurgery offers an attractive
alternative treatment technique for DVAs because
irradiation causes obliteration of blood vessels
over a prolonged period of time, thereby allowing
ample time for the development of other paths
of venous drainage from a normal part of the
brain. In addition, Hashimoto et al., in reference
to the radiosurgical effects, postulated a gradual
obstruction of the small vessels constituting the
DVA with preservation of the surrounding tissue
drainage system. Lindquist et al. treated 13
DVAs with gamma knife irradiation between
1977 and 1991 and concluded that radiosurgery
for DVAs, although conceptually attractive, does
not fulfill the rigid criteria of minimal risk for
the treatment of a lesion with a benign natural
history.
CAPILLARY TELANGIECTASIAS
Capillary telangiectasias are cerebrovascular mal-
formations that consist of dilated capillary vessels
interspersed with normal intervening brain parench-
yma. They are considered to be congenital lesions
and are thought to arise from early localized failure
in the involution of brain capillaries that normally
occurs during the second month of gestation.
Although capillary telangiectasias may be found in
virtually any part of the brain or spinal cord, they
have a predilection for the pons. For the most part,
capillary telangiectasias have a benign clinical
course and are incidental findings at autopsy. They
can often be found in association with cavernous
malformations. Radiographically, only MRI can
demonstrate these lesions consistently. MRI can
detect capillary telangiectasias as punctate areas of
decreased signal on T2-weighted images. Typically,
no treatment is recommended for capillary telan-
giectasias.
—Max K. Kole and Ghaus M. Malik
See also–Arteriovenous Malformations (AVM),
Surgical Treatment of; Capillary Telangiectasia;
Cavernous Malformations; Central Nervous
System Malformations; Cerebral Angiography;
Hemangiomas; Venous Malformation
Further Reading
Aletich, V. A., and Debrun, G. M. (1999). Intracranial
arteriovenous malformations: The approach and technique
of cyanoacrylate embolization. In Interventional Neuro-
radiology: Strategies and Practical Techniques (J. J.
Connors and J. C. Wojak, Eds.), pp. 240–258. Saunders,
Philadelphia.
Awad, I. A. (1995). Dural arteriovenous malformations.
In Neurovascular Surgery (P. L. Carter, R. F. Spetzler,
and M. G. Hamilton, Eds.), pp. 905–932. McGraw-Hill, New
York.

Gallen, C. C., Schwartz, B. J., Bucholz, R. D., et al. (1995).
Presurgical localization of functional cortex using magnetic
source imaging. J. Neurosurg. 82, 988–994.
Garner, T. B., Curling, O. D., Jr., Kelly, D. L., Jr., et al. (1991). The
natural history of intracranial venous angiomas. J. Neurosurg.
75, 715–722.
Hashimoto, M., Yokota, A., Kajiwara, H., et al. (1990).
Venous angioma treated by radiation. Neuroradiology 31,
537–540.
Linquist, C., Guo, W. Y., Karlsson, B., et al. (1993). Radiosurgery
for venous angiomas. J. Neurosurg. 78, 531–536.
Malik, G. M., and Mc Cormick, P. W. (1996). Surgical resection of
thalamocaudate arteriovenous malformations. In Neurosurgery
(R. H. Wilkins and S. S. Rengachary, Eds.), 2nd ed., Vol. 2, pp.
2455–2462. McGraw-Hill, New York.
Malik, G. M., Pearce, J. E., Ausman, J. I., et al. (1984). Dural
arteriovenous malformations and intracranial hemorrhage.
Neurosurgery 15, 332–339.
Malik, G. M., Morgan, J. K., and Boulos, R. S. (1988). Venous
angiomas: An underestimated cause of intracranial hemorrhage.
Surg. Neurol. 30, 350–358.
Martin, N. A., and Vinters, H. V. (1995). Arteriovenous
malformations. In Neurovascular Surgery (P. L. Carter, R. F.
Spetzler, and M. G. Hamilton, Eds.), pp. 875–903. McGraw-
Hill, New York.
Moriarity, J. L., Clatterbuck, R. E., and Rigamonti, D. (1999). The
natural history of cavernous malformations. Neurosurg. Clin.
North Am. 10, 411–417.
Osborne, A. G. (1994). Intracranial vascular malformations. In
Diagnostic Neuroradiology (A. G. Osborne, Ed.), pp. 284–329.
Mosby, St. Louis.
Pikus, H. J., Beach, M. L., and Harbaugh, R. E. (1998).
Microsurgical treatment of arteriovenous malformations: Ana-
lysis and comparison with stereotactic radiosurgery. J. Neuro-
surg. 88, 641–646.
Pollock, B. E., Flickinger, J. C., Lunsford, L. D., et al. (1998).
Factors associated with successful arteriovenous malformation
radiosurgery. Neurosurgery 42, 1239–1247.
Rengachary, S. S., and Kalyan-Raman, U. P. (1996). Telangiecta-
sias and venous angiomas. In Neurosurgery (R. H. Wilkins and
S. S. Rengachary, Eds.), 2nd ed., Vol. 2, pp. 2509–2514.
McGraw-Hill, New York.
Rigamonti, D., Hsu, F. P. K., and Monsein, L. H. (1996).
Cavernous malformations and related lesions. In Neurosurgery
(R. H. Wilkins and S. S. Rengachary, Eds.), 2nd ed., Vol. 2, pp.
2503–2508. McGraw-Hill, New York.
Spetzler, R. F., and Martin, N. A. (1986). A proposed grading
system for arteriovenous malformations. J. Neurosurg. 65,
476–483.
Watson, J. C., and Oldfield, E. H. (1999). The surgical manage-
ment of spinal dural vascular malformations. Neurosurg. Clin.
North Am. 10, 73–87.
Zambramski, J. M., Henn, J. S., and Coons, S. (1999). Pathology
of cerebral vascular malformations. Neurosurg. Clin. North
Am. 10, 395–410.
Cerebrum
see Brain Anatomy
CERVICAL DYSTONIA 651
Cervical Dystonia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CERVICAL DYSTONIA, also known as spasmodic
torticollis, is a movement disorder that primarily
involves the nuchal muscles. In the past it was called
caput obstipum; in the 16th century, Rabelais
identified the disorder and coined the term torty
colly. The main features of cervical dystonia are an
abnormal, involuntary head and neck posture with
sustained or intermittent twisting movements. Cervi-
cal dystonia was once attributed to involuntary
hyperkinesis of unilateral neck muscles. In the early
1900s, cervical dystonia (or wry neck) was regarded
as a psychiatric condition but later was accepted as
an organic ailment.
CLINICAL MANIFESTATIONS
Patients with cervical dystonia have sustained mus-
cular contractions that cause repetitive, involuntary
movements of head and neck muscles that result in
abnormal postures. Cervical dystonia is the most
frequent form of dystonia. The head and neck may
assume any directional combination: lateral rotation
(torticollis), forward rotation (antecollis), or back-
ward rotation (retrocollis). Typically, the shoulder is
raised on the side toward which the chin points. In
one-third of patients, dystonia involves contiguous
body parts, including the oromandibular region,
shoulder, and arms. Cervical dystonia may be
associated with head and hand tremor. Unlike other
focal dystonias, the pain associated with cervical
dystonia is remarkably high and contributes to
disability. Sensory tricks or geste antagonistique, such
as touching the face, chin, or occiput, are used by
some patients to reduce the severity of their spasms.
The mean age of onset is 38–42 years, with most
cases occurring in the fourth to sixth decades.
Claypool et al. reported an overall incidence of 1.2/
100,000 person-years. The female-to-male ratio is 2:1.
Dystonic symptoms are improved by a supine
position and sleep and are worsened by emotional
stress. During the first months or years of the
manifestation of cervical dystonia, the intensity of
dystonia worsens and the spasms may spread to the
oromandibular area, arm, and (rarely) leg. Cervical
dystonia is disabling and may lead to severe
contractures, deformities, cervical radiculopathy,
and myelopathy.

Gallen, C. C., Schwartz, B. J., Bucholz, R. D., et al. (1995).
Presurgical localization of functional cortex using magnetic
source imaging. J. Neurosurg. 82, 988–994.
Garner, T. B., Curling, O. D., Jr., Kelly, D. L., Jr., et al. (1991). The
natural history of intracranial venous angiomas. J. Neurosurg.
75, 715–722.
Hashimoto, M., Yokota, A., Kajiwara, H., et al. (1990).
Venous angioma treated by radiation. Neuroradiology 31,
537–540.
Linquist, C., Guo, W. Y., Karlsson, B., et al. (1993). Radiosurgery
for venous angiomas. J. Neurosurg. 78, 531–536.
Malik, G. M., and Mc Cormick, P. W. (1996). Surgical resection of
thalamocaudate arteriovenous malformations. In Neurosurgery
(R. H. Wilkins and S. S. Rengachary, Eds.), 2nd ed., Vol. 2, pp.
2455–2462. McGraw-Hill, New York.
Malik, G. M., Pearce, J. E., Ausman, J. I., et al. (1984). Dural
arteriovenous malformations and intracranial hemorrhage.
Neurosurgery 15, 332–339.
Malik, G. M., Morgan, J. K., and Boulos, R. S. (1988). Venous
angiomas: An underestimated cause of intracranial hemorrhage.
Surg. Neurol. 30, 350–358.
Martin, N. A., and Vinters, H. V. (1995). Arteriovenous
malformations. In Neurovascular Surgery (P. L. Carter, R. F.
Spetzler, and M. G. Hamilton, Eds.), pp. 875–903. McGraw-
Hill, New York.
Moriarity, J. L., Clatterbuck, R. E., and Rigamonti, D. (1999). The
natural history of cavernous malformations. Neurosurg. Clin.
North Am. 10, 411–417.
Osborne, A. G. (1994). Intracranial vascular malformations. In
Diagnostic Neuroradiology (A. G. Osborne, Ed.), pp. 284–329.
Mosby, St. Louis.
Pikus, H. J., Beach, M. L., and Harbaugh, R. E. (1998).
Microsurgical treatment of arteriovenous malformations: Ana-
lysis and comparison with stereotactic radiosurgery. J. Neuro-
surg. 88, 641–646.
Pollock, B. E., Flickinger, J. C., Lunsford, L. D., et al. (1998).
Factors associated with successful arteriovenous malformation
radiosurgery. Neurosurgery 42, 1239–1247.
Rengachary, S. S., and Kalyan-Raman, U. P. (1996). Telangiecta-
sias and venous angiomas. In Neurosurgery (R. H. Wilkins and
S. S. Rengachary, Eds.), 2nd ed., Vol. 2, pp. 2509–2514.
McGraw-Hill, New York.
Rigamonti, D., Hsu, F. P. K., and Monsein, L. H. (1996).
Cavernous malformations and related lesions. In Neurosurgery
(R. H. Wilkins and S. S. Rengachary, Eds.), 2nd ed., Vol. 2, pp.
2503–2508. McGraw-Hill, New York.
Spetzler, R. F., and Martin, N. A. (1986). A proposed grading
system for arteriovenous malformations. J. Neurosurg. 65,
476–483.
Watson, J. C., and Oldfield, E. H. (1999). The surgical manage-
ment of spinal dural vascular malformations. Neurosurg. Clin.
North Am. 10, 73–87.
Zambramski, J. M., Henn, J. S., and Coons, S. (1999). Pathology
of cerebral vascular malformations. Neurosurg. Clin. North
Am. 10, 395–410.
Cerebrum
see Brain Anatomy
CERVICAL DYSTONIA 651
Cervical Dystonia
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CERVICAL DYSTONIA, also known as spasmodic
torticollis, is a movement disorder that primarily
involves the nuchal muscles. In the past it was called
caput obstipum; in the 16th century, Rabelais
identified the disorder and coined the term torty
colly. The main features of cervical dystonia are an
abnormal, involuntary head and neck posture with
sustained or intermittent twisting movements. Cervi-
cal dystonia was once attributed to involuntary
hyperkinesis of unilateral neck muscles. In the early
1900s, cervical dystonia (or wry neck) was regarded
as a psychiatric condition but later was accepted as
an organic ailment.
CLINICAL MANIFESTATIONS
Patients with cervical dystonia have sustained mus-
cular contractions that cause repetitive, involuntary
movements of head and neck muscles that result in
abnormal postures. Cervical dystonia is the most
frequent form of dystonia. The head and neck may
assume any directional combination: lateral rotation
(torticollis), forward rotation (antecollis), or back-
ward rotation (retrocollis). Typically, the shoulder is
raised on the side toward which the chin points. In
one-third of patients, dystonia involves contiguous
body parts, including the oromandibular region,
shoulder, and arms. Cervical dystonia may be
associated with head and hand tremor. Unlike other
focal dystonias, the pain associated with cervical
dystonia is remarkably high and contributes to
disability. Sensory tricks or geste antagonistique, such
as touching the face, chin, or occiput, are used by
some patients to reduce the severity of their spasms.
The mean age of onset is 38–42 years, with most
cases occurring in the fourth to sixth decades.
Claypool et al. reported an overall incidence of 1.2/
100,000 person-years. The female-to-male ratio is 2:1.
Dystonic symptoms are improved by a supine
position and sleep and are worsened by emotional
stress. During the first months or years of the
manifestation of cervical dystonia, the intensity of
dystonia worsens and the spasms may spread to the
oromandibular area, arm, and (rarely) leg. Cervical
dystonia is disabling and may lead to severe
contractures, deformities, cervical radiculopathy,
and myelopathy.
652 CERVICAL DYSTONIA
Swallowing functions may be abnormal, especially
in patients with extreme retrocollis. In a recent
videofluoroscopic study of 43 patients, more than
half had objective findings of swallowing abnormal-
ities that manifested as a form of delayed swallowing
reflex and vallecular residue.
Cervical dystonia may be a component of general-
ized dystonia, which usually manifests first with
dystonic posturing of the lower limbs. Uncommonly,
generalized dystonia may start in the neck.
ETIOLOGY
The etiology of cervical dystonia remains an enigma.
The most accepted hypothesis proposes an abnorm-
ality of the basal ganglia or brainstem. Putaminal
lesions can precipitate contralateral dystonia; there-
fore, this structure and its neuroanatomical pathways
may have a role in the pathogenesis of cervical
dystonia. Cases have been associated with trauma,
multiple sclerosis, alcohol withdrawal, frontal lobe
meningiomas, and exposure to neuroleptic medica-
tions (tardive dystonia). The role of genetic transmis-
sion is unclear; however, a family history of cervical
dystonia or writer’s cramp is detected in some
patients. A genetic study of 40 patients with focal
dystonias, including cervical dystonia, found that
25% had relatives with dystonia. It was suggested
that a single autosomal dominant gene mutation may
have been involved. DYT7 gene locus on chromo-
some 18p has been suggested to account for several
large families of cervical dystonia, but in most of
cases a family history or definite inheritance pattern
is absent.
The presence of hyperexcitable blink reflexes in
cervical dystonia patients reflects the excitability of
brainstem neurons, supporting the view that cervical
dystonia is caused by an abnormality in central
mechanisms. Deuschl et al. studied the reciprocal
inhibition in forearm flexors and the extensors with
an H-reflex setup and found reduced inhibition in
patients with cervical dystonia compared with
normal individuals. Vestibuloocular reflexes are
abnormal in cervical dystonia patients and remain
abnormal even after successful treatment with
botulinium toxin. These findings further indicate
that cervical dystonia is probably a more generalized
disorder than is apparent.
A study of cervical dystonia patients using positron
emission tomography revealed no consistent focal
abnormality associated with the cerebral metabolic
rate. However, there was a bilateral breakdown of
the normal relationships between the thalamus and
basal ganglia. This observation may indicate disrup-
tion of the pallidothalamic projections and a
disturbance in the neurotransmitter g-aminobutyric
acid (GABA). Galardi et al. reported a prominent
increase in glucose metabolism in the basal ganglia,
thalamus, premotor–motor cortex, and cerebellum in
patients with cervical dystonia. Hierholzer et al.
found an increase in the number of D2 receptors
(using iodobenzamide single photon emission com-
puted tomography) in the striatum contralateral to
the direction of torticollis. Brain magnetic resonance
imaging (MRI) studies demonstrated prolonged T2
times in the caudate and putamen nucleus of patients
with cervical dystonia.
DIFFERENTIAL DIAGNOSIS
Secondary causes of cervical dystonia should be ruled
out. Various pathologies, such as septic arthritis of
the C1–C2 lateral facet joint, apharyngeal abscess, a
cervical epidural abscess, and tumors such as spinal
cord astrocytomas and ependymomas, may manifest
as cervical dystonia. Patients with trochlear nerve
palsy and vestibular disorders, which require differ-
ent approaches and treatments, may also tilt their
heads. Psychogenic cervical dystonia can also occur.
DIAGNOSTIC WORKUP
Cervical dystonia is a clinical diagnosis. However,
drug-induced dystonia and Wilson’s disease in young
patients should be excluded. Cervical spine radio-
graphs should be obtained to rule out congenital,
infectious, and traumatic causes of cervical dystonia.
Neuroimaging procedures such as brain MRI are of
little diagnostic value.
TREATMENT
Available treatments for cervical dystonia are med-
ical and surgical. Various oral medications, such as
anticholinergics (trihexyphenidyl), muscle relaxants,
clonazepam, and spasmolytics, have been used with
little efficacy. Intramuscular injections of botulinium
toxin serotype-A (BTX) often provide dramatic
symptomatic relief of cervical dystonia and the
associated pain. Proper selection of the involved
muscles is the most significant determinant of
response to BTX treatment. BTX causes presynaptic
neuromuscular blockade and induces weakness of
the dystonic muscles. The therapeutic effects of each

injection persist for 3 or 4 months. Adverse effects
include pain at the injection site, hematoma forma-
tion, irritation of the greater occipital nerve and
brachial plexus, dysphagia, weakness of neck mus-
cles, and occasionally generalized weakness. Many
investigators consider BTX as the primary treatment
for cervical dystonia.
Surgical options include thalamotomy, myotomy,
rhizotomy, and selective rhizotomy, but these proce-
dures are often unsuccessful. Another surgical
approach is selective peripheral denervation with
section of the nerve twigs innervating the dystonic
neck muscles. Supportive therapy such as physiother-
apy and occupational therapy are important aspects
of management.
—Alireza Minagar and William C. Koller
See also–Dystonia; Wilson’s Disease
Further Reading
Claypool, D. W., Duane, D. D., Ilstrup, D. M., et al. (1995).
Epidemiology and outcome of cervical dystonia (spasmodic
torticollis) in Rochester, Minnesota. Movement Disorders 10,
608–614.
Deuschl, G., Seifert, C., Heinen, F., et al. (1992). Reciprocal
inhibition of forearm flexor muscles in spasmodic torticollis.
J. Neurol. Sci. 113, 85–90.
Galardi, G., Perani, D., Grassi, F., et al. (1996). Basal ganglia and
thalamo-cortical hypermetabolism in patients with spasmodic
torticollis. Acta Neurol. Scand. 94, 172–176.
Hierholzer, J., Cordes, M., Schelosky, L., et al. (1994). Dopamine
D2 receptor imaging with iodine-123-iodobenzamide SPECT
in idiopathic rotational torticollis. J. Nucl. Med. 35, 1921–
1927.
Jankovic, J., and Schwartz, K. (1990). Botulinum toxin injections
for cervical dystonia. Neurology 40, 277–280.
Leube, B., Hendgen, T., Kessler, K. R., et al. (1997). Evidence for
DYT7 being a common cause of cervical dystonia (torticollis) in
Central Europe. Am. J. Med. Genet. 74, 529–532.
Patterson, R. M., and Little, S. C. (1943). Spasmodic torticollis. J.
Nerv. Mental Dis. 98, 571–599.
Riski, J. E., Horner, J., and Nashold, B. S., Jr. (1990). Swallowing
function in patients with spasmodic torticollis. Neurology 40,
1443–1445.
Schneider, S., Feifel, E., Ott, D., et al. (1994). Prolonged MRI T2
times of the lentiform nucleus in idiopathic spasmodic
torticollis. Neurology 44, 846–850.
Stoessl, A. J., Martin, W. R., Clark, C., et al. (1986). PET studies of
cerebral glucose metabolism in idiopathic torticollis. Neurology
36, 653–657.
Taira, T., and Hitchcock, E. (1990). Torticollis as an initial
symptom of adult-onset dystonia musculorum deformans.
Brain Nerve 42, 867–871.
Tibbetts, R. W. (1971). Spasmodic torticollis. J. Psychosom. Res.
15, 461–469.
Tolosa, E., Montserrat, L., and Bayes, A. (1988). Blink reflex
studies in focal dystonias: Enhanced excitability of brainstem
CERVICAL SPINE STABILIZATION 653
interneurons in cranial dystonia and spasmodic torticollis.
Movement Disorders 3, 61–69.
Waddy, H. M., Fletcher, N. A., and Harding, A. E. (1991).
Marsden cervical dystonia. A genetic study of idiopathic focal
dystonias. Ann. Neurol. 29, 320–324.
Cervical Radiculopathy
see Radiculopathy, Cervical
Cervical Spine Stabilization
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CERVICAL SPINE is a complex structure that must
support many functions. It must provide stability for
the skull while maintaining mobility in many
directions. It protects the spinal cord and nerve roots
and must be able to withstand significant forces.
These functions are accomplished by complex con-
nections between the individual bones of the cervical
spine.
There are seven cervical vertebrae (Fig. 1). The
first (C1), called the atlas, is a ring-shaped bone
without a vertebral body and without adjacent disks.
It serves as a transition zone between the skull base
and the second cervical vertebra or axis (C2). C2 is
also a unique vertebra, with a bony protuberance,
the dens, projecting up from the vertebral body. The
skull base condyles fit within the lateral masses of
C1, and C1 rests on the facets of C2 with the C2 dens
projecting within it. A complex set of ligaments helps
secure the skull, C1, and C2 together, thereby
stabilizing the skull and cervicovertebral junction.
The organization of this connection between the
skull base and upper cervical spine allows some
movement: Some flexion, extension, and lateral
bending are allowed at the occipitoatlantal joint,
but there is no axial rotation. The majority of axial
mobility of the spine derives from the atlantoaxial
joint, between C1 and C2.
The remaining vertebrae of the cervical spine are
more similar to those of the rest of the spine. The
vertebral body is supported on either side by
intervertebral disks, and a posterior ring of bone
completes the bony canal around the spinal cord and
exiting nerve roots. These vertebral bodies are also
connected to one another by facet joints and a

injection persist for 3 or 4 months. Adverse effects
include pain at the injection site, hematoma forma-
tion, irritation of the greater occipital nerve and
brachial plexus, dysphagia, weakness of neck mus-
cles, and occasionally generalized weakness. Many
investigators consider BTX as the primary treatment
for cervical dystonia.
Surgical options include thalamotomy, myotomy,
rhizotomy, and selective rhizotomy, but these proce-
dures are often unsuccessful. Another surgical
approach is selective peripheral denervation with
section of the nerve twigs innervating the dystonic
neck muscles. Supportive therapy such as physiother-
apy and occupational therapy are important aspects
of management.
—Alireza Minagar and William C. Koller
See also–Dystonia; Wilson’s Disease
Further Reading
Claypool, D. W., Duane, D. D., Ilstrup, D. M., et al. (1995).
Epidemiology and outcome of cervical dystonia (spasmodic
torticollis) in Rochester, Minnesota. Movement Disorders 10,
608–614.
Deuschl, G., Seifert, C., Heinen, F., et al. (1992). Reciprocal
inhibition of forearm flexor muscles in spasmodic torticollis.
J. Neurol. Sci. 113, 85–90.
Galardi, G., Perani, D., Grassi, F., et al. (1996). Basal ganglia and
thalamo-cortical hypermetabolism in patients with spasmodic
torticollis. Acta Neurol. Scand. 94, 172–176.
Hierholzer, J., Cordes, M., Schelosky, L., et al. (1994). Dopamine
D2 receptor imaging with iodine-123-iodobenzamide SPECT
in idiopathic rotational torticollis. J. Nucl. Med. 35, 1921–
1927.
Jankovic, J., and Schwartz, K. (1990). Botulinum toxin injections
for cervical dystonia. Neurology 40, 277–280.
Leube, B., Hendgen, T., Kessler, K. R., et al. (1997). Evidence for
DYT7 being a common cause of cervical dystonia (torticollis) in
Central Europe. Am. J. Med. Genet. 74, 529–532.
Patterson, R. M., and Little, S. C. (1943). Spasmodic torticollis. J.
Nerv. Mental Dis. 98, 571–599.
Riski, J. E., Horner, J., and Nashold, B. S., Jr. (1990). Swallowing
function in patients with spasmodic torticollis. Neurology 40,
1443–1445.
Schneider, S., Feifel, E., Ott, D., et al. (1994). Prolonged MRI T2
times of the lentiform nucleus in idiopathic spasmodic
torticollis. Neurology 44, 846–850.
Stoessl, A. J., Martin, W. R., Clark, C., et al. (1986). PET studies of
cerebral glucose metabolism in idiopathic torticollis. Neurology
36, 653–657.
Taira, T., and Hitchcock, E. (1990). Torticollis as an initial
symptom of adult-onset dystonia musculorum deformans.
Brain Nerve 42, 867–871.
Tibbetts, R. W. (1971). Spasmodic torticollis. J. Psychosom. Res.
15, 461–469.
Tolosa, E., Montserrat, L., and Bayes, A. (1988). Blink reflex
studies in focal dystonias: Enhanced excitability of brainstem
CERVICAL SPINE STABILIZATION 653
interneurons in cranial dystonia and spasmodic torticollis.
Movement Disorders 3, 61–69.
Waddy, H. M., Fletcher, N. A., and Harding, A. E. (1991).
Marsden cervical dystonia. A genetic study of idiopathic focal
dystonias. Ann. Neurol. 29, 320–324.
Cervical Radiculopathy
see Radiculopathy, Cervical
Cervical Spine Stabilization
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CERVICAL SPINE is a complex structure that must
support many functions. It must provide stability for
the skull while maintaining mobility in many
directions. It protects the spinal cord and nerve roots
and must be able to withstand significant forces.
These functions are accomplished by complex con-
nections between the individual bones of the cervical
spine.
There are seven cervical vertebrae (Fig. 1). The
first (C1), called the atlas, is a ring-shaped bone
without a vertebral body and without adjacent disks.
It serves as a transition zone between the skull base
and the second cervical vertebra or axis (C2). C2 is
also a unique vertebra, with a bony protuberance,
the dens, projecting up from the vertebral body. The
skull base condyles fit within the lateral masses of
C1, and C1 rests on the facets of C2 with the C2 dens
projecting within it. A complex set of ligaments helps
secure the skull, C1, and C2 together, thereby
stabilizing the skull and cervicovertebral junction.
The organization of this connection between the
skull base and upper cervical spine allows some
movement: Some flexion, extension, and lateral
bending are allowed at the occipitoatlantal joint,
but there is no axial rotation. The majority of axial
mobility of the spine derives from the atlantoaxial
joint, between C1 and C2.
The remaining vertebrae of the cervical spine are
more similar to those of the rest of the spine. The
vertebral body is supported on either side by
intervertebral disks, and a posterior ring of bone
completes the bony canal around the spinal cord and
exiting nerve roots. These vertebral bodies are also
connected to one another by facet joints and a
654 CERVICAL SPINE STABILIZATION
Figure 1
Anterior view of the cervical spine [reproduced with permission
from the Barrow Neurological Institute].
complex set of ligaments. The organization of the
cervical spine from C3 through C7 permits flexion
and extension of the neck and contributes to lateral
bending.
DIAGNOSTIC EVALUATION
Injury to the bony structure or ligamentous support
of the cervical spine can result in instability. This
instability can have several consequences, from pain
to the potential for injury to the nerve roots or spinal
cord. Such instability can be caused by direct trauma,
degenerative disease, and conditions affecting the
joints, such as rheumatoid arthritis or ankylosing
spondylitis. It is important to diagnose instability
correctly to prevent injury to the nerve roots or
spinal cord with its potentially devastating conse-
quences.
The evaluation of a patient for cervical instability
is primarily clinical and radiographical. Clinicians
must have a high level of suspicion when significant
forces have been delivered to the spine, such as in
automobile, bicycle, or pedestrian–auto accidents or
in sports injuries. If a patient has neurological
deficits that can be attributed to spinal cord or
nerve root injury, cervical stabilization must be
maintained until the cervical spine is evaluated
thoroughly. Typically, the evaluation includes plain
radiography and computed tomography (CT) and
provides valuable information about the bony
integrity of the spine. If the bony structures are
normal, magnetic resonance imaging (MRI) can be
used to detect injury to the ligamentous structures
and/or spinal cord.
In a neurologically intact patient with persistent
neck pain, suspicion must be high. Even if plain
radiographs and CT scans are normal, such patients
can have a ligamentous injury that causes instability.
Again, MRI can be used, or cervical flexion–
extension radiography can be performed. Flexion–
extension radiographs provide the best assessment of
cervical instability. However, they must be used with
caution and only in patients who are able to indicate
worsening pain or the onset of neurological symp-
toms associated with the flexion and extension
maneuvers because such instability could injure
nervous structures. When all imaging studies are
negative but the mechanism of injury is a concern
and the patient has continued neck pain, a con-
servative approach is best. In such cases, short-term
cervical immobilization in a rigid collar with radio-
graphy repeated 2 or 3 weeks later may be needed to
assure the clinician that the integrity of the spine
remains intact.
In conditions such as degenerative disease of the
spine or joint diseases involving the cervical spine
(e.g., rheumatoid arthritis), the same approach is
used for evaluation. Plain radiographs and CT scans
can be used to evaluate the bony structures, MRI to
evaluate the ligamentous structures, and dynamic
radiographs to show the instability.
TREATMENT
The goal of cervical stabilization is to enable bone
growth across the unstable segments. The fusion
stabilizes the cervical spine, preventing potential
injury to the spinal cord or nerve roots. External
immobilization or internal fixation with screws,
rods, plates, or wires provide temporary stability
while bone grafts fuse across the unstable portions
of the spine. Ultimately, the bony fusion provides
long-term stability. Much as a cast holds the
ends of a fractured bone together while it heals,
instrumentation offers only temporary fixation
of the unstable segments. In some cases, the fusion
 CERVICAL SPINE STABILIZATION 655

is at the expense of some spinal mobility, but rare. Unilateral condyle fractures are more common
protection of the spinal cord and nerve roots takes than bilateral fractures. Fractures of the condyle that
precedence. extend through the skull base are usually relatively
Depending on the nature of the instability, stable and can be treated with a rigid cervical collar.
different approaches can be used to allow the spine Fractures isolated to the condyle or with avulsion of
to heal and to restore its own stability. For instance, the condyle tend to be more unstable but can usually
external stabilization can be used to prevent hyper- be treated with halo immobilization.
mobility while some bony fractures heal. Some Atlantooccipital dislocation is caused by ligamen-
cervical fractures can be immobilized by a rigid tous disruption (e.g., distraction, lateral flexion or
cervical collar alone while the fracture heals. If the both), and its most severe form can be deadly. Initial
fracture is more complex, and adequate stability treatment is immobilization of the cervical spine in a
cannot be maintained by a cervical collar, an external neutral position. Halo vest immobilization can be
halo brace can be used. The brace affixes the skull to used, but many patients remain unstable and may
the torso, preventing motion of the cervical spine. In require surgical stabilization. Craniovertebral instabil-
some cases, however, external stabilization does not ity also originates from congenital (incomplete forma-
adequately immobilize the fractures or the ligaments tion of C1 or the occipito-C1 joints), developmental
are also injured significantly. Ligamentous injury is (basilar invagination or os odontoideum), acquired
usually irreversible. In such cases, external stabiliza- (rheumatoid arthritis with cranial settling or ankylos-
tion is insufficient to allow the spine to regain ing spondylitis), or malignant (chordomas, plasmacy-
stability. In conditions such as basilar invagination, tomas, osteoblastomas, and metastases) conditions. In
progressive gradual destruction of the bony and such cases, instability can injure the brainstem and
ligamentous support at the craniocervical junction upper cervical spine acutely or progressively.
causes the skull to progressively settle on the cervical The principal way to stabilize the craniovertebral
spine. The upper cervical spine and brainstem can junction is by occipitocervical fusion (Fig. 2). This
become compressed, and such conditions require technique fixates the base of the skull to the stable
surgical stabilization.
Depending on the nature of the injury or disease
process, internal surgical stabilization and fusion
procedures can be performed from an anterior or
posterior approach. The most common anterior
stabilization procedures include odontoid screw fixa-
tion and anterior plating after discectomy or corpect-
omy with the placement of bone graft or a bone
substitute. Posterior stabilization can be obtained
with C1–C2 transarticular screws, occipitocervical
fusion, interspinous or sublaminar wiring, and lateral
mass plates or rods followed by a bone grafting.
Again, the essential feature of stabilizing the spine is
to achieve bony fusion across the unstable segment
using instrumentation such as screws, plates, and rods
to provide temporary stability while the fusion
develops. Some patients may need additional support
from a rigid cervical collar or halo to facilitate
temporary stabilization while the bony fusion occurs.

CRANIOVERTEBRAL INSTABILITY
The complex craniovertebral junction includes ex-
tensive ligamental connections between the skull and
Figure 2
C1 and C2. Trauma is a main cause of instability Occipitocervical fusion using a contoured Steinmann pin and
here. Fractures involving only the occipital condyle, autograft [reproduced with permission from the Barrow
where the skull articulates with C1, are extremely Neurological Institute].
656 CERVICAL SPINE STABILIZATION
Figure 3
C1–C2 interspinous fusion using Songer cable fixation and
autograft [reproduced with permission from the Barrow
Neurological Institute].
portion of the cervical spine. The procedure is
performed using a posterior approach. Titanium
plates or contoured titanium rods are fixated to both
the skull base and the posterior cervical spine by
screws or cables. Bone grafts are placed over the
posterior bony surfaces to facilitate bony fusion. The
level at which the cervical spine is fused is
determined by the level at which stability is normal
and may be as low as the upper thoracic spine. While
waiting for bony fusion to develop, patients usually
require an external orthosis—either a rigid cervical
collar or halo brace depending on their degree of
preoperative instability.
An anterior approach is rarely used to treat
craniovertebral instability. However, promising tech-
niques for grafting bone between the clivus, anterior
arch of C1, and C2 are being evaluated. The grafts
are supplemented by posterior fixation.
ATLANTOAXIAL INSTABILITY
Trauma is the main cause of atlantoaxial or C1–C2
instability and may include bony and ligamentous
injury. Isolated fractures of C1 (i.e., Jefferson
fractures) may heal by treatment with external
immobilization alone using either a cervical collar
or a halo brace. If the associated occipitoatlantal
joint is affected, a posterior occipitocervical fusion,
as described previously, may be required. If C2 or the
atlantoaxial joint is affected, posterior fusion across
the C1–C2 segment can be used to attain stabiliza-
tion. Alternatives include posterior C1–C2 interspi-
nous fusion or transarticular C1–C2 screw fixation.
For C1–C2 interspinous fusion, titanium cables are
used to fixate the posterior rings of C1 to C2 with an
intervening bone graft to promote bony fusion
(Fig. 3). This technique alone usually requires halo
immobilization for 2 or 3 months to provide
additional stability while the bony fusion develops.
In some cases, C1–C2 transarticular screws may be
used to provide additional stability for the C1–C2
joint. In these cases, a rigid cervical collar can be
worn in place of a halo brace (Fig. 4).
Odontoid screw fixation can be used to stabilize
type II odontoid fractures when the associated
ligaments remain intact. The odontoid is the portion
of the C2 that projects superiorly through the C1
ring. The odontoid is especially susceptible to trauma.
The technique for odontoid screw fixation involves
an anterior approach that exposes the C2 vertebral
body at the junction of C2–C3 (Fig. 5). A specially
designed screw is threaded through both the body of
C2 and the fractured fragment. This technique
provides immediate stability, preserves normal rota-
tion at C1–C2, and may avoid the need for halo
immobilization. Because this technique reconstructs
the normal anatomical relationship of the fractured
dens to the body of C2, bony union across the
fracture can usually be achieved without the need for
bone grafts. Patients usually wear a rigid cervical
collar for 6–8 weeks while the bony fusion occurs.
SUBAXIAL SPINE FIXATION
Instability of the cervical spine below the craniover-
tebral junction can be caused by trauma and is also
Figure 4
C1–C2 fusion using interspinous wiring with C1–C2 transarticular
screws and autograft [reproduced with permission from the
Barrow Neurological Institute].
 CERVICAL SPINE STABILIZATION 657

contoured appropriately. Screw holes are drilled into

the articular masses at the levels to be fused. Their
trajectory orients the screw parallel to the facet joint,
ensuring that the nerve roots and vertebral artery will
not be violated by the screw. The screws secure plates
and rods bilaterally, and the bony fusion is augmen-
ted with bone graft.
Interspinous wiring may also be used to augment
lateral mass fixation, or it can be used alone to
provide posterior fusion. The technique is similar to
that described for C1–C2 fixation. With proper bone
grafts, interspinous wiring can provide an excellent
fusion. However, the wiring may need to be
augmented with halo immobilization while the bony
fusion develops. Posterior fusion can also be
achieved using sublaminar wires or laminar clamps.
This method provides an additional way to immo-
bilize the spine posteriorly while bony fusion occurs.
However, additional immobilization in a halo brace
is typically required.
Anterior cervical instrumentation can be used to
supplement decompression and fusion. Indications
include trauma (especially with an associated
ruptured disk that requires discectomy), flexion–
compression fractures, and fracture dislocations,

Figure 5
Anterior odontoid screw fixation [reproduced with permission
from the Barrow Neurological Institute].

associated with neoplasms and degenerative changes.

Stabilization can be achieved from either posterior or
anterior approaches, depending on the nature of the
instability and associated pathology. Posterior ap-
proaches use sublaminar wires, interspinous fixation,
or lateral mass plates or rods.
The use of lateral mass plates or rods requires a
posterior exposure (Fig. 6). The patient must have
neutral or anatomical alignment and intact bony
landmarks, which are used to place and orient the
screws correctly. Contraindications to lateral mass
plate or rod fixation include osteoporosis or osteo-
malacia because the resulting weak bones will not
hold the screws and other conditions in which
normal anatomy is not preserved.
The technique involves a posterior exposure with Figure 6
the patient in as neutral or anatomical alignment as Lateral mass fusion with plates [reproduced with permission from
possible. Titanium plates and rods are sized and the Barrow Neurological Institute].
658 CERVICAL SPINE STABILIZATION
all of which may also require some degree of
discectomy or corpectomy; extension injuries,
especially in the elderly with underlying spondy-
losis; and some facet dislocations. Anterior cervical
instrumentation is used in some cases of disk
disease, such as degenerative disk disease or
herniated disks that require discectomy. In single-
level discectomies, the use of anterior cervical
instrumentation is controversial. Typically, it is
used if the patient has documented instability on
flexion–extension radiographs or has an abnormal
curvature of the spine that may progress if
adequate fusion across the discectomy site is not
attained. For discectomies involving multiple levels
or for corpectomies, bony fusion and anterior
cervical instrumentation are more commonly used.
Tumors involving the vertebral bodies or infection
may also require anterior cervical plating and bony
fusion.
Anterior cervical plating involves placing a bone
graft at the site of discectomy or corpectomy. Either
autologous or allograft bone can be used. Recently,
titanium or carbon fiber cages and disk spacers have
been used in select cases. An anterior plate is placed
across the vertebral bodies on either side of the
discectomy or corpectomy site, with screws placed in
the intact vertebral bodies (Fig. 7). The anterior plate
provides immobilization while the bony fusion
Figure 7
Anterior cervical fusion following corpectomy using strut graft and
anterior cervical plate [reproduced with permission from the
Barrow Neurological Institute].
occurs. Most single-level discectomy and fusions
need no external immobilization. Patients under-
going multilevel discectomies and fusions with
corpectomies often wear rigid cervical collars to
obtain additional immobilization while bony fusion
develops.
CONCLUSION
The cervical spine is a complex structure that must
provide structural support and protection of nerve
structures while maintaining a high degree of stab-
ility. It can become unstable due to trauma,
neoplasm, degenerative disks, joint disease, or
infection. Adequate stability of the spine is essential
to prevent injury to the spinal cord or exiting nerve
roots. If the intrinsic stability of the cervical spine is
disrupted, varying degrees of external and internal
stabilization may be needed to facilitate surgical
fusion that will restore stability.
—Wendy Elder and Volker K. H. Sonntag
See also–Cervical Spine Stabilization, Technical
Aspects; Lumbar Spine Stabilization; Spinal Cord
Anatomy; Thoracic Spine Stabilization
Further Reading
Apostolides, P. J., Karahalios, D. G., and Sonntag, V. K. H. (1998).
Technique of occipitocervical fusion with a threaded Stein-
mann. Oper. Tech. Neurosurg. 1, 63–66.
Apostolides, P. J., Karahalios, D. G., and Sonntag, V. K. H. (1998).
Technique of posterior atlantoaxial arthrodesis with transarti-
cular facet screw fixation and interspinous wiring. Oper. Tech.
Neurosurg. 1, 67–71.
Baskin, J. J., Vishteh, A. G., Dickman, C. A., et al. (1998).
Techniques of anterior cervical plating. Oper. Tech. Neurosurg.
1, 90–102.
Cahill, D. W. (1996). Anterior cervical instrumentation. In
Principles of Spinal Surgery (A. H. Menezes and V. K. H.
Sonntag, Eds.), pp. 1105–1120. McGraw-Hill, New York.
Dickman, C. A., and Sonntag, V. K. H. (1993). Wire fixation for
the cervical spine. Biomechanical principles and surgical
techniques. BNI Q. 9, 2–16.
Dickman, C. A., Douglas, R. A., and Sonntag, V. K. H. (1990).
Occipitocervical fusion posterior stabilization of the craniover-
tebral junction and upper cervical spine. BNI Q. 6, 2–14.
Dickman, C. A., Sonntag, V. K. H., Papadopoulos, S. M., et al.
(1991). The interspinous method of posterior atlantoaxial
arthrodesis. J. Neurosurg. 74, 190–198.
Dickman, C. A., Foley, K. T., Sonntag, V. K. H., et al. (1995).
Cannulated screws for odontoid screw fixation and atlantoaxial
transarticular screw fixation. Technical note. J. Neurosurg. 83,
1095–1100.
Dickman, C. A., Apostolides, P. J., and Karahalios, D. G. (1998).
Surgical techniques for upper cervical spine decompression and
stabilization. Clin. Neurosurg. 44, 137–160.
 CERVICAL SPINE STABILIZATION, TECHNICAL ASPECTS 659

Osenbach, R. K., and Moores, L. E. (1995). Subaxial wire and
cable techniques in the cervical spine. Tech. Neurosurg. 1, 128–
138.
Sawin, P. D., and Sonntag, V. K. H. (1998). Techniques of
posterior subaxial cervical fusion. Oper. Tech. Neurosurg. 1,
72–83.
Sawin, P. D., and Traynelis, V. C. (1996). Posterior articular mass
plate fixation of the subaxial cervical spine. In Principles of
Spinal Surgery (A. H. Menezes and V. K. H. Sonntag, Eds.).
McGraw-Hill, New York.
Schulder, M. (1996). Interlaminar clamps: Indications, techniques,
and results. In Principles of Spinal Surgery (A. H. Menezes and
V. K. H. Sonntag, Eds.). McGraw-Hill, New York.
Sonntag, V. K. H., and Dickman, C. A. (1991). Occipitocervical
and high cervical stabilization. In Neurosurgical Operative
Atlas (S. S. Rengachery and R. H. Wilkins, Eds.). Williams &
Wilkins, Baltimore.
Sonntag, V. K. H., and Dickman, C. A. (1993). Craniocervical
stabilization. Clin. Neurosurg. 40, 243–272.
Sonntag, V. K. H., and Hadley, M. N. (1988). Nonoperative
management of cervical spine injuries. Clin. Neurosurg. 34,
630–649.
Vishteh, A. G., Baskin, J. J., and Sonntag, V. K. H. (1998).
Techniques of cervical discectomy with and without fusion.
Oper. Tech. Neurosurg. 1, 84–89.
Cervical stabilization uses instrumentation (i.e.,
screws, rods, plates, and wires) to hold the spine
together while the bones fuse. Fusion is the growth of
bone, which leads two or more vertebra to join
together and function as one piece of bone. Internal
instrumented fusion immediately stabilizes the spine
and in most cases prevents the need for a halo vest.
This alternative is more comfortable for patients and
may shorten hospitalization time.
Cervical stabilization can be performed from the
front (anterior approach) or from the back (posterior
approach). Occasionally, a ‘‘front and back’’ ap-
proach may be necessary to achieve optimal stabili-
zation.
ANTERIOR APPROACH
The anterior approach to the cervical spine is often
used to perform discectomies (i.e., removal of disk
material between the vertebral bodies) or corpec-
tomies (i.e., removal of the vertebral body). These
operations are often performed to relieve pressure
placed on the nerve roots or spinal cord.

Cervical Spine Stabilization,

Technical Aspects
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

CERVICAL SPINE STABILIZATION is a procedure fre-

quently performed by neurosurgeons and orthopedic
surgeons to treat spinal instability, which is the loss
of the spine’s ability to tolerate pain, structural
deformity, or neurological damage under normal
conditions. Spinal surgeons also determine instability
based on the patient’s neurological symptoms and
radiographic studies (i.e., magnetic resonance images
and computed tomography scans). Cervical instabil-
ity can be caused by traumatic injury (e.g., fractures
and torn ligaments), infection, cancer, and degen-
erative processes (e.g., arthritis, herniated disks, and
bone spurs). Surgical treatment of any of these
conditions requires removing bone, which can cause
further instability. Thus, a stabilization procedure is
needed to restore the spine to its normal condition. Figure 1
The primary goals of spinal stabilization are (i) to The neck incision is made transversely, preferably on the patient’s
right side (dotted line). Alternatively, greater exposure can be
restore stability in an unstable spine, (ii) to maintain
obtained with a longitudinal incision along the medial border of
proper alignment to allow the bones to fuse together, the sternocleidomastoid for more levels of fusion (solid line)
(iii) to prevent instability from worsening, and (iv) to (reproduced with permission from the Barrow Neurological
alleviate pain. Institute).
 CERVICAL SPINE STABILIZATION, TECHNICAL ASPECTS 659

Osenbach, R. K., and Moores, L. E. (1995). Subaxial wire and
cable techniques in the cervical spine. Tech. Neurosurg. 1, 128–
138.
Sawin, P. D., and Sonntag, V. K. H. (1998). Techniques of
posterior subaxial cervical fusion. Oper. Tech. Neurosurg. 1,
72–83.
Sawin, P. D., and Traynelis, V. C. (1996). Posterior articular mass
plate fixation of the subaxial cervical spine. In Principles of
Spinal Surgery (A. H. Menezes and V. K. H. Sonntag, Eds.).
McGraw-Hill, New York.
Schulder, M. (1996). Interlaminar clamps: Indications, techniques,
and results. In Principles of Spinal Surgery (A. H. Menezes and
V. K. H. Sonntag, Eds.). McGraw-Hill, New York.
Sonntag, V. K. H., and Dickman, C. A. (1991). Occipitocervical
and high cervical stabilization. In Neurosurgical Operative
Atlas (S. S. Rengachery and R. H. Wilkins, Eds.). Williams &
Wilkins, Baltimore.
Sonntag, V. K. H., and Dickman, C. A. (1993). Craniocervical
stabilization. Clin. Neurosurg. 40, 243–272.
Sonntag, V. K. H., and Hadley, M. N. (1988). Nonoperative
management of cervical spine injuries. Clin. Neurosurg. 34,
630–649.
Vishteh, A. G., Baskin, J. J., and Sonntag, V. K. H. (1998).
Techniques of cervical discectomy with and without fusion.
Oper. Tech. Neurosurg. 1, 84–89.
Cervical stabilization uses instrumentation (i.e.,
screws, rods, plates, and wires) to hold the spine
together while the bones fuse. Fusion is the growth of
bone, which leads two or more vertebra to join
together and function as one piece of bone. Internal
instrumented fusion immediately stabilizes the spine
and in most cases prevents the need for a halo vest.
This alternative is more comfortable for patients and
may shorten hospitalization time.
Cervical stabilization can be performed from the
front (anterior approach) or from the back (posterior
approach). Occasionally, a ‘‘front and back’’ ap-
proach may be necessary to achieve optimal stabili-
zation.
ANTERIOR APPROACH
The anterior approach to the cervical spine is often
used to perform discectomies (i.e., removal of disk
material between the vertebral bodies) or corpec-
tomies (i.e., removal of the vertebral body). These
operations are often performed to relieve pressure
placed on the nerve roots or spinal cord.

Cervical Spine Stabilization,

Technical Aspects
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.

CERVICAL SPINE STABILIZATION is a procedure fre-

quently performed by neurosurgeons and orthopedic
surgeons to treat spinal instability, which is the loss
of the spine’s ability to tolerate pain, structural
deformity, or neurological damage under normal
conditions. Spinal surgeons also determine instability
based on the patient’s neurological symptoms and
radiographic studies (i.e., magnetic resonance images
and computed tomography scans). Cervical instabil-
ity can be caused by traumatic injury (e.g., fractures
and torn ligaments), infection, cancer, and degen-
erative processes (e.g., arthritis, herniated disks, and
bone spurs). Surgical treatment of any of these
conditions requires removing bone, which can cause
further instability. Thus, a stabilization procedure is
needed to restore the spine to its normal condition. Figure 1
The primary goals of spinal stabilization are (i) to The neck incision is made transversely, preferably on the patient’s
right side (dotted line). Alternatively, greater exposure can be
restore stability in an unstable spine, (ii) to maintain
obtained with a longitudinal incision along the medial border of
proper alignment to allow the bones to fuse together, the sternocleidomastoid for more levels of fusion (solid line)
(iii) to prevent instability from worsening, and (iv) to (reproduced with permission from the Barrow Neurological
alleviate pain. Institute).
660 CERVICAL SPINE STABILIZATION, TECHNICAL ASPECTS
While under general anesthesia, the patient is
placed on his or her back. The surgeon may place a
device to exert traction on the neck. The front of the
neck is incised horizontally or vertically (Fig. 1). A
longer incision can be used for more extensive
operations. The soft tissues underneath the skin are
separated from each other to allow the surgeon to
reach the front of the spine. Using metal retractors,
the esophagus and trachea are retracted to one side,
and the sternocleidomastoid muscle, carotid artery,
and jugular vein are retracted to the other side to
expose the front of the spinal column. A second
retractor system is placed perpendicularly to help
expose the spinal column from top to bottom
(Fig. 2). Radiographs are obtained during the proce-
dure to confirm the correct level of the spine.
Once the desired level of bone is confirmed, the
disks and vertebral body are carefully removed to
relieve pressure from the nerve roots or spinal cord
(Fig. 3). This portion of the procedure is usually
performed under a microscope. The space created by
removing bone and disk material is ‘‘plugged’’ with a
piece bone, usually from the patient’s hip or fibula
(small leg bone) or from a bone bank. This bone
connects the vertebral bodies from above and below
and serves as the ‘‘bridge’’ for bony fusion. This bone
graft must be under compression from above and
below. The theory, otherwise known as Wolff’s law,
is that the compressive load increases the chance of a
successful fusion.
Figure 2
A second retractor is placed perpendicularly to the first, exposing
the vertebral column from a top-to-bottom fashion (reproduced
with permission from the Barrow Neurological Institute).
Figure 3
(A) Discectomies performed with a curette. (B) After removing the
disks above and below the vertebral body, a corpectomy is
performed using a bone rongeur or a high-speed drill (reproduced
with permission from the Barrow Neurological Institute).
The next step is internal fixation of the spine with a
titanium plate and screws. This ‘‘screw–plate’’ system
serves as a rigid device to hold the cervical spine
together, thus providing immediate stabilization and
improving the chance of fusion. Under direct radio-
graphic visualization, the surgeon aligns the plate
across the site of fusion and drills the screws into
healthy bone (Fig. 4). Extreme care is taken to avoid
the spinal cord. At the end of surgery, a final visual
inspection is made and radiographs are obtained to
ensure that the plate and screws are in the best
position and that the spine is aligned correctly. The
wound is washed with antibacterial solution and
closed with sutures. Sometimes, the surgeon may
leave a draining tube in the neck for 1 or 2 days. The
patient is required to wear a cervical collar for at least
6 weeks to allow fusion to develop. Patients with a
severe traumatic injury, extensive corpectomies, or an
underlying condition that impairs bone fusion must
sometimes wear a halo brace after surgery.
POSTERIOR APPROACH
The posterior approach is often used to treat disease
in the posterior part of the spine, such as torn
ligaments, fractures, dislocations, tumors, or infec-
tions. Through this approach, a laminectomy (re-
moval of the bone that forms the roof of the spinal
canal), a discectomy, or a foraminotomy (removal of
bone around the nerve opening) can be performed.
After general anesthesia is induced, the patient is
placed on the operating table lying face down with
the neck slightly flexed or in a neutral position
(Fig. 5A). Radiographs are obtained to ensure that
the patient’s cervical spine is aligned properly after

final positioning. The middle of the neck is incised,
and the neck muscles are retracted and separated
from the back of the spine to expose the underlying
bony structures (Fig. 5B). Once the bony spine is in
adequate view, the surgeon can perform laminec-
tomies, if necessary, to relieve pressure from the
spinal cord, can insert instrumentation to stabilize
the spine, or both.
The posterior cervical spine can be stabilized with
wires, cables, clamps, screws, plates, and rods.
Wiring techniques can be performed with or without
removal of the posterior bony structures (laminae
and spinous processes). Holes are first drilled into the
bone, and wiring cables are threaded through the
holes to fasten the adjacent vertebrae together. Pieces
of bone are usually incorporated into the wires to
improve fusion.
Alternatively, more rigid forms of instrumentation
can be used for stabilization. A titanium Halifax
clamp can be used to fixate two adjacent vertebrae at
the level of injury. This technique requires intact
laminae because the Halifax clamps act as hooks on
the laminae, which are fastened together with a screw.
Again, a bone graft can be applied to promote fusion.
If, however, the laminae and spinous processes are
removed, lateral mass plates and screws are used to
stabilize the spine. These rigid titanium plates
provide immediate stability and can fixate the spine
at more than one level. Research has shown that
these plates and screws are mechanically superior to
wires and cables. Under direct radiographic visual-
ization, holes are first drilled into the appropriate
Figure 4
Anterior cervical plating. Anterior view showing the drilling of
bone using the premade holes within the plate. Screws are then
tightened to complete the bone graft and instrumentation
construct (reproduced with permission from the Barrow
Neurological Institute).
CERVICAL SPINE STABILIZATION, TECHNICAL ASPECTS 661
Figure 5
(A) The patient is positioned prone (lying face down) in a posterior
approach. The head may rest in a padded horseshoe or in pins (as
shown). (B) After making the posterior incision, dissecting the
neck muscles and soft tissues reveals the underlying cervical spine
(reproduced with permission from the Barrow Neurological
Institute).
locations in the lateral mass of the vertebrae.
Extreme caution is taken to avoid injuring the
vertebral artery or nerve roots. The plate, which
has predetermined slots for the screws, is then
applied to the bone and fastened with screws.
In some cases of severe degenerative arthritis or
trauma, some surgeons prefer to use lateral mass
screws and rods (Fig. 6). Instead of a plate, a
titanium rod is used to align and fixate the spine.
These rods are bent to the desired contour of the
spine. First, the screws are placed at the appropriate
locations in the lateral mass. The clamp, which holds
the rod, is attached to the screw and locked with a
nut. The rod is threaded through the rod connectors
on the clamp, thus completing the system.
After the desired stabilization devices have been
applied, radiographs are obtained to confirm spinal
alignment and proper placement of the hardware.
The wound is washed and closed with sutures. Unless
a halo vest is indicated, the patient wears a cervical
collar after surgery.
COMPLICATIONS
The risks related to cervical stabilization include
injury to the nerves to the vocal cord muscles causing
hoarseness, swallowing difficulty, injury to the
nerve roots or spinal cord, leakage of spinal fluid,
wound infection, and postoperative hematoma
(blood clot). The hardware can also fail and increase
instability. The screws or plates can dislodge or
move, preventing proper fusion. Another operation is
662 CHANNELOPATHIES, CLINICAL MANIFESTATIONS
Figure 6
Lateral mass screw and rod system. Instead of plates, a bendable
rod is threaded through connectors that are fastened to the spine
by screws (reproduced with permission from Synthes USA).
then needed to revise the entire graft and instrumen-
tation construct.
CONCLUSION
An unstable cervical spine can be treated with
stabilization procedures using instrumentation and
bone graft. These surgeries can be performed through
anterior or posterior approaches or both as needed.
The surgical goal is to provide the best environment
for the formation of bone fusion.
—James K. Liu, Kaushik Das, and Volker K. H. Sonntag
See also–Cervical Spine Stabilization
Further Reading
Baskin, J. J., Vishteh, A. G., Dickman, C. A., et al. (1998).
Techniques of anterior cervical plating. Oper. Tech. Neurosurg.
1, 90–102.
Baskin, J. J., Sawin, P. D., Dickman, C. A., et al. (2000). Surgical
techniques for stabilization of the subaxial cervical spine. In
Schmidek and Sweet Operative Neurosurgical Techniques:
Indications, Methods, and Results (H. H. Schmidek and W.
H. Sweet, Eds.), 4th ed., Vol. 2, pp. 2075–2104. Saunders,
Philadelphia.
Cahill, D. W. (1996). Anterior cervical instrumentation. In
Principles of Spinal Surgery (A. H. Menezes and V. K. H.
Sonntag, Eds.), pp. 1105–1120. McGraw-Hill, New York.
Fehlings, M. G., Cooper, P. R., and Errico, T. J. (1994). Posterior
plates in the management of cervical instability: Long term
results in 44 patients. J. Neurosurg. 81, 341–349.
Liu, J. K., and Das, K. (2001). Posterior fusion of the subaxial
spine: Indications and techniques. Neurosurg. Focus 10, 1–8.
Ronderos, J. F., Dickman, C. A., and Sonntag, V. K. H. (1996).
Posterior instrumentation of the cervical spine. In Neurological
Surgery (J. R. Youmans, Ed.), 4th ed., Vol. 3, pp. 2297–2314.
Saunders, Philadelphia.
Channelopathies, Clinical
Manifestations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
GENETIC STUDIES have identified the molecular basis
for several of the disorders of skeletal muscle
membrane excitability, which result from mutations
of specific ion channels. This entry reviews the
clinical manifestations of disorders of skeletal muscle
membrane excitability resulting from ion channel
mutations, also called channelopathies.
Skeletal muscle channelopathies are characterized
by muscle stiffness, pain, and sometimes weakness,
which may be intermittent or fixed. Myotonia, an
inability of a muscle to quickly relax after contrac-
tion, occurs in several of these disorders. Myotonic
muscle disorders have been classified into those
with dystrophic changes on muscle biopsy, such as
the myotonic dystrophies, and those without
dystrophic changes, such as myotonia congenita
and paramyotonia congenita, where progressive
weakness is generally not a feature. Myotonic
dystrophy is caused by mutations of the gene
encoding a protein kinase called myotonin. Myo-
tonic dystrophy is not a channelopathy and will not
be discussed further.
Different disorders of membrane excitability result
from alterations of chloride conductance, sodium
channel gating, the density of sodium channels, and
the gating of potassium channels. Mutations in a
surface membrane calcium channel result in the most
common form of hypokalemic periodic paralysis
(HypoPP). However, the membrane pathology in
HypoPP is not a direct consequence of the calcium
channel mutations. Rather, the altered calcium
channels induce the membrane pathology by chan-
ging the properties of other ion channels. Thus,
HypoPP associated with calcium channel mutations
is an indirect channelopathy.
662 CHANNELOPATHIES, CLINICAL MANIFESTATIONS
Figure 6
Lateral mass screw and rod system. Instead of plates, a bendable
rod is threaded through connectors that are fastened to the spine
by screws (reproduced with permission from Synthes USA).
then needed to revise the entire graft and instrumen-
tation construct.
CONCLUSION
An unstable cervical spine can be treated with
stabilization procedures using instrumentation and
bone graft. These surgeries can be performed through
anterior or posterior approaches or both as needed.
The surgical goal is to provide the best environment
for the formation of bone fusion.
—James K. Liu, Kaushik Das, and Volker K. H. Sonntag
See also–Cervical Spine Stabilization
Further Reading
Baskin, J. J., Vishteh, A. G., Dickman, C. A., et al. (1998).
Techniques of anterior cervical plating. Oper. Tech. Neurosurg.
1, 90–102.
Baskin, J. J., Sawin, P. D., Dickman, C. A., et al. (2000). Surgical
techniques for stabilization of the subaxial cervical spine. In
Schmidek and Sweet Operative Neurosurgical Techniques:
Indications, Methods, and Results (H. H. Schmidek and W.
H. Sweet, Eds.), 4th ed., Vol. 2, pp. 2075–2104. Saunders,
Philadelphia.
Cahill, D. W. (1996). Anterior cervical instrumentation. In
Principles of Spinal Surgery (A. H. Menezes and V. K. H.
Sonntag, Eds.), pp. 1105–1120. McGraw-Hill, New York.
Fehlings, M. G., Cooper, P. R., and Errico, T. J. (1994). Posterior
plates in the management of cervical instability: Long term
results in 44 patients. J. Neurosurg. 81, 341–349.
Liu, J. K., and Das, K. (2001). Posterior fusion of the subaxial
spine: Indications and techniques. Neurosurg. Focus 10, 1–8.
Ronderos, J. F., Dickman, C. A., and Sonntag, V. K. H. (1996).
Posterior instrumentation of the cervical spine. In Neurological
Surgery (J. R. Youmans, Ed.), 4th ed., Vol. 3, pp. 2297–2314.
Saunders, Philadelphia.
Channelopathies, Clinical
Manifestations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
GENETIC STUDIES have identified the molecular basis
for several of the disorders of skeletal muscle
membrane excitability, which result from mutations
of specific ion channels. This entry reviews the
clinical manifestations of disorders of skeletal muscle
membrane excitability resulting from ion channel
mutations, also called channelopathies.
Skeletal muscle channelopathies are characterized
by muscle stiffness, pain, and sometimes weakness,
which may be intermittent or fixed. Myotonia, an
inability of a muscle to quickly relax after contrac-
tion, occurs in several of these disorders. Myotonic
muscle disorders have been classified into those
with dystrophic changes on muscle biopsy, such as
the myotonic dystrophies, and those without
dystrophic changes, such as myotonia congenita
and paramyotonia congenita, where progressive
weakness is generally not a feature. Myotonic
dystrophy is caused by mutations of the gene
encoding a protein kinase called myotonin. Myo-
tonic dystrophy is not a channelopathy and will not
be discussed further.
Different disorders of membrane excitability result
from alterations of chloride conductance, sodium
channel gating, the density of sodium channels, and
the gating of potassium channels. Mutations in a
surface membrane calcium channel result in the most
common form of hypokalemic periodic paralysis
(HypoPP). However, the membrane pathology in
HypoPP is not a direct consequence of the calcium
channel mutations. Rather, the altered calcium
channels induce the membrane pathology by chan-
ging the properties of other ion channels. Thus,
HypoPP associated with calcium channel mutations
is an indirect channelopathy.

CHLORIDE CHANNEL DISORDERS
Chloride channel disorders include autosomal domi-
nant myotonia congenita (Thomsen’s disease) and
recessive generalized myotonia congenita (Becker-
type myotonia; Table 1). Both myotonias arise from
mutations in the skeletal muscle voltage-gated
chloride channel gene (CLC1) on chromosome 7q.
The recessive generalized form occurs much more
frequently than the dominant form.
Autosomal dominant myotonia congenita (Thom-
sen’s disease) manifests in infancy or early childhood
with painless myotonia resulting in muscle stiffness.
The hallmark of myotonia congenita is stiffness that
manifests when the patient attempts to initiate
movement and diminishes with repeated muscle
contractions. Stiffness is prominent with a forceful
muscle contraction after a period of rest. Thus,
patients describe a ‘‘warm-up’’ period during which
they can work through the muscle stiffness by
continued exercise. Some patients describe worsen-
ing of symptoms in the cold. Stiffness is not
progressive over time, and there is no associated
weakness. In contrast, patients are often quite strong.
Muscle hypertrophy is common, probably due to the
almost constant state of muscle contraction. Grip
and percussion myotonia and the lid lag phenomen-
on are easily elicited.
The autosomal recessive form of myotonia con-
genita is more common than the dominant form.
Onset is usually later in childhood compared to that
for the dominant form, but the recessive and
dominant forms of myotonia congenita have similar
manifestations. Males are more severely affected
than females, and stiffness may be more severe than
in the dominant form. Although weakness is not a
feature of autosomal dominant myotonia congenita,
minor progressive weakness and wasting of distal
muscles may occur in the recessive form. Further-
more, some patients experience transient attacks of
true weakness that tend to occur after initiating a
sudden movement after rest and are relieved with
exercise. This transient weakness may be quite
disabling because it is often generalized. Muscle
hypertrophy is common in the legs and gluteal
muscles, whereas the upper extremities may appear
underdeveloped. Grip and percussion myotonia and
the lid lag phenomenons are easily elicited.
In both forms of myotonia congenita, routine
motor and sensory nerve conduction studies are
normal. Needle electromyography (EMG) generally
shows widespread myotonic discharges, which are
CHANNELOPATHIES, CLINICAL MANIFESTATIONS 663
easily elicited with minimal needle movement. In the
dominant form, the motor unit action potentials
(MUAPs) and recruitment patterns are normal. In the
recessive form, the MUAPs may be small, short, and
polyphasic with early recruitment in distal muscles,
consistent with a mild myopathy.
The responses to muscle cooling can differentiate
myotonia congenita from paramyotonia congenita.
Muscle cooling is best accomplished by wrapping the
limb in a plastic bag and submerging it in ice water
for 10–20 min. After the skin temperature is lowered
to 201C, needle EMG of the extremity is repeated. In
dominant myotonia congenita muscle cooling to
201C may produce myotonic bursts that are longer
in duration and more easily elicited than at room
temperature. In paramyotonia congenita, muscle
cooling to 201C produces electrical silence as the
muscle goes into a prolonged contracture, which is
pathognomonic for paramyotonia congenita.
Serum creatine kinase (CK) level in the dominant
form of myotonia congenita may be slightly elevated,
and in the recessive form it may be moderately
elevated. Muscle in myotonia congenita may have a
dearth of type 11B fibers.
Treatment of Patients with Chloride
Channel Myotonias
Some patients with minor complaints may need no
treatment at all and learn to accommodate their
activities and lifestyle to reduce symptoms. When
treatment of myotonic stiffness is required, medica-
tions that stabilize the muscle membrane are most
effective. The mainstay of treatment is the lidocaine
derivative mexiletine, beginning at 150 mg bid by
mouth and increasing slowly as needed up to 300 mg
tid by mouth. Tocainide (400–1200 mg a day),
another lidocaine derivative, is useful for patients
who do not respond to mexiletine. However,
tocainide should be used with extreme caution
because of the potential for bone marrow suppres-
sion. Alternatively, procainamide or quinine can be
used, and these may be used intermittently as needed.
Phenytoin 300–400 mg a day by mouth is often
effective and can be used on a daily basis with few
side effects.
Less commonly used medications include dantro-
lene, which has shown benefit in some severe cases.
However, fatal and nonfatal hepatotoxicity have
been reported, and the risk–benefit ratio must be
weighed on an individual basis. Acetazolamide is
also beneficial in some patients. Doses generally
begin at 125 mg by mouth twice a day, slowly
Table 1 CLINICAL FEATURES OF SKELETAL MUSCLE CHANNELOPATHIESa

Myotonia
congenita,
dominant Myotonia congenita, Sodium channel Paramyotonia HyperPP, Na Andersen’s
(Thomsen) recessive (Becker) myotonias congenita channel HyperPP, K channel HypoPP types 1 and 2 syndrome

Age of onset Infancy Early childhood Childhood, Infancy Infancy to early Childhood Adolescence Infancy if
adolescence childhood dysmorphic
features present;
otherwise
childhood
Inheritance Autosomal Autosomal Autosomal Autosomal Autosomal Autosomal dominant Autosomal dominant Autosomal
dominant recessive dominant dominant dominant dominant with
variable
expression of
dysmorphic
features, cardiac
arrhythmias,
and periodic
weakness
Mutant Cl channel Cl channel Na channel Na channel Na channel K channel—MinK/ Type 1, L-type K channel—
channel Kv3.4 complex calcium channel Kir2.1, inward
(channel complex Type 2, Na channel rectifier K
contributes to channel (channel
regulating the resting complex
potential) contributes to
regulating the
resting
potential)
Myotonia Yes Yes Yes (painful) Yes Yes No No No
Myotonia Generalized Generalized Proximal4distal Face, hands, thighs Generalized, if None None None
distribution present
Periodic No Yes, in some No Yes Yes Yes Yes Yes with K levels
weakness patients that vary among
patients
Weakness None Minutes None Minutes to days Minutes to days Minutes to hours Hours to days Minutes to hours
duration
Progressive No Rarely No No Variable Uncertain Yes Yes
weakness
Provocative Exercise Exercise after rest Potassium, rest Cold, repeated Cold, rest after Rest after exercise, Cold, rest after Cold, rest after
factors after rest and cold after exercise, exercise, and exercise, fasting, fasting, and exercise, exercise, and
and cold and fasting fasting and potassium potassium intake carbohydrate carbohydrate
intake intake intake
Alleviating Repeated Repeated exercise Warming Carbohydrate intake Carbohydrate intake Potassium ingestion
factors exercise and exercise and exercise and exercise
a
Adapted from Shapiro and Ruff (2001).

increasing to 250 mg by mouth three times a day as
required and as tolerated by the patient.
SODIUM CHANNEL DISORDERS
Patients with skeletal muscle sodium channelopa-
thies present with a variety of symptoms, including
myotonia, stiffness, pain, and weakness (Table 1). It
is not known why some patients with sodium
channel myotonia experience pain, whereas the
myotonia associated with chloride channelopathies
are usually painless. Patients with sodium channel
myotonia have painful stiffness and spasms second-
ary to myotonia, and symptoms are worsened or
provoked by potassium. In contrast, patients with
paramyotonia congenita and hyperkalemic periodic
paralysis (HyperPP) experience periodic weakness,
and symptoms are worsened or provoked by the
cold. Those with paramyotonia congenita and some
patients with HyperPP experience stiffness secondary
to myotonia. There is not a strict relationship
between the sodium channel mutation and the
phenotype.
The phenotypic variations associated with many
mutations suggest that several unrecognized factors
may modify the phenotype. Only a few families with
HyperPP without myotonia have been studied.
Consequently, the single channel defects associated
with this phenotype are not known. There are some
alterations in single sodium channel behavior that
can predict the phenotype. Impaired sodium channel
slow inactivation is usually associated with HyperPP,
whereas impaired deactivation has only been asso-
ciated with paramyotonia and myotonia.
Sodium Channel Myotonia (Potassium
Aggravated Myotonia)
There are several variants of sodium channel
myotonia, also referred to as potassium aggravated
myotonia (Table 1), including myotonia fluctuans,
myotonia permanens, and acetazolamide-responsive
myotonia. They are all associated with mutations of
the a subunit of the human skeletal muscle sodium
channel gene (SCN4A) on chromosome 17q23 and
inherited in an autosomal dominant fashion. Sodium
channel myotonias have a similar incidence as that of
Becker myotonia and are much more common than
Thomsen’s myotonia congenita.
Patients present in childhood or adolescence with
episodes of generalized stiffness secondary to myo-
tonia. Distinguishing features include painful myo-
tonia that is quite potassium sensitive, with
CHANNELOPATHIES, CLINICAL MANIFESTATIONS 665
worsening of symptoms induced by potassium
ingestion; hence the designation potassium aggra-
vated myotonia. Patients do not experience true
episodic weakness and are not cold sensitive.
Myotonia fluctuans presents in adolescence with
fluctuating muscle stiffness. Myotonia may be painful
and has a singular feature of being exercise induced,
but onset is delayed for several minutes after exercise.
In contrast, in paramyotonia myotonia the myotonia
occurs immediately after exercise. The myotonia is
worsened by the intake of potassium but not by the
cold. Percussion and grip myotonia and lid lag
phenomenon may be present. There is no weakness.
Myotonia permanens presents in childhood with
severe and unremitting generalized myotonia. Pa-
tients have neck and shoulder muscle hypertrophy.
Worsening of symptoms with potassium intake may
be very severe and may affect thoracic muscles,
resulting in hypoventilation, which can be life
threatening.
Acetazolamide-responsive myotonia, also known
as atypical myotonia congenita, manifests with
painful myotonia beginning in childhood. The
myotonia has a predilection for axial and proximal
limb musculature. Symptoms are provoked or
worsened by fasting, infection, and intake of
potassium. Cold temperature may worsen the myo-
tonia but does not induce paralysis. Symptoms are
markedly reduced with acetazolamide, although
mexiletine is also effective. There is no periodic
weakness. Percussion and grip myotonia are present.
Sodium and chloride channel myotonia can
usually be distinguished by the painful myotonia
and worsening of myotonia with potassium ingestion
noted with sodium channel myotonia. Patients with
myotonia fluctuans display the characteristic phe-
nomenon of exercise-induced, delayed-onset myoto-
nia not seen in myotonia associated with chloride
channel mutations. The marked relief of symptoms
with acetazolamide in patients with acetazolamide-
responsive myotonia helps differentiate these
patients.
Patients with sodium channel myotonia and
paramyotonia congenita experience generalized stiff-
ness and worsening of symptoms in the cold.
However, patients with paramyotonia congenita
display extreme cold sensitivity resulting in true
weakness not seen in sodium channel myotonia.
Additionally, the exercise-induced, delayed-onset
myotonia noted in myotonia fluctuans differs from
the immediate worsening of myotonia with exercise
noted in patients with paramyotonia congenita.
666 CHANNELOPATHIES, CLINICAL MANIFESTATIONS
Patients with sodium channel myotonia do not
experience periodic weakness and are therefore
unlikely to be confused with any of the periodic
paralyses.
Treatment of Patients with Sodium
Channel Myotonias
Acetazolamide, especially in those patients with
acetazolamide-responsive myotonia, helps reduce
stiffness and pain. Doses generally begin at 125 mg
by mouth twice a day, slowly increasing to 250 mg
by mouth three times a day, as required and as
tolerated by the patient. Membrane-stabilizing
agents, including mexiletine and tocainide, are also
helpful. Mexiletine is especially helpful in patients
with myotonia fluctuans, starting at 150 mg bid by
mouth and increasing slowly as needed up to 300 mg
tid by mouth. Nonsteroidal anti-inflammatory med-
ications are helpful adjuncts in reducing severe
muscle pain in some patients. General anesthesia
may produce worsening of stiffness and myotonia,
even in patients with normal contracture testing for
malignant hyperthermia. Depolarizing muscle relax-
ants during anesthesia must be used cautiously
because these agents aggravate myotonia and may
cause adverse anesthesia-related events, especially in
patients with myotonia fluctuans.
Paramyotonia Congenita
(Eulenburg Disease)
Paramyotonia congenita is an autosomal dominant
inherited disorder that was first described by Eulen-
burg in 1886. Muscle stiffness is brought on by
repeated muscle contractions or exercise and is
extremely cold sensitive (Table 1). In contrast, in
myotonia a warm-up period of repeated muscle
contractions alleviates the muscle stiffness; thus the
designation paradoxical or paramyotonia.
Patients with paramyotonia congenita present in
infancy with muscle stiffness primarily affecting
bulbofacial, neck, and hand muscles. Cold induces
stiffness followed by true weakness. Patients have
grip and percussion myotonia and the lid lag
phenomenon. Paramyotonia congenita has appreci-
able overlap with sodium channel myotonia and
HyperPP.
The differential diagnosis of paramyotonia con-
genita comprises a small group of diseases with
prominent myotonia. These include myotonia con-
genita associated with chloride channel mutations,
sodium channel myotonia, HyperPP, the myotonic
dystrophies, and Schwartz–Jampel syndrome. Para-
myotonia congenita can usually be distinguished
from these disorders based on characteristic clinical
features, including extreme cold sensitivity resulting
in stiffness followed by true weakness, as well as the
phenomenon of worsening of symptoms with re-
peated muscle contractions. Muscle cooling to 201C
may have a profound effect on the needle EMG,
which is pathognomonic for paramyotonia congeni-
ta. Transient dense fibrillation potentials appear with
cooling that eventually disappear below 281C. As the
muscle cools down further, the myotonic discharges
completely disappear below 201C, giving way to
muscle paralysis. At this point, the muscle is
inexcitable to electrical or mechanical stimulation
and goes into a long-lasting electrically silent
contracture.
Serum CK level is often mildly to moderately
elevated. Potassium level during attacks of weakness
may be low, normal, or elevated, depending on the
phenotype. In patients with cold-induced weakness,
the potassium level is usually low or normal.
Treatment of Paramyotonia
Patients with paramyotonia congenita often do not
require daily treatment because they learn to avoid
situations such as exposure to the cold, especially
during exercise, that provoke symptoms of stiffness
and weakness. The lidocaine derivative mexiletine is
helpful for patients who require treatment. This
medication prevents or alleviates stiffness and weak-
ness induced by cold as well as the periodic weakness
experienced by some patients. Doses begin at 150 mg
bid by mouth, with slow increases up to 300 mg tid
by mouth. Patients with spontaneous attacks of
periodic weakness that are not related to temperature
usually require treatment and may benefit from a
combination of mexiletine with hydrochlorothiazide
(HCTZ). The mexiletine reduces the cold-induced
stiffness, and the HCTZ prevents spontaneous
attacks of weakness not precipitated by cold or
exercise, presumably by lowering the potassium
level. Tocainide can reduce stiffness and weakness
in some patients with paramyotonia congenita at
doses of 400–1200 mg a day. However, it should be
used only with extreme caution because of the
potential for bone marrow suppression. Acetazola-
mide, either alone or in combination with mexiletine,
has proved beneficial in some patients with tempera-
ture-independent periodic weakness. Doses generally
begin at 125 mg by mouth twice a day, slowly
increasing to 250 mg by mouth three times a day, as
required and as tolerated by the patient. Acetazola-

mide has provoked weakness in some patients with
paramyotonia congenita with cold-induced weak-
ness, probably by lowering the potassium level.
Thus, it is crucial to determine whether weakness is
temperature dependent because there are clear
implications regarding treatment options. As with
other myotonic disorders, care must be taken with
the use of depolarizing muscle relaxants during
anesthesia because they aggravate myotonia and
may cause adverse anesthesia-related events.
Hyperkalemic Periodic Paralysis
HyperPP was initially described in the 1950s and
differentiated from HypoPP by elevated potassium
during attacks. Gamstorp used the term ‘‘adynamia
episodica hereditaria’’ to refer to the disorder (Table
1). Most cases of HyperPP arise from mutations of
the human skeletal muscle sodium channel gene.
There is usually complete penetrance in both sexes,
although rarely patients have been described with
mutations where penetrance was incomplete. Re-
cently, Abbott et al. described two families with a
clinical syndrome of HyperPP without myotonia
who had a mutation in a potassium channel subunit.
Three variants are described: HyperPP without
myotonia, HyperPP with clinical or EMG evidence of
myotonia, and HyperPP with paramyotonia. Patients
present in early childhood with attacks of periodic
weakness often in the morning. Attacks of flaccid
weakness usually last from minutes to hours. Attacks
vary in frequency, and myotonia, if present, is
variable. The frequency of attacks generally lessens
in middle age, and some adults develop fixed
progressive proximal weakness.
Provocative factors include rest after exercise,
fasting, emotional stress, cold, and potassium load-
ing. The potassium level is usually elevated during
attacks, although it rarely reaches life-threatening
levels. In all cases, the potassium level returns to
normal after the attack. Symptoms are relieved by
ingesting carbohydrates or inhaling a b-adrenergic
agent. The distinction between HyperPP and Hy-
poPP can usually be made based on age of onset,
factors that provoke or alleviate an attack, and by
determining the potassium level during an attack.
Patients with HyperPP generally present in early
childhood, in contrast to HypoPP, which usually
manifests in adolescence.
Treatment of HyperPP
Management of HyperPP is directed toward prevent-
ing or decreasing the frequency of attacks and
CHANNELOPATHIES, CLINICAL MANIFESTATIONS 667
treating major paralytic attacks once they occur. To
prevent attacks, patients must eat regular meals,
especially carbohydrate-rich and low-potassium
meals, and avoid situations that precipitate attacks,
such as strenuous activity followed by rest. Many
patients can forestall an impending attack, at least
for a while, by engaging in mild exercise, ingesting
carbohydrates such as a candy bar, or inhaling a b-
adrenergic agent once they note an impending attack.
Thiazide diuretics, such as HCTZ or acetazolamide,
are effective in reducing the frequency and severity of
attacks in the majority of patients. Patients are often
unaware of minor daily attacks of weakness until
they begin daily preventative therapy, when they note
improvement in daily functioning. However, it is
unclear whether preventing attacks will preclude
later development of fixed proximal weakness.
Diuretics can be taken daily or intermittently as
needed, using the lowest dose and frequency needed
to prevent attacks. A reasonable starting dose of
acetazolamide is 125 mg orally twice a day, which
can be slowly increased as tolerated to 250 mg orally
four times a day. Some patients may require a higher
dose, up to 1500 mg a day, to prevent attacks or
reduce the severity of attacks. Side effects include
nausea, anorexia, and paraesthesias. A randomized
double-blind placebo-controlled trial showed that
dichlorphenamide, a potent carbonic anhydrase
inhibitor, reduced the frequency and severity of
attacks in HyperPP. Dichlorphenamide can be
used at a starting dose of 25 mg by mouth twice a
day and can be slowly increased to 25–50 mg
two or three times a day. Rarely, acute paralytic
attacks require aggressive treatment with intrave-
nous glucose and insulin to lower the potassium
level under strict supervision, with electrocardio-
graph and serum electrolyte monitoring. Depolariz-
ing muscle relaxants must be used cautiously during
anesthesia because these agents may aggravate
myotonia and may cause adverse anesthesia-related
events.
HYPOKALEMIC PERIODIC PARALYSIS,
TYPES 1 AND 2
Type 1 is the most common of the inherited periodic
paralyses (Table 1). It is an autosomal dominant
inherited disorder with reduced penetrance in wo-
men, associated with mutations of a muscle calcium
channel gene (CACNA1S). In 1994, Plassart et al.
reported a large French family with HypoPP that did
not link to the calcium channel gene, but the family
668 CHANNELOPATHIES, CLINICAL MANIFESTATIONS
was clinically indistinguishable from other patients.
Subsequently, mutations were identified in the a
subunit of the sodium channel gene and the term
HypoPP type 2 was used to designate these patients.
Because of the similarities in clinical presentation and
pathogenesis, these disorders are discussed together.
Patients generally present in adolescence with
periodic attacks of weakness, although rare patients
present in childhood or in their twenties. Attacks are
provoked by cold, carbohydrate ingestion, alcohol,
emotional stress, and rest after exercise. Typical
attacks occur upon awakening from sleep, especially
after strenuous physical activity or a large carbohy-
drate meal the previous day. Untreated, attacks of
weakness may be quite prolonged, lasting from
several hours to days, generally occurring upon
awakening from sleep. The weakness may be quite
severe, resulting in flaccid quadriplegia with loss of
reflexes. In rare individuals, bulbar and respiratory
muscles are involved, which can be life-threatening
during prolonged attacks. The potassium level is
usually low during attacks (2.0–3.0 mEq/liter). This
may lead to bradycardia or sinus arrhythmias if the
hypokalemia is profound. In some patients the
potassium level is normal during attacks. Myotonia
is not present, with the exception of eyelid myotonia
in a few patients.
Treatment of HypoPP
To prevent paralytic attacks, patients are advised to
follow a low-carbohydrate, low-sodium diet and
avoid activities that precipitate attacks, such as
strenuous activity or eating a high carbohydrate
meal or consuming alcohol followed by rest. Most
patients require some form of maintenance therapy
to prevent attacks. Acetazolamide is effective in
reducing the frequency and severity of attacks and
reducing interattack weakness in the majority of
patients. A reasonable starting dose is 125 mg orally
twice a day, and this can be slowly increased as
tolerated to 250 mg orally four times a day to
prevent attacks or reduce the severity of attacks. A
randomized double-blind placebo-controlled trial
showed that dichlorphenamide, a potent carbonic
anhydrase inhibitor, reduced the frequency and
severity of paralytic attacks in HypoPP. Dichlorphe-
namide can be used at a starting dose of 25 mg by
mouth twice a day and slowly increased to 25–50 mg
two or three times a day. Patients who do not
respond to carbonic anhydrase inhibitors may
respond to potassium sparing diuretics, such as
triamterene or spironolactone, although these must
be used with caution in patients who are also taking
oral potassium supplements. Daily maintenance
therapy with oral potassium chloride, either alone
or in conjunction with a carbonic anhydrase in-
hibitor, is useful in preventing or reducing the
frequency and severity of attacks. Acute paralytic
attacks are treated with oral potassium chloride,
0.25 mEq/kg body weight, repeating every half hour
until weakness improves. Electrolyte monitoring
should be done during severe attacks requiring
extensive potassium supplementation.
ANDERSEN’S SYNDROME
Andersen’s syndrome is a rare multisystem disorder
characterized by three cardinal features: periodic
paralysis, cardiac arrhythmias, and dysmorphic
features (Table 1). The dysmorphic features include
short stature, scoliosis, clinodactyly, hypertelorism,
broad forehead, and micrognathia. The cardiac
arrhythmias are associated with long QT syndrome
and include asymptomatic long QT syndrome,
ventricular ectopy, ventricular tachycardia, torsades
de pointes, and cardiac arrest. Patients may manifest
one, two, or all three of the cardinal features of
Andersen’s syndrome. Plaster et al. described
several families in whom Andersen’s syndrome was
associated with mutations of a Kir2.1 potassium
channel subunit. An inward rectifier potassium
channel in skeletal and cardiac muscle is formed by
four Kir2.1 subunits. The mutant subunits form
nonfunctional inward rectifier potassium channels.
When mutant subunits are mixed 1:1 with normal
subunits, the inward rectifier potassium current is
less than that produced by the normal subunits
alone, which indicates that inward rectifier
channels containing mutant Kir2.1 subunits are
dysfunctional.
Treatment of Andersen’s syndrome is focused on
reducing the risk of cardiac arrhythmias. Patients
may need an implanted defibrillator to prevent
cardiac arrest. Treatment of the periodic paralysis is
similar to the treatment of HyperPP or HypoPP,
depending on whether attacks are associated with
elevated or reduced serum potassium levels.
HOW DO MUTATIONS OF DIFFERENT
CHANNELS RESULT IN
SIMILAR PHENOTYPES?
Having reviewed the different syndromes associated
with channelopathies, we can address the issue of

how dysfunctions of different membrane ion chan-
nels can produce similar clinical findings. Myotonia
results from membrane hyperexcitability and is
associated with dysfunction of Cl
channels or
Na þ channels. The key to understanding myotonia
is the fact that low-level depolarization can bring the
membrane closer to the threshold for initiating an
action potential. Skeletal muscle has a singularly high
Cl
conductance, which serves to stabilize mem-
brane excitability. A unique feature of skeletal
muscle is the presence of the transverse tubule (T-
tubule) system. The T-tubule system is composed of
elongated invaginations of the surface membrane,
which conduct the action potential inside a muscle
fiber to trigger release of calcium from the sarco-
plasmic reticulum. The T-tubule system is essential
for synchronous activation of myofibrils. An adverse
consequence of the T-tubule system is that due to the
extremely small volume of the T-tubules, K þ
released during the repolarizing phase of the action
potential can accumulate within the T-tubules.
Sufficient K þ accumulates within the T-tubules to
depolarize the adjacent surface membrane. The
membrane depolarization produced by K þ accumu-
lation within the T-tubules would trigger repeated
action potentials if the membrane was not stabilized
by a high resting Cl
conductance. Pharmacologi-
cally reducing Cl
conductance produces myotonia,
which can be stopped by mechanically disrupting the
T-tubule system. Hence, the high membrane Cl

conductance in skeletal muscle is needed to counter
the membrane depolarization produced by K þ
accumulation within the T-tubules. Another way to
depolarize the membrane beyond the usual duration
of the action potential is to disrupt sodium channel
fast inactivation. Fast inactivation is disrupted by all
the Na þ channel point mutations associated with the
production of myotonia or paramyotonia. Conse-
quently, reducing Cl
conductance or impairing
Na þ channel fast inactivation can both result in
low-level membrane depolarization, which produces
the repeated action potentials, the cardinal feature of
myotonia.
Weakness is present in channelopathies that
produce paramyotonia, HyperPP, or HypoPP. Com-
mon features of weakness associated with skeletal
muscle channelopathies are flaccid paresis associated
with prolonged membrane depolarization producing
membrane inexcitability. Membrane inexcitability
results because the prolonged depolarization inacti-
vates normal Na þ channels. In paramyotonia and
HyperPP, the Na þ channel point mutations enable
CHANNELOPATHIES, CLINICAL MANIFESTATIONS 669
altered Na þ channels to remain open or to
repeatedly open, which causes prolonged membrane
depolarization. A key difference in the sodium
channel mutations that produce HyperPP or para-
myotonia compared with the mutations that produce
sodium channel myotonias is the duration of the
membrane depolarization produced by the mutation.
The mutations associated with sodium channel
myotonias do not produce prolonged membrane
depolarization. The brief depolarizations produced
by some Na þ channel mutations cause myotonia
without weakness, whereas the persistent depolar-
ization produced by other mutations can result in
initial hyperexcitability followed by depolarization-
induced membrane inexcitability. Interruption of
Na þ channel slow inactivation facilitates the
production of a persistent depolarizing Na þ current
and slow inactivation is disrupted by several
of the point mutations associated with HyperPP.
Disruption of both inactivation processes enables the
mutant channels to remain open or to repeatedly
open for prolonged periods of time. Slow inactiva-
tion is not disturbed by the mutations that
produce Na þ channel myotonias. It is not known
how reduced temperature induces paralysis in
paramyotonia.
Weakness in both forms of HypoPP is produced
by prolonged membrane depolarization leading to
loss of membrane excitability. The mechanism of
membrane depolarization in type 1 HypoPP is
better understood. The Ca2 þ channel mutations
in type 1 HypoPP alter membrane excitability
indirectly by changing the properties of inward
rectifier K þ channels and Na þ channels. Reduced
K þ conductance facilitates membrane depolariza-
tion, and a decreased density of Na þ channels
reduces membrane excitability in HypoPP and
facilitates depolarization-induced loss of membrane
excitability. Reduced density of functional Na þ
channels is characteristic of both type 1 and type 2
HypoPP. The low density of Na þ channels in both
forms of HypoPP prevents membrane hyperexcit-
ability from developing with membrane depolariza-
tion. Consequently, myotonia is not present in
HypoPP.
The mechanism of paralysis in HyperPP associated
with a K channel mutation and in Andersen’s
syndrome may be destabilization of the resting
potential. The K channel variant of HyperPP is
associated with mutations in the KCNE3 gene,
which encodes the MinK-related peptide 2 (MiRP2).
MiRP2 coassembles with a voltage-gated K channel
670 CHANNELOPATHIES, CLINICAL MANIFESTATIONS
subunit, Kv3.4, to form a channel complex that
contributes to regulating the resting potential. Four
Kir2.1 subunits assemble to form an inward rectifier
K channel that helps to set the resting potential of
cardiac and skeletal muscle cells. Andersen’s syn-
drome is associated with mutations of Kir2.1. Of
note, HypoPP type 1 is associated with dysfunction
of an ATP-dependent inward rectifier K channel that
contributes to setting the resting potential.
CONCLUSION
Skeletal muscle channelopathies produce disorders of
membrane excitability (Table 1). Membrane hyper-
excitability manifests as myotonia or paramyotonia.
Reduced membrane excitability manifests as flaccid
weakness. In some disorders, such as paramyotonia
congenita and HyperPP with myotonia, the skeletal
muscle membrane may manifest both hyperexcit-
ability and reduced excitability. Both forms of Cl

channel myotonia, Na þ channel myotonias, all
forms of HyperPP, HypoPP type 2, and Andersen’s
syndrome are direct channelopathies. The altered
behavior of the mutant ion channels directly explains
the disturbed membrane excitability. In contrast,
HypoPP type 1 is an indirect channelopathy. HypoPP
type 1 is associated with point mutations in a L-type
skeletal muscle Ca2 þ channel. However, the dis-
turbed membrane excitability seen in HypoPP type 1
mutations results from altered function of an
ATP-dependent inward rectifier K þ channel and
reduced density of surface membrane Na þ channels.
Hence, with HypoPP type 1 the mutated Ca2 þ
channels indirectly cause reduced membrane
excitability by impairing the function of inward
rectifier K þ channels and reducing the expression of
Na þ channels. The clinical manifestations of the
different channelopathies are sufficiently distinct to
define distinguishable syndromes, summarized in
Table 1.
—Barbara E. Shapiro, Jacob Levitt, and Robert L. Ruff
See also–Calcium; Channelopathies, Genetics;
Gap Junctions; Ion Channels, Overview;
Myotonia
Acknowledgment
This work was supported by the Office of Research and
Development, Medical Research Service of the Department of
Veterans Affairs.
Further Reading
Abbott, G. W., Butler, M. H., Bendahhou, S., et al. (2001).
MiRPw forms potassium channels in skeletal muscle with
Kv3.4 and is associated with periodic paralysis. Cell 104,
217–231.
Bendahhou, S., Cummins, T. R., Griggs, R. C., et al. (2001).
Sodium channel inactivation defects as a mechanism for
acetazolamide-exacerbated hypokalemic periodic paralysis.
Ann. Neurol. 50, 417–420.
Bulman, D. E., Scoggan, K. A., van Oene, M. D., et al. (1999). A
novel sodium channel mutation in a family with hypokalemic
periodic paralysis. Neurology 53, 1932–1936.
Deymeer, F., Cakirkaya, S., Serdaroglu, P., et al. (1998).
Transient weakness and compound muscle action potential
decrement in myotonia congenita. Muscle Nerve 21, 1334–
1337.
Hanna, M. G., Steward, J., and Schapira, A. H. V. (1998).
Salbutamol treatment in a patient with hyperkalemic periodic
paralysis due to a mutation in the skeletal muscle sodium
channel gene (SCN4A). J. Neurol. Neurosurg. Psychiatr. 68,
248–250.
Jurkat-Rott, K., Mitrovic, N., Hang, C., et al. (2000).
Voltage sensor sodium channel mutations cause hypokalemic
periodic paralysis type 2 by enhanced inactivation and
reduced current. Proc. Natl. Acad. Sci. USA 97, 9549–
9554.
Lehmann-Horn, F., and Jurkat-Rott, K. (1999). Voltage-gated
ion channels and hereditary disease. Physiol. Rev. 79, 1317–
1372.
Plaster, N. M., Tawil, R., Tristani-Firouzi, M., et al. (2001).
Mutations in Kir2.1 cause the developmental and episodic
electrical phenotypes of Andersen’s syndrome. Cell 105, 511–
519.
Richmond, J. E., VanDeCarr, D., Featherstone, D. E., et al. (1997).
Defective fast inactivation recovery and deactivation account
for sodium channel myotonia in the I1160V mutant. Biophys. J.
73, 1896–1903.
Rüdel, R., Hanna, M. G., and Lehmann-Horn, F. (1999). Muscle
channelopathies: Malignant hyperthermia, periodic paralyses,
paramyotonia, and myotonia. In Muscle Diseases (A. H.
Schapira and R. C. Griggs, Eds.). Butterworth-Heinemann,
New York.
Ruff, R. L. (1999). Insulin acts in hypokalemic periodic paralysis
by reducing inward rectifier K þ current. Neurology 53, 1556–
1563.
Ruff, R. L. (2000). Skeletal muscle sodium current is reduced in
hypokalemic periodic paralysis. Proc. Natl. Acad. Sci. USA 97,
9832–9833.
Shapiro, B. E., and Ruff, R. L. (2001). Disorders of skeletal muscle
membrane excitability: Myotonia congenita, Paramyotonia
congenita, periodic paralysis and related syndromes. In
Neuromuscular Disorders in Clinical Practice (B. Katirji, H. J.
Kaminski, D. Preston, R. L. Ruff, and B. E. Shapiro, Eds.).
Butterworth-Heinemann, Boston.
Tawil, R., McDermott, M. P., Brown, R., et al. (2000).
Randomized trials of dichlorphenamide in the periodic
paralyses. Ann. Neurol. 47, 46–53.
Wagner, S., Lerche, H., Mitrovic, N., et al. (1997). A novel sodium
channel mutation causing a hyperkalemic paralytic and para-
myotonic syndrome with variable clinic expressivity. Neurology
49, 1018–1025.

Channelopathies, Genetics
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHANNELOPATHIES are disorders caused by defects in
ion channels. Channelopathies that result from
mutations in ion channel genes are the focus of this
entry. Ion channels are membrane proteins that
permit rapid and selective movement of ions across
cell membranes. Most ion channels are gated.
Ligand-gated ion channels open in response to
neurotransmitters such as acetylcholine, GABA,
and glycine. Voltage-gated ion channels open in
response to changes in membrane potential; they are
named for the permeable ion. The regulation of gap
junction channels is incompletely understood; gap
junction channels allow the passive exchange of ions
among adjacent groups of cells. Since ion channels
are particularly important in the function of ex-
citable cells such as nerve and muscle, it is not
surprising that mutations in ion channels have been
found to cause wide-ranging syndromes affecting the
nerve and muscle, including periodic paralysis,
cardiac arrhythmia, episodic ataxia, migraine, and
epilepsy (Table 1).
The fruit fly mutant Shaker, which shook inces-
santly when exposed to ether, defined the first
channelopathy. The decades-old observation of ab-
normal potassium currents in muscles in Shaker led to
the eventual cloning of voltage-gated Shaker potas-
sium channels. The first ion channel mutations in
human were found in a gene encoding muscle sodium
channels, leading to hyperkalemic periodic paralysis.
Hyperkalemic periodic paralysis is an autosomal
dominantly inherited disorder characterized by at-
tacks of muscle weakness and paralysis triggered by
exertion, emotional stress, or potassium loading, and
it is often responsive to acetazolamide, a carbonic
anhydrase inhibitor. Some patients develop a slowly
progressive myopathy. The identification of large
kindreds made possible the mapping of the disease
locus to the long arm of chromosome 17 by genome
scanning and linkage analysis. The clinical observa-
tion of abnormal muscle sodium currents triggered by
elevated extracellular potassium levels prompted the
search for a sodium channel in the candidate region.
SCN4A, a gene encoding the pore-forming and
voltage-sensing subunit of a voltage-gated sodium
channel expressed in muscle, was found, and
numerous mutations in this gene have been identified
(Mendelian Inheritance in Man 170500).
CHANNELOPATHIES, GENETICS 671
These mutations are thought to be disease causing
rather than benign polymorphisms for several
reasons. They segregated with the disease phenotype.
They were not present in normal control subjects.
They altered highly conserved amino acid residues.
Spontaneous mutations were found in sporadic cases.
Expression studies showed that mutations altered
channel properties that interfered with muscle
excitation–contraction coupling. Different mutations
in the same gene can lead to different clinical
manifestations, causing myotonia and hypokalemic
periodic paralysis (precipitated by low extracellular
potassium) as well as hyperkalemic periodic paraly-
sis. Each mutation has helped reveal new functional
domains of this ion channel important in the
regulation of the rate and the voltage dependence
of channel activation and inactivation. Furthermore,
mutations in genes encoding calcium channels,
potassium channels, and chloride channels expressed
in skeletal muscles have all been discovered to cause
periodic paralysis or myotonia, providing insight into
how cells carefully orchestrate different ion channel
proteins to carry out normal activities. That different
disease mechanisms can lead to a common final
pathway is perhaps best exemplified at the neuro-
muscular junction, where presynaptic, synaptic, and
postsynaptic defects can produce fluctuating weak-
ness, fatigability, and progressive muscle atrophy.
Congenital myasthenic syndromes are nonimmune-
mediated disorders of neuromuscular transmission.
As a genetic counterpart to myasthenia gravis (with
autoantibodies against postsynaptic acetylcholine
receptor complexes), mutations have been found in
genes encoding different subunits of acetylcholine
receptor channels, with impaired agonist dissocia-
tion, shortened or prolonged channel opening,
abnormal spontaneous opening, or reduced expres-
sion—all leading to myasthenia.
Ion channel defects have long been hypothesized to
cause other neurological disorders that share simila-
rities with periodic paralyses in their episodic nature,
precipitating factors, therapeutic responses, and
degenerative features. Indeed, the same strategy of
ascertaining monogenic phenotype, identifying large
kindreds for linkage analysis, candidate gene screen-
ing, and mutation identification has been successfully
applied in characterizing channelopathies affecting
ion channels expressed in the central nervous system
manifesting as episodic ataxia, migraine, and epi-
lepsy. Episodic ataxia is an unusual, heterogeneous
syndrome characterized by attacks of incoordination
and imbalance triggered by exertion or emotional
672 CHANNELOPATHIES, GENETICS

Table 1 DISEASES THAT RESULT FROM MUTATIONS IN ION CHANNEL GENES

Ion channel Gene Tissue distribution Phenotype MIMa

Sodium SCN4A Skeletal muscle Hyperkalemic periodic paralysis 603967

Paramyotonia congenita
Myotonia fluctuans
Atypical myotonia congenita
Hypokalemic periodic paralysis
SCN5A Cardiac muscle Cardiac arrhythmia/long QT syndrome 3 600163
SCN1B Cortical neurons GEFS þ (generalized epilepsy with febrile seizures plus) 600235
type 1
SCN1A Cortical neurons GEFS þ type 2 182389
SCN2A Cortical neurons Benign familial neonatal–infantile convulsions
Potassium KCNQ1 Cardiac muscle and cochlea Long QT syndrome 1 192500
Cardioauditory syndrome of Jervell and Lange–Nielsen
KCNH2 Cardiac muscle Long QT syndrome 2 152427
KCNE1 Cardiac muscle Long QT syndrome 5 176261
KCNE2 Cardiac muscle Long QT syndrome 6 603796
KCNE3 Skeletal muscle Hypokalemic periodic paralysis 170400
KCNJ2 Skeletal/cardiac muscle Andersen’s syndrome (periodic paralysis, cardiac 170390
arrhythmias, and dysmorphic features)
KCNA1 Cortical/cerebellar neurons Episodic ataxia with myokymia (type 1) 160120
and motor neurons
KCNQ2 Cortical neurons Benign familial neonatal convulsions type 1 602235
KCNQ3 Cortical neurons Benign familial neonatal convulsions type 2 602232
KCNQ4 Outer hair cell Deafness 603537
Calcium CACNA1A Cortical/cerebellar neurons Episodic axtaxia with nystagmus (type 2) 601011
and motor neurons
Familial hemiplegic migraine
Spinocerebellar axtaxia type 6
Congenital myasthenic syndrome
Seizure disorder
CACNA1S Skeletal muscle Hypokalemic period paralysis 114208
RYR1 Sarcoplasmic reticulum Malignant hyperthermia 180901
Central core disease
Chloride CLCN1 Skeletal muscle Myotonia congenita 160800
Acetylcholine CHRNA4 Cortical neurons Nocturnal frontal lobe epilepsy 600513
CHRNB2
CHRNA1 Skeletal muscle Congenital myasthenic syndrome 601462
CHRNB1
CHRNE1
GABA GABRG2 Cortical neurons GEFS þ type 3 137164
GABRA1 Juvenile myoclonic epilepsy 606904
Glycine GLRA1 Neurons Hyperekplexia 138491
gap junction CX26, GJB2 Cochlea Deafness 121011
CX46, GJA3 Eye Congenital cataract 601885
CX32, GJB1 Peripheral nerve Charcot–Marie–Tooth disease 304040
a
Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov).

stress that may be dramatically responsive to perinodal regions along motor neuron axons cause
acetazolamide. Mutations in the potassium channel episodic ataxia with interictal myokymia. Mutations
gene KCNA1 expressed centrally and also in the in CACNA1A encoding the pore-forming subunit of

a neuronal voltage-gated calcium channel complex
expressed centrally (most abundantly in the cerebel-
lum) and at the neuromuscular junction cause
episodic ataxia with nystagmus and myasthenic
syndrome. Furthermore, some mutations in CAC-
NA1A cause familial hemiplegic migraine with
associated cerebellar degeneration. A small expan-
sion of glutamine-encoding CAG repeats in CAC-
NA1A causes spinocerebellar ataxia type 6, a
progressive ataxia syndrome of late onset. Mutations
in CACNA1A and CACNB4 (encoding an accessory
subunit) have also been associated with seizure
disorders in human, similar to ataxia and seizures
observed in mouse models with mutations in
orthologous genes. Mutations in ligand (acetylcho-
line)-gated and voltage-gated channels expressed in
cortical neurons have been discovered to cause rare
familial epilepsy syndromes. Mutations in GLRA1
encoding glycine receptor channels at inhibitory
synapses cause hyperekplexia with exaggerated
startle response and hypertonia. Expression studies
have revealed impaired agonist sensitivity or dis-
rupted coupling of agonist binding and channel
activation in mutant channels.
The disease phenotype is determined by the tissue
distribution of gene expression. Mutations in
KCNQ1 encoding a potassium channel important in
the regulation of excitability in cardiac muscle cells
and endolymph homeostasis involving stria vascularis
in the inner ear cause dominant cardiac arrhythmia
with prolonged QT intervals and the recessive
cardioauditory syndrome of Jervell and Lange–
Nielsen, in which affected individuals are deaf and
may die of cardiac arrhythmia triggered by fright or
rage. In Andersen’s syndrome, mutations in KCNJ2
encoding a potassium channel heavily expressed in
skeletal and cardiac muscles cause periodic paralysis
and cardiac arrhythmia. The associated dysmorphic
features suggest a previously unrecognized role for
this channel in embryonic development. Mutations in
genes encoding tissue-specific gap junction proteins
can cause symptoms ranging from deafness to
cataract and peripheral neuropathy.
How mutations in ion channel genes lead to
paroxysmal symptoms and progressive degeneration
is a challenging question. Physiological, biochemical,
structural, and anatomical characterization of the
mutant channels will continue to reveal new func-
tional domains and cellular mechanisms regulating
biogenesis. The identification of disease-causing
mutations in KCNQ4, KCNE3, and others has
helped characterize ion channels with no previously
CHARCOT, JEAN-MARTIN 673
known function and has contributed to a better
understanding of the physiology of skeletal muscle
cells and hair cells. Expression studies have shown
that mutations can lead to ion channel hypoactivity
or hyperactivity causing overlapping clinical symp-
toms. Patients will therefore benefit from agonists or
antagonists depending on the nature of the molecular
defects. Interventions that enhance compensatory
mechanisms are also promising. Understanding the
phenotypic expression of these rare, monogenic
channelopathies may help elucidate similar mechan-
isms in other paroxysmal neurological disorders,
such as migraine, epilepsy, and movement disorders.
—Joanna C. Jen
See also–Acetylcholine; Calcium; Channelo-
pathies, Clinical Manifestations; Gamma
Aminobutyric Acid (GABA); Gap Junctions; Ion
Channels, Overview; Myotonic Disorders
Further Reading
Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov.
Papazian, D. M., Schwarz, T. L., Tempel, B. L., et al. (1987).
Cloning of genomic and complementary DNA from Shaker, a
putative potassium channel gene from Drosophila. Science 237,
749–753.
Ptacek, L. J., George, A. L., Jr., Griggs, R. C., et al. (1991).
Identification of a mutation in the gene causing hyperkalemic
periodic paralysis. Cell 67, 1021–1027.
Charcot, Jean-Martin
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
Jean-Martin Charcot shown in his official portrait by Tofano
in August 1881 when he became professor of clinical diseases
of the nervous system at the Faculté de Médecine, Paris.
IN THE history of neurology, few leaders have had
the scientific and personal impact of Jean-Martin
676 CHARCOT–MARIE–TOOTH DISEASE
nearby countryside village of Neuilly. His power,
however, likely alienated many of the people who
survived him, and as a consequence many of the
concrete elements of his heritage have survived
poorly. The Charcot Museum has disappeared and
the Bibliothèque Charcot today houses only a
fraction of the original documents from Charcot’s
time. Largely due to the publishing efforts of
Charcot’s student, Bourveville, most of Charcot’s
most celebrated lectures were published in his
Oeuvres Complètes in several languages and these
texts have been the major source for modern readers
to learn of Charcot’s contributions. Wider availabil-
ity of his other texts and lessons permits students to
appreciate the specific contributions made by Char-
cot and the pivotal role he played in the evolution of
contemporary neurology as it is practiced nearly 100
years after his death.
—Christopher G. Goetz
See also–Amyotrophic Lateral Sclerosis (ALS);
Charcot–Marie–Tooth Disease; Child Neurology,
History of; Gilles de la Tourette, Georges; (see
Index entry Biography for complete list of
biographical entries)
Further Reading
Goetz, C. G. (1987). Charcot the Clinician: The Tuesday Lessons.
Raven Press, New York.
Goetz, C. G., Bonduelle, M., and Gelfand, T. (1995). Constructing
Neurology: Jean-Martin Charcot. Oxford Univ. Press, New
York.
Guillain, G. (1959). J. M. Charcot—His Life and Work (P. Bailey,
Trans.). Hoeber, New York.
Charcot–Marie–Tooth Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHARCOT–MARIE–TOOTH disease (CMT) refers to the
inherited peripheral neuropathies named for the
three investigators who described them in the late
1800s. Because CMT diseases affect approximately 1
in 2500 people, they are among the most common
inherited neurological disorders. The majority of
CMT patients have autosomal dominant inheritance,
although X-linked dominant and autosomal recessive
forms also exist. What appear to be sporadic cases
also occur since even dominantly inherited disorders
may begin as a new mutation in a given patient. The
majority of cases are demyelinating, although up to
one-third appear to be primary axonal or neuronal
disorders. Most patients have a ‘‘typical’’ CMT
phenotype characterized by distal weakness, sensory
loss, foot deformities (pes caus and hammer toes),
and absent reflexes. However, some patients develop
severe disability in infancy (Dejerine–Sottas disease
or congenital hypomyelination), whereas others
develop few if any symptoms of disease. During the
past decade, remarkable progress has been made
toward understanding the genetic causes of many
types of CMT. Recently, advances in cell biology
have provided clues as to how particular mutations
cause disease. In this entry, we review the genetics
and clinical, electrodiagnostic, and molecular fea-
tures of inherited peripheral neuropathies.
CLASSIFICATION
In landmark studies, Dyck and Lambert subdivided
hereditary motor and sensory neuropathies
(HMSNs) into dominantly inherited demyelinating
HMSN I (CMT1) and dominantly inherited axonal
HMSN II (CMT2) forms based on electrophysiolo-
gical and neuropathological criteria. Other types
were then classified as HMSN III–VII, depending on
the inheritance type and accompanying features.
Once specific genetic causes for the CMT were
identified, however, the classification had to be
expanded and modified (Table 1). Here, we classify
CMT as CMT1 if the patient has an autosomal
dominantly inherited demyelinating neuropathy,
CMT2 if the neuropathy is dominantly inherited
and axonal, CMTX if the patient has an X-linked
neuropathy, and CMT4 if the neuropathy is reces-
sive. In addition, cases of CMT1, CMT2, and CMT4
are further subdivided based on differences in genetic
abnormalities or linkage studies. However, the
classification of CMT remains confusing and will
certainly require further modifications as new genetic
forms of the neuropathies are identified.
A particularly confusing classification problem
concerns the disorder known as Dejerine–Sottas
disease (DSD). DSD was classified by Dyck and
Lambert to identify patients with severe disability
beginning in infancy who had an autosomal recessive
inheritance pattern. Subsequently, it has been shown
that many presumed DSD patients have autosomal
dominant mutations caused by mutations in periph-
eral myelin protein 22kD (PMP22), myelin protein
zero (MPZ), and early growth response 2 (EGR2).
Although many nerve conduction velocities (NCVs)
 CHARCOT–MARIE–TOOTH DISEASE 677

Table 1 CLASSIFICATION OF CMT a

Disease Inheritance pattern Locus Gene

CMT1
CMT1A AD 17p11.2 PMP22 duplication and mutation
CMT1B AD 1q21–23 P0 mutation
CMT1C ? ?
CMT1D AD 10q21–22 EGR2
HNPP AD 17p11.2 PMP22 deletion
CMT2
CMT2A AD 1p35–36 KIFIBb
CMT2B AD 3q13–22 ?
CMT2C AD ? ?
CMT2D AD 7p15 ?
CMT2E AD 8p21 NF-light mutation
CMTX AD Xq13–22 Connexin mutation
DSD AD 1q22–23 P0 mutation
AD 17p11.2 PMP22 mutation
AD 10q21–22 EGR2 mutation
CMT4
CMT4A (demyelinating form) AR 8q13 GDAP1
AR 8q24 N-myc downstream-regulated gene-1 mutation
CMT4B (demyelinating form) AR 5q23–33 ?
AR 10q23.2 ?
AR 11q23 Myotubularin-related protein-2 mutation
CMT4C (axonal form) AR 1q21.2–21.3 ?
AR 19q13.3 ?
AR 19q13.13 l-Periaxin mutation
a
Abbreviations used: AD, autosomal dominant; AR, autosomal recessive.

in DSD patients were extremely slow (o15 m/sec),
some severely disabled children did not have slow
NCVs. Moreover, although sural nerve biopsies in
many DSD children revealed severe demyelination,
others revealed predominantly axonal loss. To
minimize confusion, in this entry we use DSD to
define all patients with severe onset in infancy.
Specifically, we use the following diagnostic criteria:
(i) onset by 2 years of age with delayed motor
milestones and (ii) severe motor, sensory, and skeletal
deficits with frequent extension to proximal muscles,
sensory ataxia, and scoliosis.
CMT CAUSED BY DOMINANTLY INHERITED
MUTATIONS IN GENES EXPRESSED IN
SCHWANN CELLS
Genetics
Since 1991, specific genetic defects causing distinct
forms of CMT1 have been identified. As predicted,
based on the demyelinating features of the neuro-
pathies, the mutations were found in genes expressed
in myelinating Schwann cells. CMT1A, the most
common form of CMT1, was shown to be caused by
a duplication on chromosome 17, containing the
gene-encoding PMP22. The function of PMP22 in
Schwann cells remains unknown. Between 60 and
90% of CMT1 patients have this duplication. There
is convincing evidence that the duplication of PMP22
causes CMT1A: (i) Missense mutations in PMP22
cause the Trembler and Trembler J, which are
naturally occurring mouse models of CMT1; (ii)
the transgenic mice and rats bearing extra copies of
PMP22 develop a CMT1A-like neuropathy; and (iii)
some patients with missense mutations in PMP22
also develop a similar phenotype to CMT1A.
Interestingly, a deletion of exactly the same 1.5-
Mb region containing PMP22 is now known to cause
an entirely different disorder—hereditary neuropathy
with liability to develop pressure palsies (HNPP).
Missense mutations in the major peripheral nervous
system (PNS) myelin protein gene on chromosome 1,
encoding MPZ, cause CMT1B. MPZ is a member of
678 CHARCOT–MARIE–TOOTH DISEASE
the immunoglobulin superfamily, has a single trans-
membrane domain, and is necessary for the adhesion
of concentric myelin wraps in the PNS internode.
Missense mutations in early growth response 2
(EGR2, also called krox20), on chromosome 10,
cause CMT1D. EGR2 is a transcription factor
involved in the regulations of unspecified genes in
the myelinating Schwann cell.
The second most common form of CMT, compris-
ing 10–16% of cases, is caused by missense muta-
tions in the connexin 32 kDa (Cx32) gene located on
the X chromosome. Cx32, localized in the uncom-
pacted myelin of the paranodal loops and Schmidt–
Lanterman incisures, presumably function as a gap
junction protein permitting the passage of small
molecules and ions between adjacent loops of the
paranode or incisures. Currently, more than 200
different mutations of Cx32 have been identified.
Because they have a single X chromosome, men tend
to develop CMTX more severely than their female
counterparts. Probably because of X inactivation of
the abnormal chromosome, women usually have
milder disease, although most are affected to some
degree.
Clinical Manifestations
CMT1A: Most CMT1 patients (85%) become
symptomatic clinically in their first two decades of
life. The largest group, those with CMT1A, usually
develop a typical CMT phenotype. They are slow
runners in childhood, develop foot problems in their
teenage years, and often require orthotics for ankle
support as adults. Variable degrees of hand weakness
occur, typically lagging approximately 10 years
behind the development of foot weakness. Sensory
loss, also variable, occurs in both large (vibration and
proprioception) and small (pain and temperature)
modalities. Although the combination of weak ankles
and decreased proprioception often leads to problems
with balance, the vast majority of patients remain
ambulatory throughout their lives, which are not
shortened by their disease. Almost all patients with
CMT1A have absent deep tendon reflexes. Most have
foot deformities with high arches and hammer toes.
One may be able to palpate the enlarged nerve trunks
in subcutaneous tissue. Additional features, including
postural tremor (Roussy–Levy syndrome) and muscle
cramps, may also occur. Although this phenotype is
typical for CMT1A patients, it is not invariable.
Occasional patients develop a severe phenotype in
infancy, whereas others develop minimal disability
throughout life. Since phenotypic variability occurs
within the same generation within the same family, it
is not possible to predict who will have more
disabling forms of the disease.
HNPP: As mentioned previously, HNPP is caused
by a deletion of the same region of chromosome 17
that is duplicated in CMT1A. HNPP patients present
with a variety of patterns, including no symptoms or
abnormalities on neurological examination, a ten-
dency to develop transient entrapment syndromes,
and the development of chronic difficulties such as
occur in CMT1A. Occasionally, a brachial plexo-
pathy may be the presenting symptom. However,
HNPP is a distinct disorder from hereditary brachial
plexus neuropathy.
CMT1B and CMT1D: Phenotypes are also quite
variable in other forms of CMT1. Based on initial
reports, most patients with CMT1B were thought to
have the typical CMT phenotype described for
CMT1A patients, perhaps with more pronounced
calf wasting. However, it is now evident that patients
with MPZ mutations actually have a wide range of
phenotypes ranging from the very severe (congenital
hypomyelination presenting in utero and DSD
presenting in infancy) to milder CMT2-like cases
presenting in adulthood. The type and location of the
mutation on the MPZ coding region appear to
determine the severity of the neuropathy, although
careful genotype–phenotype correlations remain to
be performed.
Missense mutations in EGR2 also cause variable
phenotypes, probably depending on the site and
nature of the specific mutation. To date, most
mutations have caused severe disease, classified as
Dejerine–Sottas or congenital hypomyelination. Re-
cently, however, cases have been described with
milder phenotypes that do not present until adult-
hood.
CMTX: CMTX patients usually develop symp-
toms in the late teenage years or young adulthood.
Several patients we have evaluated were varsity
athletes in high school, although they were never
fast runners. Wasting of calf muscles is often more
pronounced in CMTX than in CMT1A patients.
Interestingly, despite the more than 200 different
mutations described, few if any appear to have severe
Dejerine–Sottas or congenital hypomyelination phe-
notypes. As with CMT1A patients, abnormalities are
usually slowly progressive, limited to the distal legs
and hands, and do not shorten a patient’s life span.

Occasional female patients have presented in adult-
hood with a CIDP-like (chronic inflammatory
demyelinating polyneuropathy) neuropathy.
Nerve Conduction Velocities
NCVs have played an important role in characteriz-
ing CMT disorders since their initial use in separat-
ing CMT1 from CMT2. In the early 1980s, Lewis
and Sumner demonstrated that most cases of
inherited neuropathies had uniformly slow NCVs,
whereas acquired demyelinating neuropathies had
asymmetric slowing. Thus, NCVs could be used,
along with a patient’s pedigree, to distinguish
between inherited and acquired neuropathies. Dur-
ing the past decade, however, this approach has had
to be qualified. Most CMT1 patients, particularly
those with CMT1A, have uniformly slow NCVs of
approximately 20 m/sec (although values as high as
38 m/sec have been reported and this is used as a
cutoff value). However, asymmetric slowing is
characteristic of HNPP and may be found in patients
with missense mutations in PMP22, MPZ, EGR2,
and Cx32. Since all these disorders may present
without a clear family history of neuropathy, one
must be cautious when using NCVs to distinguish
acquired from inherited demyelinating neuropathies.
Forms of inherited neuropathies associated with
uniform and nonuniformly slowed NCVs are illu-
strated in Table 2.
The use of NCVs to distinguish between demye-
linating and axonal neuropathies is also important.
All forms of CMT1 have axonal loss as well as
demyelination, and it is likely that axonal loss
correlates better than demyelination with the pa-
tient’s actual disability. Thus, reductions in com-
pound muscle action potential (CMAP) and sensory
nerve action potential (SNAP) amplitudes are found
in most CMT1 patients; in our series of 43 CMT1A
patients, 34 had unobtainable peroneal CMAPs and
41 had unobtainable sural SNAPs.
The distinction between demyelinating and axonal
features of NCV is particularly confusing in CMTX.
NCVs in CMTX patients are faster than in most
patients with CMT1, often with prominent reduc-
tions in CMAP and SNAP amplitudes. Thus, CMTX
has been described as an ‘‘axonal’’ neuropathy.
However, a careful analysis of the conductions will
reveal the primary demyelinating features of the
neuropathy. The conduction velocities in men are not
normal but usually between 30 and 40 m/sec—values
that would be considered an intermediate range
between CMT1 and CMT2. Moreover, distal motor
CHARCOT–MARIE–TOOTH DISEASE 679
Table 2 ELECTROPHYSIOLOGICAL FINDINGS OF INHERITED
DEMYELINATING NEUROPATHIES
Inherited disorders with uniform conduction slowing
Charcot–Marie–Tooth 1A
Charcot–Marie–Tooth 1B
Dejerine–Sottas
Metachromatic leukodystrophy
Cockayne’s disease
Krabbe’s disease
Inherited disorders with multifocal conduction slowing
Hereditary neuropathy with liability to pressure palsies
Charcot–Marie–Tooth X
Adrenomyeloneuropathy
Pelizeus–Merzbacher disease with proteolipid protein null
mutation
Refsum’s disease
Inherited disorders with incompletely characterized
electrophysiology
PMP 22 point mutations
P0 point mutations
Adult-onset leukodystrophies
Merosin deficiency
Early growth response-2 mutations
latencies and F wave latencies are usually prolonged.
Some women with CMTX, probably through in-
activation of their mutant X chromosome, have
normal NCVs, although many have values similar to
those of their male counterparts. In distinguishing
between the demyelinating and axonal features of
CMTX, it is important to remember that the disease
is caused by mutations in Cx32, which is expressed
in the myelinating Schwann cell.
Pathology of CMT1, HNPP, and CMTX
CMT1: There is overlap between the various
forms of CMT1; thus, their pathologies are discussed
together. Segmental demyelination, remyelination,
and axonal loss are characteristic features. In cases
of DSD, demyelination is severe. Onion bulbs of
concentric Schwann cell lamellae are less frequent in
children than in adults. In adults, the presence of
onion bulbs may dominate the pathology. Axonal
loss varies with individual patients. There is a loss of
both small- and large-diameter myelinated fibers in
nerve biopsies of CMT1 patients. Some fibers have
relatively thickened myelin sheaths, resulting in
lowered mean g ratios (axon diameter/fiber dia-
meter). Focal, sausage-like thickenings of the myelin
sheath (tomacula) may be present in various types of
680 CHARCOT–MARIE–TOOTH DISEASE
CMT1, although their numbers have been reported
to be higher in patients with CMT1B. However,
neither disorder has tomaculi present to the extent
seen in HNPP.
Immunoelectron miscroscopic analysis of sural
nerve biopsies from CMT1A patients demonstrates
increased PMP22 labeling compared to controls. The
effect of the duplication on other myelin proteins is
unclear. P0 and MBP levels were found to be similar
to those of controls in three CMT1A patients, but P0
levels were reduced by 50% in a fourth patient. In a
patient with a PMP22 missense mutation causing
formation of a truncated protein, P0 and PMP22
levels were reduced. Immunoelectron microscopic
studies on two CMT1B patients demonstrated
normal levels of PMP22 and MBP but reduced levels
of P0. The clinical, physiological, and pathological
findings suggest that it is likely that different
mutations of the same gene will lead to different
clinical phenotypes, and that alterations in expres-
sion patterns of other myelin genes may depend on
the particular mutation in question.
HNPP: Segmental demyelination, remyelination,
and some loss of large-diameter axons have all been
described in nerve biopsies from HNPP patients.
Tomaculi are hallmarks of HNPP and have been
identified in at least one patient prior to the develop-
ment of clinical symptoms. Immunoelectron micro-
scopic studies of sural nerve biopsies have demon-
strated the predicted underexpression of PMP22.
CMTX: Pathological features of patients with
Cx32 mutations reveal an age-related loss of myeli-
nated nerve axons. The demyelinating nature of the
neuropathies is demonstrated by abnormally thin
myelin-ensheathing large-caliber axons. Onion bulbs
are infrequent. Teased fiber analysis reveals frequent
widening at the nodal gap, paranodal retractions,
and, less frequently, segmental demyelination.
CMT CAUSED BY RECESSIVELY INHERITED
MUTATIONS IN GENES EXPRESSED IN
SCHWANN CELLS
CMT4 s, the autosomal recessively inherited neuro-
pathies, are also a heterogeneous group of disorders.
CMT4 cases are rare and usually more severe than the
autosomal dominantly inherited disorders, and many
patients may have systemic symptoms, such as
cataracts and deafness. CMT4 s are separable into
demyelinating (4A and 4B) and axonal (4C) forms.
CMT4A is linked to a 5-cm region of 8q13–q21.1.
The disorder was first described in four highly inbred
families in Tunisia. Clinical onset began in the first 2
years of life, with delayed developmental milestones
such as sitting or walking. Weakness spread to
proximal muscles by the end of the first decade of
life, and many patients became wheelchair dependent.
Sensory loss was mild, deep tendon reflexes were
absent, and motor NCVs slowed to an average of 30/
sec in the upper limbs. Pathological studies from sural
nerve biopsies revealed a loss of large-diameter
myelinated fibers and hypomyelination but no ab-
normalities of myelin folding. So-called basal lamina
onion bulbs, characterized by concentric layers of
basal lamina without intervening regions of Schwann
cell cytoplasm, have been described in biopsies.
Kalaydjieva and colleagues reported a separate
disorder with linkage to chromosome 8q24 in a
Gypsy population with an autosomal recessive
inheritance pattern. The neuropathy has presented
with distal muscle wasting and weakness, sensory
loss, both foot and hand deformities, and loss of deep
tendon reflexes. Disability usually begins in the first
decade of life and becomes severe by the fifth decade.
Deafness is invariant and usually develops by the third
decade. Brainstem auditory evoked responses are
markedly abnormal with prolonged interpeak laten-
cies. NCVs are severely reduced in younger patients
and unobtainable after 15 years of age. Pathologically,
there are decreased numbers of myelinated axons,
with thinly myelinated large-caliber axons and onion
bulbs present. A subsequent study identified muta-
tions in the ‘‘N-myc downstream-regulated gene’’ in
these patients. It is unknown how the gene abnorm-
ality leads to the disorder.
An additional autosomal recessive form of demye-
linating CMT has been identified on chromosome
5q23–33 in two large Algerian families with ex-
tensive consanguinity. Patients in these kindreds
develop a sensorimotor neuropathy with onset in
childhood or adolescence. Pes cavus and scoliosis are
frequent. Median motor nerve conduction velocities
of 20–30 m/sec have been reported.
Recently, another autosomal recessive form of
demyelinating CMT was reported—hereditary motor
and sensory neuropathy–Russe (HMSNR). Patients
develop primarily severe sensory loss, although
motor NCVs are moderately reduced (on average,
31.9 m/sec for ulnar and median nerves). The locus
of HMSNR is located on 10q23.2, a small interval
telomeric to the EGR2 gene.
CMT4B is a recessively inherited disorder char-
acterized clinically by a unique pathological

feature—the presence of focally folded myelin
sheaths in nerve biopsy. The genetic locus is on
chromosome 11q23 and encodes a gene called
myotubularin-related protein-2. It is not known
how a ‘‘dual-specific’’ phosphatase causes a demye-
linating neuropathy. Affected patients become symp-
tomatic early, with an average age of onset of 34
months. Unlike most forms of CMT, both proximal
and distal weakness are prominent. Motor conduc-
tion velocities are severely reduced (typically 14–17
m/sec) with temporal dispersion, CMAPS are re-
duced, and SNAPs are frequently absent. Segmental
demyelination is also demonstrated in nerve biopsies.
To date, two loci of axonal CMT4 have been
described (CMT4C). The first locus is on chromo-
some 1q21.2–21.3. Age of onset of the disease is in
the second decade of life (10–18 years). Although
distal weakness is a predominant feature, many
affected members in the family show proximal
weakness. Motor conduction velocities are 50–53
m/sec in ulnar and median nerves, but the amplitude
of SNAPs is severely reduced or absent.
A second locus has been mapped to chromosome
19q13.3. Age of onset of disease in these cases is
older, between 28 and 42 years. Clinically, distal
weakness is the predominant feature. Although Leal
et al. designate the neuropathy as axonal, motor
conduction velocities in median nerves range from
28.8 to 54.4 m/sec, so demyelination cannot be
excluded.
Finally, a novel, severe form of recessive CMT has
been designated CMT4F and defined in a large
Lebanese family in which mutations have been found
in the periaxin (PRX) gene on chromosome 19. PRX,
expressed in Schwann cells, encodes two proteins
that contain PDZ domains that usually interact with
other PDZ domain-bearing proteins in intracellular
signal transduction pathways. Binding partners for
PRX in Schwann cells have not been identified, nor
have the signal transduction pathways involving
PRX been delineated. NCVs in patients with PRX
mutations were markedly slowed and onion bulbs
were present on sural nerve biopsies.
CMT CAUSED BY DOMINANTLY INHERITED
MUTATIONS IN GENES EXPRESSED
IN NEURONS
CMT2
CMT2 represents up to one-third of cases with
autosomal dominant CMT. In most respects, the
CHARCOT–MARIE–TOOTH DISEASE 681
clinical phenotype of CMT2 patients is similar to
that of patients with CMT1. CMT2 patients also
have distal weakness, atrophy, sensory loss, and foot
deformities. In general, CMT2 patients may have a
wider age range of onset and disability than those
with CMT1, and CMT2 patients are more likely to
maintain their deep tendon reflexes. However, it is
impossible to accurately distinguish CMT1 from
CMT2 patients clinically without utilizing electro-
diagnostic testing. Reduced CMAP and SNAP
amplitudes with normal or mildly slow conduction
velocities are hallmarks of CMT2. With needle
electromyography (EMG), changes of denervation
and partial reinnervation are common. The electro-
physiological features are consistent with pathologi-
cal findings from sural nerve biopsies that
demonstrate axonal loss without evidence of demye-
lination.
Molecular genetic studies prove that CMT2 is a
heterogeneous disorder, like CMT1. Five subtypes of
CMT2 (CMT2A–CMT2E) have been identified by
linkage analysis. Although the gene loci for CMT2A,
-B, -D, and -E have been identified, only in CMT2E
has the specific genetic cause been identified.
CMT2A patients have typical CMT clinical pre-
sentations with sensorimotor peripheral neuropa-
thies. The locus of CMT2A is at chromosome 1p36.
A family with CMT2A has recently been identified
carrying a missense mutation in the gene encoding
kinesin KIF1B, a protein expressed in neurons that is
involved in microtubule-mediated axonal transport.
The kinesin mutation in this family alters the amino
terminal portion of the protein, prevents binding to
microtubules, and thus alters transport of organelles
along the axon. Consistent with these data, mice
with one of two KIF1B genes inactivated by
homologous recombination (KIF1B7mice) also have
an axonal peripheral neuropathy. Interestingly, trans-
port of synaptotagmin, a precursor for synaptic
vesicles, is decreased in distal axons of KIF1B7ani-
mals, suggesting that the inability to transport
synaptic vesicle components is responsible for the
resultant axonal neuropathy in these animals.
Although polymorphisms in the amino acid sequence
of KIF1B have been identified in other families with
CMT2A, none of these mutations segregate with the
neuropathy, suggesting that CMT2A might be caused
by mutation in an additional closely linked gene on
chromosome 1. Taken together, however, these data
lend further credence to the hypothesis that altera-
tion of axonal transport can cause peripheral
neuropathy.
682 CHARCOT–MARIE–TOOTH DISEASE
CMT2B is a predominantly sensory disorder
and there is debate as to whether cases should
be considered under pure sensory neuropathies.
The disorder has been mapped to chromosome
3q13.
CMT2C is a rare disorder in which patients
have paresis of vocal cords, pupillary abnormal-
ities, and hearing loss in addition to other
characteristics of CMT2. CMAP amplitude of
the diaphragm on phrenic nerve stimulation is
reduced or absent. The genetic locus linked to
CMT2C has not been identified and there remains
controversy as to whether CMT2C is a distinct
genetic entity.
CMT2D is a confusing disorder because some
patients appear to have sensorimotor neuropathies,
whereas others have pure motor syndromes char-
acterized as hereditary motor neuropathy (HMN)
type V. At least one family has been described with
some individuals having the pure motor syndrome
and others also having sensory loss, suggesting that
the two disorders are likely different phenotypes of
the same disease. The CMT2D locus is on chromo-
some 7p15. Recently, an additional locus for CMT2
was detected with linkage to chromosome 8p21.
Subsequent studies have identified mutations in the
neurofilament light (NEFL) gene as the cause of this
neuropathy, now known as CMT2E. Since the
NEFL protein is an important constituent of the
neurofilaments used in axonal transport systems,
and neurofilament phosphorylation is known to be
abnormal in demyelinating forms of CMT, CMT2E
may provide important clues regarding the mechan-
isms of axonal damage not only in CMT2 but also
in CMT1.
Giant Axonal Neuropathy
Giant axonal neuropathy is a rare autosomal
recessive disorder presenting in childhood and
progressing to death by the end of the third decade.
Recently, the genetic cause of the disease was
demonstrated to be mutations in a novel cytoskeletal
gene termed gigaxonin. The name of the disorder
derives from the characteristic pathological abnorm-
alities that result from the general disorganization of
intermediate filaments in nerve axons in both the
central nervous system and PNS. Because of dis-
organized intermediate filaments, many but not all
patients also have characteristic kinky hair. NCVs
reveal severe reductions in CMAP and SNAP
amplitudes and needle EMGs reveal denervation.
DISTAL HEREDITARY MOTOR
NEURONOPATHIES AND
HEREDITARY SENSORY AND
AUTONOMIC NEUROPATHIES
HMN
HMNs are a heterogeneous group of disorders
loosely grouped into proximal and distal disorders.
The proximal HMNs include the spinal muscular
atrophies SMA1 (Werdnig–Hoffman disease) and
SMA2 (Kugelberg–Welander disease) as well as the
X-linked bulbospinal neuronopathy (Kennedy’s dis-
ease). These disorders are often considered to be
motor neuron disorders and will not be discussed in
this entry. By contrast, the distal HMNs are often
referred to as spinal forms of CMT and will be
discussed here.
Distal HMNs comprise approximately 10% of all
HMNs and have been tentatively classified into seven
subtypes based on clinical presentations, age of
onset, and mode of inheritance. Four of the subtypes
have autosomal dominant inheritance patterns, with
the first two presenting with leg weakness but
distinguished by juvenile (type I) and adult (type II)
onset of symptoms. The third autosomal dominant
form, type V, is characterized by onset in the arms.
Type VII is also autosomal dominant, but there is
vocal cord paralysis in addition to weakness. The
three autosomal recessive forms—types III, IV, and
VI—are separated by age of onset and severity, and
all begin with leg weakness. In general, the recessive
distal HMNs have been more severe than the
dominantly inherited disorders. Based on the con-
siderable phenotypic variability of other forms of
inherited neuropathies, it seems reasonable to predict
that several of these disorders may prove to be
variable phenotypes of single mutated genes and that
this classification will ultimately have to be modified.
Genetic loci for several subtypes of distal HMN have
been identified.
Distal HMN II has been linked in a large Belgian
family to chromosome 12q24.3. Patients typically
develop weakness in foot dorsiflexion by their late
teens and some, but not all, become wheelchair
bound in later years. Occasional patients have been
described with decreased vibratory sensation. NCVs
are normal, whereas needle EMG demonstrates
evidence of chronic denervation.
Distal HMN V has been localized to chromosome
7p. As mentioned previously, it is probably the same
disorder as CMT2D. In a large Bulgarian family with
30 affected members, hand weakness and wasting

usually occurred in the late teenage years. Although
foot weakness ultimately developed in 40% of cases,
this was usually mild and patients were still
ambulatory at age 60. One branch of the family
was noted to have mild pyramidal features including
Babinski signs. NCVs were normal except for
reduced CMAP amplitudes in wasted muscles.
A novel recessive distal HMN has been termed the
Jerash type based on a large Jordanian family with a
locus mapped to chromosome 9p21.1–p12. Patients
develop gait instability and foot drop prior to the age
of 10 and a few years later develop wasting and
weakness of hand muscles. Occasionally, milder
phenotypes have been identified in patients older
than age 50. Initially, patients have presented with
upper motor neuron signs, including hyper-reflexia,
spasticity, and upturned toes. Subsequently, ankle
reflexes are lost and plantar responses were described
as downward moving. The ultimate course of this
disorder is relatively benign, with the oldest affected
patient ambulatory at age 80.
An additional distal motor syndrome has been
mapped to 9q34 and has been classified as an
autosomal dominant form of amyotrophic lateral
sclerosis (ALS4). As expected, the majority of
patients have upper as well as lower motor neuron
signs, including brisk reflexes and upturned toes.
However, the clinical course of these patients is
much milder than typical ALS. Patients typically
develop difficulties walking in their second decade
and proximal weakness in their fourth or
fifth decade, with many ultimately becoming wheel-
chair bound. Useful hand function is often not
lost until the sixth decade. Patients have lived into
their 80s. An autopsy on one such patient, who
died of a myocardial infarction, revealed atrophy of
both ventral and dorsal roots, chromatolysis
and axonal swelling in both ventral and dorsal roots,
and a loss of anterior horn cells. NCV studies
revealed decreased CMAP amplitudes in weak
wasted muscles, and needle EMG demonst-
rated chronic changes of denervation and partial
reinnervation.
Hereditary Sensory and
Autonomic Neuropathies
Rare cases of heritable sensory neuropathies, often
with autonomic features, have been described. The
specific genetic causes of three of these unusual
disorders have been identified.
Hereditary sensory and autonomic neuropathy
(HSAN) type I has been shown to be caused by
CHARCOT–MARIE–TOOTH DISEASE 683
mutations in the serine palmitoyltransferase subunit-
1 gene on 9q22, which encodes the rate-limiting
enzyme in ceramide synthesis. Patients with HSAN I
(also referred to as HSN1) develop symptoms of
small sensory fiber dysfunction between the second
and fourth decades of life. Typically, these symptoms
include the development of neuropathic pain, plantar
ulcers, loss of pain and temperature sensation, and,
in some cases, autonomic problems. Occasionally,
large-fiber modalities, such as vibration sensation
and proprioception, have also been abnormal. Deep
tendon reflexes are decreased in lower extremities,
and patients may have atrophy of distal muscles and
pes cavus. NCVs are normal but SNAP amplitudes
are reduced. Pathological studies reveal neuronal loss
in DRGs and sympathetic ganglia, with subsequent
length-dependent degeneration of small-fiber axons,
although all sizes of sensory axons are affected to
some degree. Cases have been described with
associated deafness or weakness; whether these are
the same disorder is not known.
HSAN II is a recessive disorder with an early
severe onset. Fingers as well as toes are involved, and
patients develop paronychia, whitlows, and ulcera-
tions of their fingers in addition to foot ulcerations.
Sensory loss affects both small- and large-fiber
modalities. Sweating is reduced, although patients
do not develop orthostatic hypotension, sphincter
dysfunction, or (in males) impotence. NCVs reveal
absent SNAPs, and sural nerve biopsies demonstrate
both an absence of myelinated fibers and a reduction
of nonmyelinated fibers.
Familial dysautonomia (HSAN III), also known as
the Riley–Day syndrome, has recently been demon-
strated to be caused by mutations in the IKAP gene
on chromosome 9q31. Although the intronic muta-
tion is present in all cells, it appears to disrupt
splicing in a tissue-specific manner in DRG and
sympathetic neurons, leading to a truncated protein.
The role of IKAP is unknown, although it is thought
that it may play a role in regulating transcription of
several genes even though it is not a transcription
factor in its own right. HSAN III is particularly
frequent in the Ashkenazi Jewish population. Some
estimates indicate the frequency of carriers in Israel is
as high as 18 per 100,000. Clinically, patients display
abnormalities from birth, including an absence of
fungiform papilla on the tongue, poor sucking,
difficulties swallowing, alacrima (loss of overflow
tears), and blotching of the skin with emotions.
Autonomic abnormalities include labile blood pres-
sure, with severe postural hypotension, and both
684 CHARCOT–MARIE–TOOTH DISEASE
excesses and decreases of sweating. Intradermal
injections of histamine fail to produce the character-
istic histamine flare. Deep tendon reflexes are
typically decreased. Most patients have loss of
pain and temperature sensation. Corneal reflexes
are absent, consistent with trigeminal nerve involve-
ment. Vibration and position sense are also abnormal
in some patients. Motor NCVs can be mildly slow
and SNAPs reduced. Morphological studies show a
loss of neurons in both cervical and thoracic
sympathetic ganglia. Decreased numbers of small,
unmyelinated fibers have been reported in sural nere
biopsies.
Congenital insensitivity to pain with anhydrosis
has been classified as HSAN IV. Patients present with
a congenital insensitivity to painful stimuli and
anhydrosis despite normal-appearing sweat glands
on skin biopsy. Temperature sensation is also
defective and 20% of patients die due to hyperpyr-
exia, usually before the age of 3. Body temperatures
as high as 109o have been reported. Patients have
been known to bite off the tips of their tongues when
they develop dentition and self-mutilate their lips
and tips of their fingers. Most children are also
mentally retarded, with IQs between 41 and 78.
Sural nerve biopsies reveal a loss of myelinated and
nonmyelinated axons. Mice in which the nerve
growth factor receptor TrkA has been deleted also
have insensitivity to pain, and missense mutations
in the human homolog of TrkA, NTRK1, deletions
of NTRK1, and splice site abnormalities of
NTRK1 have all been detected in patients with the
disease.
HEREDITARY BRACHIAL PLEXUS
NEUROPATHY/HEREDITARY
NEURALGIC AMYOTROPHY
Hereditary brachial plexus neuropathy (HBPN) has
been mapped to chromosome 17q24–25. This
unusual autosomal dominant disorder presents with
episodes of pain, weakness, and sensory loss in the
upper extremities. Almost invariably, the onset of
weakness is preceded by pain in the affected arm.
Recovery usually occurs, beginning several weeks to
months after the onset of symptoms. Attacks may
subsequently occur in the same or opposite arm.
Several minor dysmorphic features, including short
stature, hypotelorisms, epicanthal folds, and cleft
palate, have been associated with HBPN but do not
appear to be invariant. NCV reports have been
variable, demonstrating normal values, entrapment
syndromes, or asymmetrically reduced CMAPs and
SNAPs. Nerve biopsies have demonstrated tomaculi,
leading to the other name for this disorder, tomacu-
lous neuropathy. This disorder is genetically distinct
from HNPP.
NEUROPATHY AND MITOCHONDRIAL
DISEASE
Peripheral neuropathies have been described in a
variety of mitochondrial disorders, including
MELAS (mitochondrial myopathy, encephalopathy,
lactic acidosis, and stroke-like episodes), MERRF
(myoclonus epilepsy and ragged red fibers), Leigh’s
syndrome, and Kearns–Sayre syndrome, and are a
required component of the NARP syndrome (neuro-
pathy, ataxia, and retinitis pigmentosa). Typically,
the neuropathies are axonal with a motor predomi-
nance. How mitochondrial disorders cause neuro-
pathy is not well understood, but axonal transport
of mitochondria is an important source of energy
for the elongated axons of motor and sensory
neurons.
DIAGNOSIS
The initial step in diagnosing an inherited neuro-
pathy is obviously to determine that the patient has a
peripheral nerve disorder. Clinically, patients usually
have symptoms of length-dependent weakness and
sensory loss in a symmetrical pattern. The neurolo-
gical examination typically reveals weakness of foot
dorsiflexion and eversion, out of proportion to
plantar flexion and inversion weakness. Patients
often have abnormalities in dorsiflexing their fingers
and performing fine movements of their hands.
Muscle wasting in feet and hands is frequent, as are
foot abnormalities such as pes cavus. Scoliosis is also
frequent. Autonomic symptoms or signs are usually
not found in most forms of inherited neuropathies,
excluding those disorder in which autonomic ab-
normalities are part of the disease criteria, such as the
HSANs. Reflexes are often but not always decreased.
Typically, the inherited neuropathies are chronic
diseases with symptoms extending back to child-
hood, although some atypical forms can have onset
in adulthood and present asymmetrically. Other
causes of peripheral neuropathy, such as diabetes
mellitus, monoclonal gammopathy, renal disease,
medications, and alcohol abuse, need to be excluded.
NCVs are essential to determine whether patients are
likely to have demyelinating forms of neuropathy

and whether the disorders are asymmetric. We
emphasize the importance of evaluating NCVs care-
fully for subtle signs of demyelination, such as
prolonged distal motor latencies or F wave latencies,
in determining whether the underlying cause is likely
axonal or demyelinating. In our opinion, sural nerve
biopsies are rarely helpful in diagnosing inherited
neuropathies, although they may prove invaluable
for future research investigating pathogenic mechan-
isms of disease.
Obtaining a careful pedigree is critical in the
diagnosis of inherited neuropathies not only to
determine that there is an inherited neuropathy but
also to determine who is at risk for developing the
neuropathy. Careful pedigrees usually require a
history of at least three generations. Excluding
male-to-male transmission is the only way to exclude
an X-linked inheritance. Although positive pedigrees
may prove invaluable, caution must be taken when
interpreting negative pedigrees. Even dominantly
inherited diseases can start in a particular patient,
so the parents may have no signs of neuropathy.
Similarly, family histories will usually be negative in
recessive disorders. In some circumstances, genetic
testing is necessary to determine the genetic cause
of the neuropathy and to predict at-risk family
members.
Genetic testing has therefore become an important
tool in the diagnosis of CMT. Characteristics
of the neuropathy are a critical factor for determin-
ing if a genetic test is needed. We believe that a
reasonable approach is to order testing when
NCVs are slow and when other members of the
family have not been tested. Once one family
member with CMT1 has been genotyped, it is
usually not necessary to test other family members
but they should be screened by clinical examination
and nerve conduction studies. However, as genetic
causes of axonal forms of inherited neuropathy
are identified, and because mutations in myelin
genes may have relatively normal NCVs, it is
likely that the frequency of genetic testing of patients
with inherited neuropathies will increase in the
future.
MANAGEMENT
There are no specific cures for inherited neuropa-
thies. Most patients will require some form
of physical or occupational therapy. Orthotics or
ankle bracing is the cornerstone of foot care and if
done well can help patients ambulate independently
CHARCOT–MARIE–TOOTH DISEASE 685
throughout their lives. Difficulties with fine move-
ments of the fingers are also frequent in patients
with CMT. In these cases, occupational therapy
can help with techniques to aid in buttoning,
zippering, and other hand movements requiring
dexterity.
In our experience, genetic counseling is critical in
the management of patients. Many patients are
uninformed about the frequently complicated genet-
ics underlying CMT. Who is at risk in the family and
what options are available to the parents are major
concerns. In addition, the genetic counselor can be
invaluable in the time-consuming task of obtaining
careful pedigrees from patients.
A final point concerns medications and their
effects on CMT patients. In general, medications
that have clear neurotoxic affects, such as vincristine
or cisplatinum, should be avoided in CMT patients
because they are likely to exacerbate the existing
neuropathy. There have been reports of severe,
Guillain–Barré-type weakness in patients with
CMT who were given vincristine. For other
medications, the situation is less clear. The Char-
cot–Marie–Tooth Association publishes a list of
medications that may exacerbate CMT. The degree
of risk varies with the individual medication, and in
some cases the risk may be small compared to the
medical need. Good judgment by the physician
regarding the risk/benefit ratio of a given medication
can probably surmise as a guide for the use of these
medicines.
CONCLUSION
With advances in medical genetics, the clinical
spectrum of inherited neuropathies has been
dramatically expanded and will undoubtedly con-
tinue to expand. There are at least 12 genes known to
cause inherited neuropathies and more than 50
distinct loci have been identified. Genetic testing
for several forms of CMT is now available that,
in addition to providing accurate diagnosis, will
provide genotypic–phenotypic correlations in the
future.
How mutated proteins cause neuropathy is not
established, but information from patients with
inherited neuropathies will permit the delineation
of mechanisms of demyelination, Schwann cell
axonal signaling, and axonal degeneration, which
are all important for understanding the basis of
neurological disease. Moreover, increased under-
standing of the molecular mechanisms underlying
686 CHEMOKINES
these pathways will provide targets for future
therapeutic intervention.
—Jun Li, Richard A. Lewis, and Michael E. Shy
See also–Cerebellar Disorders; Charcot, Jean-
Martin; CIDP (Chronic Inflammatory
Demyelinating Polyradiculoneuropathy);
Demyelinating Disease, Pathology of; Foot Drop;
Gap Junctions; Genetic Testing, Molecular;
Neuropathies, Entrapment; Neuropathies,
Overview
Acknowledgments
This work was supported in part by grants from the MDA and
Charcot–Marie–Tooth Association.
Further Reading
Chance, P. F. (1999). Overview of hereditary neuropathy
with liability to pressure palsies. Ann. N. Y. Acad. Sci. 883,
14–21.
Dyck, P. J., and Lambert, E. H. (1968). Lower motor and
primary sensory neuron diseases with peroneal muscular
atrophy. II. Neurologic, genetic, and electrophysiologic find-
ings in various neuronal degenerations. Arch. Neurol. 18,
619–625.
Hahn, A. F., Ainsworth, P. J., Naus, C. C., et al. (2000). Clinical
and pathological observations in men lacking the gap junction
protein connexin 32. Muscle Nerve 23, S39–S48.
Harding, A. (1993). Inherited neuronal atrophy and degeneration
predominantly of lower motor neurons. In Peripheral Neuro-
pathy (P. J. Dyck, J. Griffin, P. Low, and J. Poduslo, Eds.), pp.
1051–1064. Saunders, Philadelphia.
Kamholz, J., Menichella, D., Jani, A., et al. (2000). Charcot–
Marie–Tooth disease type 1: Molecular pathogenesis to gene
therapy. Brain 123, 222–233.
Krajewski, K. M., Lewis, R. A., Fuerst, D. R., et al. (2000).
Neurological dysfunction and axonal degeneration in Charcot–
Marie–Tooth disease type 1A. Brain 123, 1516–1527.
Lewis, R. A., Sumner, A. J., and Shy, M. E. (2000). Electro-
physiological features of inherited demyelinating neuropathies:
A reappraisal in the era of molecular diagnosis. Muscle Nerve
23, 1472–1487.
Nicholson, G., and Nash, J. (1993). Intermediate nerve conduction
velocities define X-linked Charcot–Marie–Tooth neuropathy
families. Neurology 43, 2558–2564.
Thomas, P. K., Marques, W., Davis, M. B., et al. (1997). The
phenotypic manifestations of chromosome 17p11.2 duplica-
tion. Brain 120, 465–478.
Vance, J. M. (2000). The many faces of Charcot–Marie–Tooth
disease. Arch. Neurol. 57, 638–640.
Warner, L. E., Hilz, M. J., Appel, S. H., et al. (1996). Clinical
phenotypes of different MPZ (P0) mutations may include
Charcot–Marie–Tooth type 1B, Dejerine–Sottas, and congenital
hypomyelination. Neuron 17, 451–460.
Zhao, C., Takita, J., Tanaka, Y., et al. (2001). Charcot–Marie–
Tooth disease type 2A caused by mutation in a microtubule
motor KIF1Bbeta. Cell 105, 587–597.
Chemokines
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MOVEMENT OF LEUKOCYTES from the blood-
stream into sites of tissue injury or infection is a
fundamental defensive response of the host that
provides protection, promotes repair, and is essential
for survival. The past decade has witnessed a
spectacular leap forward in our understanding of
the molecular mechanisms that govern this response
with the discovery of a superfamily of small,
cytokine-like molecules termed chemokines. In sim-
ple terms, chemokines are defined as small (8–15
kDa) proteins that induce chemotaxis, tissue extra-
vasation, and sometimes functional modulation of
different classes of leukocytes during inflammation.
These biological actions result from the binding of
chemokines at the cell surface to seven-transmem-
brane domain G protein-coupled receptors.
In view of their properties, much interest has
focused on the possible involvement of chemokines in
regulating nervous tissue leukocyte migration in
neurological disorders such as multiple sclerosis
(MS). Consequently, it has been determined that cells
intrinsic to the nervous system, including neurons,
macroglia, and microglia, all have the ability to
produce chemokines. Moreover, the surfaces of these
cells are adorned with a variety of different chemo-
kine receptors. Therefore, it is not surprising that
neural cells can also respond to the presence of
chemokines in their milieu. Therefore, although
initially chemokines were found to be involved in
the pathogenesis of many significant neuroinflamma-
tory diseases, recent data attest to the fact that
chemokines are plurifunctional mediators of cellular
communication in the normal nervous system.
THE CHEMOKINE SUPERFAMILY AND
THEIR RECEPTORS
Chemokines are grouped into four distinct subfami-
lies according to the number and spacing of two to
four highly conserved N-terminal cysteines. The
terminology for chemokines and their receptors has
recently been rationalized by a consensus of investi-
gators in the field and a systematic nomenclature has
been adapted (Table 1). Two groups with the largest
number of members are the CXC or alpha subfamily
(well-known members include IL-8/CXCL8, GRO-1/
CXCL1, SDF-1/CXCL12, and IP-10/CXCL10) and

a neuronal voltage-gated calcium channel complex
expressed centrally (most abundantly in the cerebel-
lum) and at the neuromuscular junction cause
episodic ataxia with nystagmus and myasthenic
syndrome. Furthermore, some mutations in CAC-
NA1A cause familial hemiplegic migraine with
associated cerebellar degeneration. A small expan-
sion of glutamine-encoding CAG repeats in CAC-
NA1A causes spinocerebellar ataxia type 6, a
progressive ataxia syndrome of late onset. Mutations
in CACNA1A and CACNB4 (encoding an accessory
subunit) have also been associated with seizure
disorders in human, similar to ataxia and seizures
observed in mouse models with mutations in
orthologous genes. Mutations in ligand (acetylcho-
line)-gated and voltage-gated channels expressed in
cortical neurons have been discovered to cause rare
familial epilepsy syndromes. Mutations in GLRA1
encoding glycine receptor channels at inhibitory
synapses cause hyperekplexia with exaggerated
startle response and hypertonia. Expression studies
have revealed impaired agonist sensitivity or dis-
rupted coupling of agonist binding and channel
activation in mutant channels.
The disease phenotype is determined by the tissue
distribution of gene expression. Mutations in
KCNQ1 encoding a potassium channel important in
the regulation of excitability in cardiac muscle cells
and endolymph homeostasis involving stria vascularis
in the inner ear cause dominant cardiac arrhythmia
with prolonged QT intervals and the recessive
cardioauditory syndrome of Jervell and Lange–
Nielsen, in which affected individuals are deaf and
may die of cardiac arrhythmia triggered by fright or
rage. In Andersen’s syndrome, mutations in KCNJ2
encoding a potassium channel heavily expressed in
skeletal and cardiac muscles cause periodic paralysis
and cardiac arrhythmia. The associated dysmorphic
features suggest a previously unrecognized role for
this channel in embryonic development. Mutations in
genes encoding tissue-specific gap junction proteins
can cause symptoms ranging from deafness to
cataract and peripheral neuropathy.
How mutations in ion channel genes lead to
paroxysmal symptoms and progressive degeneration
is a challenging question. Physiological, biochemical,
structural, and anatomical characterization of the
mutant channels will continue to reveal new func-
tional domains and cellular mechanisms regulating
biogenesis. The identification of disease-causing
mutations in KCNQ4, KCNE3, and others has
helped characterize ion channels with no previously
CHARCOT, JEAN-MARTIN 673
known function and has contributed to a better
understanding of the physiology of skeletal muscle
cells and hair cells. Expression studies have shown
that mutations can lead to ion channel hypoactivity
or hyperactivity causing overlapping clinical symp-
toms. Patients will therefore benefit from agonists or
antagonists depending on the nature of the molecular
defects. Interventions that enhance compensatory
mechanisms are also promising. Understanding the
phenotypic expression of these rare, monogenic
channelopathies may help elucidate similar mechan-
isms in other paroxysmal neurological disorders,
such as migraine, epilepsy, and movement disorders.
—Joanna C. Jen
See also–Acetylcholine; Calcium; Channelo-
pathies, Clinical Manifestations; Gamma
Aminobutyric Acid (GABA); Gap Junctions; Ion
Channels, Overview; Myotonic Disorders
Further Reading
Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov.
Papazian, D. M., Schwarz, T. L., Tempel, B. L., et al. (1987).
Cloning of genomic and complementary DNA from Shaker, a
putative potassium channel gene from Drosophila. Science 237,
749–753.
Ptacek, L. J., George, A. L., Jr., Griggs, R. C., et al. (1991).
Identification of a mutation in the gene causing hyperkalemic
periodic paralysis. Cell 67, 1021–1027.
Charcot, Jean-Martin
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
Jean-Martin Charcot shown in his official portrait by Tofano
in August 1881 when he became professor of clinical diseases
of the nervous system at the Faculté de Médecine, Paris.
IN THE history of neurology, few leaders have had
the scientific and personal impact of Jean-Martin
674 CHARCOT, JEAN-MARTIN
Charcot (1825–1893). Born in Paris in 1825, the son
of a carriage maker, Charcot studied medicine after
wavering between careers in art and science. He
received his medical degree in 1853 and spent part of
his internship at the Salpêtrière Hospital, where he
would return as a faculty member in 1862 and
remain throughout the rest of his career. In 1872, he
received the post of professor of pathological
anatomy, and in 1882 a new chair was specifically
created for him, professor of clinical diseases of the
nervous system, the first neurological professorship
in Europe. He died unexpectedly during a summer
vacation in 1893 in rural France with his students.
He left behind him the first major school of
neurology, a younger generation of international
students devoted to neuroscience, and a framework
for thinking about the nervous system both clinically
and anatomically. This heritage persists in the
practice of contemporary neurology.
CHARCOT’S NEUROLOGICAL WORK
Charcot’s work can be divided into three categories:
general medicine, diseases of the brain and spinal
cord, and hysteria/hypnotism. Curiously, the last is
often remembered more than the other two, although
Charcot’s long-term contributions to general medi-
cine and neurology remain incontestably more
important than his psychiatric work. In regard to
general medicine, he studied rheumatism and gout,
endocarditis, tuberculosis, syphilis, and pneumonia
as well as diseases of the liver and kidneys. These
subjects occupied his early career, and because the
Salpêtrière was largely a nursing home for elderly
destitute women, he was exposed to the gamut of
diseases affecting the geriatric population.
Charcot’s neurological contributions were both
conceptual and specific. He developed the first major
nosology for neurology and offered medicine a
diagnostic method for studying neurological diseases.
He attempted to classify diseases anatomically rather
than phenomenologically, focusing on distinctions
between cortical vs brainstem lesions and myelopa-
thies vs peripheral nerve and muscle lesions.
Although largely expanded today, this method of
disease categorization remains the pillar of neuro-
logical practice.
THE ANATOMOCLINICAL METHOD
To achieve his goals, Charcot developed the French
anatomoclinical method to its fullest expression. In
this two-part discipline, the clinician defined a
condition based on scrupulous examination of large
numbers of patients with the same presumed condi-
tion. From this population study, the archetype or
classic form could be defined and the variants
differentiated. Accurate recording of neurological
signs and documentation of the evolution of diseases
in individual cases formed the foundation of this
purely clinical step, and Charcot developed elaborate
facilities to accomplish this task. He wrote extensive
notes on the patients and used his artistic expertise to
capture their postures and deformities in numerous
sketches and ink drawings. Later, he engaged
professional artists and developed a photographic
studio within the Salpêtrière to provide a rich visual
documentation to his research efforts. He also
founded two journals devoted to photographic
documentation of clinical illness. Ancillary wings in
electrophysiology, neuroophthalmology, and neuro-
psychology complimented the clinical evaluation of
the Salpêtrière patients. The second step of the
anatomoclinical method involved postmortem anat-
omy and detailed correlation of identified lesions
with the previously documented clinical signs with
lesions. A large autopsy anatomy and histology
department developed under Charcot’s surveillance,
and patients’ neurological systems were system-
atically examined after death to link type and
location of lesions with specific clinical signs. This
effort was facilitated by the institutional organiza-
tion of the Salpêtrière because most patients were
destitute and long-term hospital inhabitants who
died without family. The discipline of clinical–
pathological correlation in contemporary neurology
can be directly traced to Charcot’s work.
AMYOTROPHIC LATERAL SCLEROSIS:
CHARCOT’S DISEASE
Of all Charcot’s anatomoclinical contributions, the
most important was his description of amyotrophic
lateral sclerosis (ALS). Known today under several
names, including motor neuron disease and Lou
Gehrig’s disease, historically ALS is termed Charcot’s
disease in recognition of his fundamental contribu-
tions to the delineation of this disorder. The history of
Charcot’s research on ALS crystalizes the technique
and fruition of a systematic application of the
anatomoclinical method. Charcot identified two pri-
mary clinical–pathological correlations of weakness.
The first type was associated with atrophy or wasting
of muscles and spontaneous rippling movements of the

weakened muscles, called fasiculations. When this
syndrome occurred, distinct loss of the nerve cells in
the anterior horn of the spinal cord also occurred. The
second type of weakness was associated with con-
tractures of the joints and spasticity, and in these cases
abnormalities of the lateral nerve fiber columns of the
spinal cord occurred. Finally, when the two types of
weakness occurred in the same patient, at autopsy
Charcot demonstrated the coexistence of anterior
horn cell loss and lateral column degeneration.
As a result of these tenacious studies, Charcot
suggested with conviction that specific clinical signs
predictably occurred when certain spinal cord lesions
were present and predictably did not occur when the
signs were absent. He established for the first time a
medical paradigm for a direct relationship between a
neurological lesion and a patient’s problem. With
ALS, Charcot opened new horizons for the study of
direct relationships between clinical and anatomi-
cally pathological states and presented the revolu-
tionary concept that a precise anatomical diagnosis
could be made before death. His own later descrip-
tion of the importance of the work is not overinflated
(February 28, 1888):
I do not think that elsewhere in medicine, in pulmonary or
cardiac pathology, greater precision can be achieved. The
diagnosis as well as the anatomy and physiology of the
condition ‘‘amyotrophic lateral sclerosis’’ is one of the most
completely understood conditions in the realm of clinical
neurology.
OTHER SCIENTIFIC CONTRIBUTIONS
Charcot’s specific neurological contributions are
many: He differentiated the clinical picture of multi-
ple sclerosis from Parkinson’s disease, two conditions
predominated by tremor and heretofore confused; he
differentiated epilepsy from pseudoepilepsy; he
graphically described the trophic changes that occur
in spinal and cerebral diseases; he extensively studied
and defined the lesions of numerous spinal cord and
cortical/subcortical syndromes; and with his stu-
dents, he studied tic disorders (Gilles de la Tourette
syndrome), hereditary neuropathies, miliary aneur-
ysms and cerebral hemorrhage, aphasia, and tabetic
syndromes.
Beginning in the early 1870s, Charcot added
hysteria to his research focus and made several
pivotal contributions to the understanding of this
neuropsychiatric condition. Charcot was impressed
that many patients without anatomical lesions none-
theless shared some neurological signs with subjects
having established brain or spinal cord damage. He
CHARCOT, JEAN-MARTIN 675
studied these hysterics as working models of emo-
tionally based physiological alterations of the same
nervous system areas affected by anatomically
defined lesions. In his work, he strove to consider
hysteria as a neurological condition worthy of
scientific research and established that the disease is
one shared by both men and women, although
perhaps with different specific presentations. His
work in hysteria was more controversial than his
work with anatomically confirmed neurological
syndromes, and his studies of hysteria and hypnotism
especially brought him international attention and,
in some cases, severe scientific criticism.
CHARCOT AS TEACHER
Charcot’s legacy further remains with modern
neurology in the form of clinical teaching that
typifies the discipline. At the Salpêtrière, Charcot
developed clinical teaching to its apogee and brought
to it a new scientific respect. Although the Salpêtrière
was considered an outlying hospital, far from the
centrally placed medical school and other ‘‘down-
town’’ hospitals, Charcot’s personality and teaching
method gradually attracted a large following of
impassioned students to his courses. The celebrated
Canadian-born physician, William Osler wrote
Half an hour before the lecture the front rows were filled with
enthusiastic students, and by the time the lecture began there
was standing-room only. Without any attempt at display or
effect, interesting cases were brought in, the symptoms
analyzed, the diagnosis made, the anatomical condition
discussed, usually with the aid of blackboard and chalks,
followed in conclusions by a few general comments. It was a
clinical lecture in the true sense of the term. Without volubility,
Charcot possessed in a marked degree that charming lucidity in
the presentation of a subject so characteristic of his country-
men.
CHARCOT, THE MAN
Charcot was a dominant figure, difficult to work
with, highly authoritarian, and intolerant of views
different from his own. He was a friend to such
writers as Victor Hugo and Alphonse Daudet and a
close associate with political figures such as Gam-
betta. He was physician to many of the royal families
and a social, political, and scientific figure of his
time. His talents covered more areas than medicine;
he was an accomplished sketcher and ceramist, and
he understood and read numerous languages. His
marriage to a wealthy widow and his successful
career provided a sumptuous lifestyle with an
exquisite mansion in central Paris and a villa in the
676 CHARCOT–MARIE–TOOTH DISEASE
nearby countryside village of Neuilly. His power,
however, likely alienated many of the people who
survived him, and as a consequence many of the
concrete elements of his heritage have survived
poorly. The Charcot Museum has disappeared and
the Bibliothèque Charcot today houses only a
fraction of the original documents from Charcot’s
time. Largely due to the publishing efforts of
Charcot’s student, Bourveville, most of Charcot’s
most celebrated lectures were published in his
Oeuvres Complètes in several languages and these
texts have been the major source for modern readers
to learn of Charcot’s contributions. Wider availabil-
ity of his other texts and lessons permits students to
appreciate the specific contributions made by Char-
cot and the pivotal role he played in the evolution of
contemporary neurology as it is practiced nearly 100
years after his death.
—Christopher G. Goetz
See also–Amyotrophic Lateral Sclerosis (ALS);
Charcot–Marie–Tooth Disease; Child Neurology,
History of; Gilles de la Tourette, Georges; (see
Index entry Biography for complete list of
biographical entries)
Further Reading
Goetz, C. G. (1987). Charcot the Clinician: The Tuesday Lessons.
Raven Press, New York.
Goetz, C. G., Bonduelle, M., and Gelfand, T. (1995). Constructing
Neurology: Jean-Martin Charcot. Oxford Univ. Press, New
York.
Guillain, G. (1959). J. M. Charcot—His Life and Work (P. Bailey,
Trans.). Hoeber, New York.
Charcot–Marie–Tooth Disease
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHARCOT–MARIE–TOOTH disease (CMT) refers to the
inherited peripheral neuropathies named for the
three investigators who described them in the late
1800s. Because CMT diseases affect approximately 1
in 2500 people, they are among the most common
inherited neurological disorders. The majority of
CMT patients have autosomal dominant inheritance,
although X-linked dominant and autosomal recessive
forms also exist. What appear to be sporadic cases
also occur since even dominantly inherited disorders
may begin as a new mutation in a given patient. The
majority of cases are demyelinating, although up to
one-third appear to be primary axonal or neuronal
disorders. Most patients have a ‘‘typical’’ CMT
phenotype characterized by distal weakness, sensory
loss, foot deformities (pes caus and hammer toes),
and absent reflexes. However, some patients develop
severe disability in infancy (Dejerine–Sottas disease
or congenital hypomyelination), whereas others
develop few if any symptoms of disease. During the
past decade, remarkable progress has been made
toward understanding the genetic causes of many
types of CMT. Recently, advances in cell biology
have provided clues as to how particular mutations
cause disease. In this entry, we review the genetics
and clinical, electrodiagnostic, and molecular fea-
tures of inherited peripheral neuropathies.
CLASSIFICATION
In landmark studies, Dyck and Lambert subdivided
hereditary motor and sensory neuropathies
(HMSNs) into dominantly inherited demyelinating
HMSN I (CMT1) and dominantly inherited axonal
HMSN II (CMT2) forms based on electrophysiolo-
gical and neuropathological criteria. Other types
were then classified as HMSN III–VII, depending on
the inheritance type and accompanying features.
Once specific genetic causes for the CMT were
identified, however, the classification had to be
expanded and modified (Table 1). Here, we classify
CMT as CMT1 if the patient has an autosomal
dominantly inherited demyelinating neuropathy,
CMT2 if the neuropathy is dominantly inherited
and axonal, CMTX if the patient has an X-linked
neuropathy, and CMT4 if the neuropathy is reces-
sive. In addition, cases of CMT1, CMT2, and CMT4
are further subdivided based on differences in genetic
abnormalities or linkage studies. However, the
classification of CMT remains confusing and will
certainly require further modifications as new genetic
forms of the neuropathies are identified.
A particularly confusing classification problem
concerns the disorder known as Dejerine–Sottas
disease (DSD). DSD was classified by Dyck and
Lambert to identify patients with severe disability
beginning in infancy who had an autosomal recessive
inheritance pattern. Subsequently, it has been shown
that many presumed DSD patients have autosomal
dominant mutations caused by mutations in periph-
eral myelin protein 22kD (PMP22), myelin protein
zero (MPZ), and early growth response 2 (EGR2).
Although many nerve conduction velocities (NCVs)
686 CHEMOKINES
these pathways will provide targets for future
therapeutic intervention.
—Jun Li, Richard A. Lewis, and Michael E. Shy
See also–Cerebellar Disorders; Charcot, Jean-
Martin; CIDP (Chronic Inflammatory
Demyelinating Polyradiculoneuropathy);
Demyelinating Disease, Pathology of; Foot Drop;
Gap Junctions; Genetic Testing, Molecular;
Neuropathies, Entrapment; Neuropathies,
Overview
Acknowledgments
This work was supported in part by grants from the MDA and
Charcot–Marie–Tooth Association.
Further Reading
Chance, P. F. (1999). Overview of hereditary neuropathy
with liability to pressure palsies. Ann. N. Y. Acad. Sci. 883,
14–21.
Dyck, P. J., and Lambert, E. H. (1968). Lower motor and
primary sensory neuron diseases with peroneal muscular
atrophy. II. Neurologic, genetic, and electrophysiologic find-
ings in various neuronal degenerations. Arch. Neurol. 18,
619–625.
Hahn, A. F., Ainsworth, P. J., Naus, C. C., et al. (2000). Clinical
and pathological observations in men lacking the gap junction
protein connexin 32. Muscle Nerve 23, S39–S48.
Harding, A. (1993). Inherited neuronal atrophy and degeneration
predominantly of lower motor neurons. In Peripheral Neuro-
pathy (P. J. Dyck, J. Griffin, P. Low, and J. Poduslo, Eds.), pp.
1051–1064. Saunders, Philadelphia.
Kamholz, J., Menichella, D., Jani, A., et al. (2000). Charcot–
Marie–Tooth disease type 1: Molecular pathogenesis to gene
therapy. Brain 123, 222–233.
Krajewski, K. M., Lewis, R. A., Fuerst, D. R., et al. (2000).
Neurological dysfunction and axonal degeneration in Charcot–
Marie–Tooth disease type 1A. Brain 123, 1516–1527.
Lewis, R. A., Sumner, A. J., and Shy, M. E. (2000). Electro-
physiological features of inherited demyelinating neuropathies:
A reappraisal in the era of molecular diagnosis. Muscle Nerve
23, 1472–1487.
Nicholson, G., and Nash, J. (1993). Intermediate nerve conduction
velocities define X-linked Charcot–Marie–Tooth neuropathy
families. Neurology 43, 2558–2564.
Thomas, P. K., Marques, W., Davis, M. B., et al. (1997). The
phenotypic manifestations of chromosome 17p11.2 duplica-
tion. Brain 120, 465–478.
Vance, J. M. (2000). The many faces of Charcot–Marie–Tooth
disease. Arch. Neurol. 57, 638–640.
Warner, L. E., Hilz, M. J., Appel, S. H., et al. (1996). Clinical
phenotypes of different MPZ (P0) mutations may include
Charcot–Marie–Tooth type 1B, Dejerine–Sottas, and congenital
hypomyelination. Neuron 17, 451–460.
Zhao, C., Takita, J., Tanaka, Y., et al. (2001). Charcot–Marie–
Tooth disease type 2A caused by mutation in a microtubule
motor KIF1Bbeta. Cell 105, 587–597.
Chemokines
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE MOVEMENT OF LEUKOCYTES from the blood-
stream into sites of tissue injury or infection is a
fundamental defensive response of the host that
provides protection, promotes repair, and is essential
for survival. The past decade has witnessed a
spectacular leap forward in our understanding of
the molecular mechanisms that govern this response
with the discovery of a superfamily of small,
cytokine-like molecules termed chemokines. In sim-
ple terms, chemokines are defined as small (8–15
kDa) proteins that induce chemotaxis, tissue extra-
vasation, and sometimes functional modulation of
different classes of leukocytes during inflammation.
These biological actions result from the binding of
chemokines at the cell surface to seven-transmem-
brane domain G protein-coupled receptors.
In view of their properties, much interest has
focused on the possible involvement of chemokines in
regulating nervous tissue leukocyte migration in
neurological disorders such as multiple sclerosis
(MS). Consequently, it has been determined that cells
intrinsic to the nervous system, including neurons,
macroglia, and microglia, all have the ability to
produce chemokines. Moreover, the surfaces of these
cells are adorned with a variety of different chemo-
kine receptors. Therefore, it is not surprising that
neural cells can also respond to the presence of
chemokines in their milieu. Therefore, although
initially chemokines were found to be involved in
the pathogenesis of many significant neuroinflamma-
tory diseases, recent data attest to the fact that
chemokines are plurifunctional mediators of cellular
communication in the normal nervous system.
THE CHEMOKINE SUPERFAMILY AND
THEIR RECEPTORS
Chemokines are grouped into four distinct subfami-
lies according to the number and spacing of two to
four highly conserved N-terminal cysteines. The
terminology for chemokines and their receptors has
recently been rationalized by a consensus of investi-
gators in the field and a systematic nomenclature has
been adapted (Table 1). Two groups with the largest
number of members are the CXC or alpha subfamily
(well-known members include IL-8/CXCL8, GRO-1/
CXCL1, SDF-1/CXCL12, and IP-10/CXCL10) and
 CHEMOKINES 687

Table 1 STANDARDIZED NOMENCLATURE FOR COMMON CHEMOKINES AND THEIR RECEPTORSa

Family Standardized name Common name Receptor

CXC CXCL1 GRO-1 CXCR24CXCR1

CXCL8 IL-8 CXCR14CXCR2
CXCL9 Mig CXCR3
CXCL10 IP-10 CXCR3
CXCL12 SDF-1a/b CXCR4

CC CCL2 MCP-1 CCR8

CCL3 MIP-1a CCR1, CCR5
CCL4 MIP-1b CCR5
CCL5 RANTES CCR1, CCR2, CCR5
CCL7 MCP-3 CCR1, CCR2, CCR3
CCL8 MCP-2 CCR3
CCL11 Eotaxin CCR3

C XCL1 Lymphotactin XCR1

CX3C CX3CL1 Fractalkine CX3CR1

a
Adapted from Zlotnik, A., and Yoshie, O. (2000). Chemokines: A new classification system and their role in immunity. Immunity 12,
121–127. Abbreviations used: GRO, growth-regulated oncogene; IL-8, interleukin-8; IP-10, interferon-induced protein 10 kDa; MCP,
monocyte chemotactic protein; Mig, monokine-induced by interferon-g; MIP, macrophage inflammatory protein; RANTES, regulated on
activation normal T cell expressed and secreted; SDF, stromal cell-derived factor.

the CC or beta subfamily (examples include eotaxin/
CCL11, MIP-1a/CCL3 and -1b/CCL4, MCP-1/
CCL2 and -2/CCL8, and RANTES/CCL5). The
remaining CX3C or delta subfamily and the C or
gamma subfamily currently contain only a single
member each, named fractalkine/CXC3L1 and lym-
photactin/XCL1, respectively. The CXC chemokines
are further subdivided into those that contain the
sequence glutamic acid–leucine–arginine (ELR motif)
near their N terminal (e.g., IL-8 and GRO-1) and
those that do not contain this motif (e.g., IP-10 and
SDF-1). In general, within each chemokine subfamily
the individual members show considerable homology
in their amino acid sequence and often possess
overlapping chemoattractant specificity. Thus, CC
chemokines commonly attract monocytes, basophils,
eosinophils, and T lymphocytes but have little or no
effect on neutrophils, whereas the ELR motif CXC
chemokines are effective chemoattractants for neu-
trophils but not monocytes. In contrast, non-ELR
CXC chemokines are poor chemoattractants for
neutrophils but attract lymphocytes and monocytes.
The G protein-coupled cell surface receptors that
mediate the effects of chemokines are named
according to their chemokine subfamily classifica-
tion. Currently, there are five CXC receptors,
CXCR1–CXCR5, and 10 CC receptors, CCR1–
CCR10. Receptors CX3CR1 and XCR1 bind frac-
talkine and lymphotactin, respectively. A remarkable
feature of many chemokine receptors is their
promiscuity, with individual chemokine receptors
often having the ability to bind several different
chemokines. For example, CCR1 binds RANTES,
MIP-1a, MCP-2, and MCP-3, but RANTES also
binds to CCR3 and CCR5. The promiscuity of the
chemokine receptor/ligand interactions explains the
often broadly overlapping actions of many chemo-
kines. However, not all chemokine receptors exhibit
promiscuity for ligand binding; for example, the only
known ligand for the CXCR4 receptor is SDF-1. In
such cases, chemokine/chemokine receptor interac-
tions result in very specific actions that are invariably
nonredundant. This is well illustrated in the case of
SDF-1, whose interaction with CXCR4 is obligatory
for the normal development of many organ systems
including the brain.
CHEMOKINES AND THEIR RECEPTORS
EXPRESSED IN THE NERVOUS SYSTEM
UNDER NORMAL CONDITIONS
In the nervous system, as in the periphery, the
chemokine gene superfamily can generally be divided
into two groups based on their functional expres-
688 CHEMOKINES
sion—the constitutive and the inducible chemokines.
Currently, two chemokines, SDF-1 and fractalkine,
are known to be constitutively produced in the
central nervous system (CNS), and SDF-1 is also
found in the peripheral nervous system. SDF-1 is
present predominantly in astrocytes and neurons in
the brain and in Schwann cells in the periphery. The
receptor for SDF-1, CXCR4, is widely distributed in
the normal brain, being found on astrocytes, micro-
glia, and neurons. SDF-1 is highly conserved across
species (human and mouse SDF-1 proteins differ only
by one amino acid residue), suggesting it has a vital
function. Studies in mutant mice generated with
deletions of the genes encoding SDF-1 or its receptor
confirm this view. Thus, these animals die soon after
birth with major defects in their vascular, hemato-
poietic, and nervous systems. In the nervous system,
development of the cerebellum is severely compro-
mised due to the aberrant migration of the granule
neurons. The precise mechanism involved in this
process is not known, although these studies clearly
establish that the SDF-1/CXCR4 receptor/ligand
system is essential for normal neuronal cell migration
and patterning during development.
Similar to SDF-1, fractalkine is found at high levels
in the rat, mouse, and primate brain, where it is
localized in neurons but not in astrocytes or
microglia. What could be the function of fractalkine
in the nervous system? Fractalkine is unique among
the chemokines and is tethered to the membrane by a
mucin stalk, which is well suited for communication
with adjacent cells expressing the fractalkine recep-
tor CX3CR1. The major candidate for such an
interaction is the microglial cell, which displays high
levels of CX3CR1 and in vitro responds to treatment
with fractalkine by increasing intracellular calcium
levels. A further possibility is that fractalkine
influences neuronal function and survival. Despite
suggestions that fractalkine mediates essential signal-
ing between neurons and from neurons to microglia
following injury, mice deficient for CX3CR1 (and
therefore lacking responsiveness to fractalkine) have
normal neuronal–glial responses to nerve injury. The
apparent absence of other nervous system defects in
the CX3CR1-deficient mouse also suggests that
fractalkine, unlike SDF-1, is dispensable for normal
CNS development and neuronal survival. Thus, the
function of fractalkine awaits clarification.
In addition to CXCR4 and CX3CR1, neurons also
posses an array of other chemokine receptors (Table
2) that are coupled to G-protein-activated signaling
pathways. In cultured neuronal preparations, bind-
ing of the cognate ligand to these receptors results in
increased intracellular Ca2 þ levels. The properties of
chemokine/chemokine receptor interaction and the
signaling pathways they activate are, in many
respects, analogous to those of classic neurotrans-
mitters such as angiotensin. In turn, the consequence
of chemokine actions, like that of neurotransmitters,
is the modulation of neuronal functional activity.
CHEMOKINES IN THE NERVOUS SYSTEM
DURING PATHOLOGICAL STATES
By far the greatest number of chemokines in the
nervous system fall into the category of the inducible
group, whose production is activated during disease
states (Table 2). The levels of the constitutively
expressed chemokines SDF-1 and fractalkine can
also be significantly upregulated in certain patholo-
gical states. Leukocyte infiltration of the CNS is a
central feature in the pathogenesis of diverse
inflammatory neurological disorders, which range
from bacterial and viral meningoencephalitis to
multiple sclerosis, human immunodeficiency virus
(HIV) encephalitis, cerebral malaria, and cerebral
ischemia. In view of their function as leukocyte
chemoattractants, the chemokines may play a defin-
ing role in controlling CNS leukocyte migration in
these different neuroinflammatory disease states.
Consistent with this, there is coordinate induction
in the CNS of a number of chemokine genes
belonging to the alpha, beta, delta, and gamma
subfamilies (Table 1). Many chemokines (e.g., IP-10,
MIP-1a, and MCP-1) are produced by cells that are
intrinsic to the brain, such as astrocytes and
microglia. Early localized production of chemokines
often follows an insult, such as a viral infection,
providing a means by which communication can be
made with the periphery for the recruitment of
leukocytes. As proof of concept here, CNS-targeted
expression of chemokines in transgenic mice or using
viral vectors is sufficient to promote the migration of
specific leukocytes into the brain.
Specific differences in the chemokine gene expres-
sion patterns occur in different neuroinflammatory
diseases and likely dictate the phenotype of the
infiltrating leukocytes. In experimental and clinical
bacterial meningoencephalitis, neutrophils and
monocytes are the major cell types in the brain and
there is dominant cerebral production of the neu-
trophil and monocyte attractant chemokines such as
IL-8 and MCP-1. In contrast, in viral meningoence-
phalitis, where lymphocytes and monocytes are
 CHEMOKINES 689

Table 2 CHEMOKINE AND CHEMOKINE RECEPTOR EXPRESSION BY CELLS OF THE NERVOUS SYSTEM AND IN
DIFFERENT DISEASESa

Chemokine Chemokine receptor

Cell type CXC CC CX3C CXCR CCR CX3CR Disease expression

Astrocyte IL-8 MIP-1a F’kine CXCR2 CCR1 AD

IP-10 RANTES CXCR4 CCR5 MS
SDF-1 MCP-1 HIV dementia
GRO-1 Stroke
Astrocytoma
Bacteria meningitis
Viral meningitis

Microglia IP-10 MIP-1a CXCR4 CCR3 CX3CR1 AD

SDF-1 MCP-1 CCR5 MS
MCP-3 HIV dementia
Stroke
Astrocytoma
Bacteria meningitis
Viral meningitis

Neuron F’kine CXCR2 CCR1 CX3CR1 AD

CXCR4 CCR5 HIV dementia

Oligodendrocyte ? ? ? CXCR2? ? ?
?
Schwann cell SDF-1 MCP-1
RANTES ? ? ? GBS
a
Abbreviations used: AD, Alzheimer’s disease; F’kine, fractalkine; GBS, Guillain–Barre syndrome; HIV, human immunodeficiency virus;
MS, multiple sclerosis.

abundant in the brain, dominant production occurs
for the lymphocyte and monocyte chemoattractants
IP-10, MCP-1, and RANTES. More ‘‘fine tuning’’ of
leukocyte trafficking is evident in MS, which is
thought to be a type 1 T cell-dependent chronic
inflammatory disease. The chemokines Mig, IP-10,
RANTES, MCP-1, and MIP-1a are typically induced
in the cerebrospinal fluid and active plaque lesions of
MS patients. Type 1 T cells, which characteristically
display a preponderance of the CXCR3 (the receptor
for Mig and IP-10) and CCR5 (the receptor for
RANTES and MIP-1a) chemokine receptors on their
surface, are significantly enriched in these same
locations in the MS patient group. Such concordance
implies a causative role for specific chemokine/
chemokine receptor interactions in MS and points
to a potential new molecular target for therapeutic
intervention.
The case of HIV dementia or ‘‘neuroAIDS’’
provides the most clear-cut illustration of the multi-
functional and potent influence of chemokines and
their receptors in the CNS. The cause of neuroAIDS
is not clear, although it is known that macrophage/
microglia and not neurons are the predominant CNS
reservoir for the virus and that the demise of neurons
in this disorder is due to indirect mechanisms
probably involving host and viral factors. Evidence
indicates that chemokines and their receptors are
involved at various levels in the pathogenesis of
neuroAIDS. First, together with the leukocyte
marker CD4, chemokine receptors serve as key
cofactors for the entry of HIV-1 into host cells, with
the major receptors being CCR5, CCR3, and
CXCR4. Microglial expression of both CCR3 and
CCR5 promotes efficient infection of these cells with
HIV-1, providing a conduit for HIV-1 infection of the
CNS. Second, cerebral expression of various chemo-
kines is increased in neuroAIDS. This not only may
promote the recruitment of monocytes and lympho-
cytes that contribute to HIV encephalitis but also
690 CHEMOKINES

may modulate HIV entry and spread in the brain via

competition with the virus for binding to target
receptors. Finally, chemokines and/or their receptors
can modulate neuronal apoptosis, which is a key cell
death pathway in neuroAIDS. For example, binding
of HIV gp120 to the SDF-1 receptor CXCR4 on
neurons activates apoptotic cell death in these cells.
SDF-1, which shows elevated levels in the HIV-
infected brain, is also capable of causing neuronal
apoptosis in vitro. On the other hand, fractalkine,
MIP-1a, and RANTES protect cultured neurons from
HIV gp120-mediated apoptosis. Therefore, thera-
peutic strategies employing pharmacological chemo-
kine antagonists to inhibit HIV gp120 binding to the
chemokine coreceptors might prove to be effective in
reducing apoptotic neuronal death in neuroAIDS as
well as suppressing HIV-1 infection in the brain.
Given their pleiotropism, it is not surprising that
chemokine involvement appears likely in neurologi-
cal disorders other than the classic immunoinflam-
matory and infectious diseases noted previously. For
example, in Alzheimer’s disease, it has been specu-
lated that trophic signaling via increased neuronal
CXCR2 receptor expression might contribute in part
to an abnormal neuronal sprouting response. Inter- Figure 1
estingly, the production of IL-8 (a chemokine with Chemokine actions in different neurological disease states. Binding
neurotrophic actions that binds to CXCR2) from of chemokines to membrane-integrated heptahelical chemokine
human glial cells is stimulated by the amyloid b receptors activates G-protein-coupled signal transduction
peptide. However, it remains to be determined if pathways that modulate cellular responses such as leukocyte
chemotaxis. HIV-1 gains entry to target microglial cells via
expression of IL-8 is increased in the Alzheimer’s chemokine coreceptors. This event can also activate the chemokine
brain. Trophic signaling is also mediated by another signal transduction pathway, which in turn might contribute to
chemokine, GRO-1, which amplifies platelet-derived neurotoxicity in HIV dementia. In addition, the cognate
growth factor-induced oligodendrocyte proliferation. chemokine can competitively inhibit binding of HIV gp120 to the
Levels of GRO-1 correlate with oligodendrocyte chemokine receptor and thereby antagonize HIV-1 infection in the
brain.
precursor proliferative activity in the injured mouse
spinal cord, implicating this chemokine in oligoden-
drocyte regeneration.
actions may arise from the inappropriate extension
of a normally physiological function of a particular
CONCLUSION chemokine. Alternatively, the actions of the chemo-
kines may be beneficial, promoting repair and
Although the study of chemokines in neurology is in
regeneration. Determining the precise role of che-
its infancy, findings to date indicate that these
mokines in perturbed neurological states is clearly a
molecules and their receptors are truly plurifunc-
high priority for future research efforts. The payoff is
tional with the potential for considerable impact on
that not only will we have a greater understanding of
the normal as well as the diseased nervous system.
the basic pathogenetic mechanisms underlying these
The involvement of the chemokines and their
states but also new molecular targets will be
receptors in neurological disease goes well beyond
identified for therapeutic intervention.
leukocyte chemoattraction in more classic neuroim-
—Iain L. Campbell
munological disorders such as MS and includes novel
actions that might contribute to the pathogenesis of
neuroAIDS and nonimmune disorders such as See also–Hematolymphopoietic Growth Factors;
Alzheimer’s disease (Fig. 1). These pathogenetic HIV Infection, Neurological Complications of;

Immune System, Overview; Multiple Sclerosis,
Basic Biology; Neuroimmunology, Overview
Further Reading
Asensio, V. C., and Campbell, I. L. (1999). Chemokines and their
receptors in the CNS: Plurifunctional mediators in diverse
states. Trends Neurosci. 22, 504.
Glabinski, A. R., and Ransohoff, R. M. (1999). Chemokines and
chemokine receptors in CNS pathology. J. Neurovirol. 5, 3.
Luster, A. D. (1998). Chemokines—Chemotactic cytokines that
mediate inflammation. N. Engl. J. Med. 338, 436.
Miller, R. J., and Meucci, O. (1999). AIDS and the brain: Is there a
chemokine connection? Trends Neurosci. 22, 471.
Xia, M. Q., and Hyman, B. T. (1999). Chemokines/chemokine
receptors in the central nervous system and Alzheimer’s disease.
J. Neurovirol. 5, 32.
Chemonucleolysis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CONCEPT of treating the abnormal portion of the
disk (i.e., the nucleus pulposus), without resorting to
an open operation has intrigued surgeons since the
modern surgical era began. Chemonucleolysis is one
such form of intradiskal therapy. The experimental
and clinical data leading to the discovery and clinical
use of chymopapain for chemonucleolysis are well
summarized in Macnab and McCulloch’s book
Sciatica and Chymopapain. Thomas first described
the effect of papain on hyaline cartilage in rabbit
ears, and Hirsh was among the first to discuss the use
of proteolytic enzymes for the treatment of lumbar
disk disease.
In 1964, Lyman Smith reported a series of patients
treated with an enzyme called chymopapain. The
enzyme seemed to decompress or stabilize the
nucleus pulposus of a damaged disk sufficiently to
relieve back pain and sciatic nerve symptoms in a
significant number of patients. Smith named the
process diskolysis or chemonucleolysis.
The procedure is based on the anatomy of the disk
and the chemical components of the nucleus pulpo-
sus. The disk is situated between the vertebral bodies
of the spine. The outer portion or annulus is
composed of interlacing bands of elastic fibrous
material. The annulus anchors the disk to the
surrounding bony structures holding them in posi-
tion. It also forms a rind around the softer inner
material called the nucleus pulposus (Fig. 1). The
nucleus pulposus is a partially compressible fibrous
CHEMONUCLEOLYSIS 691
Figure 1
Normal lumbar disk (reproduced with permission from the
Barrow Neurological Institute).
material formed of a lattice of collagen fibrils
interlaced in a mucopolysaccharide protein gel.
Injecting an appropriate enzyme into the nucleus
hydrolyzes the proteoglycan but leaves the collagen
fibers intact. After the mucopolysaccharide complex
has been disrupted, the water-binding capacity of the
disk is impaired. The disk structure then becomes
dehydrated and collapses. The reduction in the
bulk of the nucleus pulposus decompresses the
affected nerve in the spinal canal. Chymopapain
is selective for the nucleus pulposus, including
extruded or sequestered fragments. Its effect is dose
dependent.
After Smith’s initial publication, thousands of disk
spaces of patients in the United States, Canada, and
Europe were injected with chymopapain. In 1955,
unfavorable outcomes from a double-blind prospec-
tive study caused the U.S. Food and Drug Adminis-
tration to withdraw its approval of chymopapain for
use in humans. Experimental clinical work contin-
ued, and chymopapain again was released for clinical
use in the early 1980s. Because chymopapain was
easy to use and early clinical results were favorable,
spine surgeons and patients with back pain accepted
the treatment enthusiastically. Thousands of disk
spaces were again injected. However, side effects,
especially postinjection muscle spasms and the drug’s
allergenic potential, led to a loss of enthusiasm for its
use. Still, many physicians continue to use it
successfully. If patients are selected carefully and a
low dosage of chymopapain is administered, the side
effects, especially muscle spasm, can be minimized
and favorable outcomes maintained. Recent clinical
studies report that 75–85% patients are better 1 year
after treatment with chymopapain. The ideal patient
for the procedure has a contained disk (i.e., no
nuclear material has extruded beyond the annulus;

Immune System, Overview; Multiple Sclerosis,
Basic Biology; Neuroimmunology, Overview
Further Reading
Asensio, V. C., and Campbell, I. L. (1999). Chemokines and their
receptors in the CNS: Plurifunctional mediators in diverse
states. Trends Neurosci. 22, 504.
Glabinski, A. R., and Ransohoff, R. M. (1999). Chemokines and
chemokine receptors in CNS pathology. J. Neurovirol. 5, 3.
Luster, A. D. (1998). Chemokines—Chemotactic cytokines that
mediate inflammation. N. Engl. J. Med. 338, 436.
Miller, R. J., and Meucci, O. (1999). AIDS and the brain: Is there a
chemokine connection? Trends Neurosci. 22, 471.
Xia, M. Q., and Hyman, B. T. (1999). Chemokines/chemokine
receptors in the central nervous system and Alzheimer’s disease.
J. Neurovirol. 5, 32.
Chemonucleolysis
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THE CONCEPT of treating the abnormal portion of the
disk (i.e., the nucleus pulposus), without resorting to
an open operation has intrigued surgeons since the
modern surgical era began. Chemonucleolysis is one
such form of intradiskal therapy. The experimental
and clinical data leading to the discovery and clinical
use of chymopapain for chemonucleolysis are well
summarized in Macnab and McCulloch’s book
Sciatica and Chymopapain. Thomas first described
the effect of papain on hyaline cartilage in rabbit
ears, and Hirsh was among the first to discuss the use
of proteolytic enzymes for the treatment of lumbar
disk disease.
In 1964, Lyman Smith reported a series of patients
treated with an enzyme called chymopapain. The
enzyme seemed to decompress or stabilize the
nucleus pulposus of a damaged disk sufficiently to
relieve back pain and sciatic nerve symptoms in a
significant number of patients. Smith named the
process diskolysis or chemonucleolysis.
The procedure is based on the anatomy of the disk
and the chemical components of the nucleus pulpo-
sus. The disk is situated between the vertebral bodies
of the spine. The outer portion or annulus is
composed of interlacing bands of elastic fibrous
material. The annulus anchors the disk to the
surrounding bony structures holding them in posi-
tion. It also forms a rind around the softer inner
material called the nucleus pulposus (Fig. 1). The
nucleus pulposus is a partially compressible fibrous
CHEMONUCLEOLYSIS 691
Figure 1
Normal lumbar disk (reproduced with permission from the
Barrow Neurological Institute).
material formed of a lattice of collagen fibrils
interlaced in a mucopolysaccharide protein gel.
Injecting an appropriate enzyme into the nucleus
hydrolyzes the proteoglycan but leaves the collagen
fibers intact. After the mucopolysaccharide complex
has been disrupted, the water-binding capacity of the
disk is impaired. The disk structure then becomes
dehydrated and collapses. The reduction in the
bulk of the nucleus pulposus decompresses the
affected nerve in the spinal canal. Chymopapain
is selective for the nucleus pulposus, including
extruded or sequestered fragments. Its effect is dose
dependent.
After Smith’s initial publication, thousands of disk
spaces of patients in the United States, Canada, and
Europe were injected with chymopapain. In 1955,
unfavorable outcomes from a double-blind prospec-
tive study caused the U.S. Food and Drug Adminis-
tration to withdraw its approval of chymopapain for
use in humans. Experimental clinical work contin-
ued, and chymopapain again was released for clinical
use in the early 1980s. Because chymopapain was
easy to use and early clinical results were favorable,
spine surgeons and patients with back pain accepted
the treatment enthusiastically. Thousands of disk
spaces were again injected. However, side effects,
especially postinjection muscle spasms and the drug’s
allergenic potential, led to a loss of enthusiasm for its
use. Still, many physicians continue to use it
successfully. If patients are selected carefully and a
low dosage of chymopapain is administered, the side
effects, especially muscle spasm, can be minimized
and favorable outcomes maintained. Recent clinical
studies report that 75–85% patients are better 1 year
after treatment with chymopapain. The ideal patient
for the procedure has a contained disk (i.e., no
nuclear material has extruded beyond the annulus;
692 CHIARI MALFORMATIONS
Figure 2
Contained disk with nuclear material still within striated or torn
annular fibers (reproduced with permission from the Barrow
Neurological Institute).
Fig. 2), minimal preexisting degenerative changes,
and more pain in the sciatic distribution than back
pain.
Lower dosages of chymopapain and other enzymes
with less allergenic potential show promise for
continued use of this methodology in selected
patients.
—Timothy R. Harrington
See also–Diskectomy; Intervertebral Disk; Sciatic
Nerve; Spinal Cord Anatomy
Further Reading
Brown, M. D. (1996). Update on chemonucleolysis. Spine 21,
62S–68S.
Hirsch, C. (1959). Studies on the pathology of low back pain. J.
Bone Jt. Surg. Br. 41, 237–243.
Javid, M. J., and Nordby, E. J. (1996). Lumbar chymopapain
nucleolysis. Neurosurg. Clin. North Am. 7, 17–27.
Kubo, S., Tajima, N., Katunuma, N., et al. (1999). A comparative
study of chemonucleolysis with recombinant human cathepsin
L and chymopapain. A radiologic, histologic, and immunohis-
tochemical assessment. Spine 24, 120–127.
McCulloch, J. A., and Macnab, I. (1983). Sciatica and Chymopa-
pain. Williams & Wilkins, Baltimore.
Nordby, E. J., and Wright, P. H. (1994). Efficacy of chymopapain
in chemonucleolysis. A review. Spine 19, 2578–2583.
Nordby, E. J., Wright, P. H., and Schofield, S. R. (1993). Safety of
chemonucleolysis. Adverse effects reported in the United States,
1982–1991. Clin. Orthop. 293, 122–134.
Poynton, A. R., O’Farrell, D. A., Mulcahy, D., et al. (1998).
Chymopapain chemonucleolysis: A review of 105 cases. J. R.
Coll. Surg. Edinburgh 43, 407–409.
Schwetschenau, P. R., Ramirez, A., Johnston, J., et al. (1976).
Double-blind evaluation of intradiskal chymopapain for
herniated lumbar disks. Early results. J. Neurosurg. 45,
622–627.
Smith, L. (1964). Enzyme dissolution of the nucleus pulposus in
humans. J. Am. Med. Assoc. 187, 137–140.
Smith, L., Garvin, P. J., Gesler, R. M., et al. (1963). Enzyme
dissolution of the nucleus pulposus. Nature 198, 1311–1312.
Stern, I. J., and Smith, L. (1967). Dissolution by chymopapain in
vitro of tissue from normal or prolapsed intervertebral disks.
Clin. Orthop. 50, 269–277.
Thomas, L. (1956). Reversible collapse of rabbit ears after
intravenous papain and prevention by cortisone. J. Csp. Med.
104, 245.
van de Belt, H., Franssen, S., and Deutman, R. (1999). Repeat
chemonucleolysis is safe and effective. Clin. Orthop. 363,
121–125.
Chiari Malformations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN 1891, Hans Chiari, professor of pathological
anatomy at the German University in Prague,
described an anomaly characterized by elongated
‘‘peg-like’’ cerebellar tonsils that projected into the
cervical spinal canal. He described a second type of
hindbrain anomaly in which the vermis, pons, fourth
ventricle, and medulla were displaced inferiorly into
the cervical canal to the level of the fifth cervical
vertebra. Furthermore, he described the presence of a
‘‘cerebellar–cervical hydroencephalocele.’’ When
combined with multiple cerebellar and brainstem
anomalies, this latter condition has been termed the
Chiari type III malformation. Chiari related the
herniation of the contents of the posterior fossa to
excessive intracranial pressure (ICP) from hydroce-
phalus.
Although the initial description of the pathology
originally derived from Chiari, his name became
secondarily associated with the syndrome in con-
temporary terminology. In 1907, Schwalbe and
Gredig attached Arnold’s name to the condition
apparently because their work was done in the
laboratory of the German pathologist Julius Arnold.
Chiari’s most important contribution was the char-
acterization of the different types of this disease
according to the degree of inferior displacement of
the involved structures.
TYPES OF CHIARI MALFORMATIONS
Type I malformations are characterized by cerebellar
tonsils below the foramen magnum. The embryogen-
esis of the Chiari type I malformation is thought to
be related to maldevelopment of the posterior fossa
692 CHIARI MALFORMATIONS
Figure 2
Contained disk with nuclear material still within striated or torn
annular fibers (reproduced with permission from the Barrow
Neurological Institute).
Fig. 2), minimal preexisting degenerative changes,
and more pain in the sciatic distribution than back
pain.
Lower dosages of chymopapain and other enzymes
with less allergenic potential show promise for
continued use of this methodology in selected
patients.
—Timothy R. Harrington
See also–Diskectomy; Intervertebral Disk; Sciatic
Nerve; Spinal Cord Anatomy
Further Reading
Brown, M. D. (1996). Update on chemonucleolysis. Spine 21,
62S–68S.
Hirsch, C. (1959). Studies on the pathology of low back pain. J.
Bone Jt. Surg. Br. 41, 237–243.
Javid, M. J., and Nordby, E. J. (1996). Lumbar chymopapain
nucleolysis. Neurosurg. Clin. North Am. 7, 17–27.
Kubo, S., Tajima, N., Katunuma, N., et al. (1999). A comparative
study of chemonucleolysis with recombinant human cathepsin
L and chymopapain. A radiologic, histologic, and immunohis-
tochemical assessment. Spine 24, 120–127.
McCulloch, J. A., and Macnab, I. (1983). Sciatica and Chymopa-
pain. Williams & Wilkins, Baltimore.
Nordby, E. J., and Wright, P. H. (1994). Efficacy of chymopapain
in chemonucleolysis. A review. Spine 19, 2578–2583.
Nordby, E. J., Wright, P. H., and Schofield, S. R. (1993). Safety of
chemonucleolysis. Adverse effects reported in the United States,
1982–1991. Clin. Orthop. 293, 122–134.
Poynton, A. R., O’Farrell, D. A., Mulcahy, D., et al. (1998).
Chymopapain chemonucleolysis: A review of 105 cases. J. R.
Coll. Surg. Edinburgh 43, 407–409.
Schwetschenau, P. R., Ramirez, A., Johnston, J., et al. (1976).
Double-blind evaluation of intradiskal chymopapain for
herniated lumbar disks. Early results. J. Neurosurg. 45,
622–627.
Smith, L. (1964). Enzyme dissolution of the nucleus pulposus in
humans. J. Am. Med. Assoc. 187, 137–140.
Smith, L., Garvin, P. J., Gesler, R. M., et al. (1963). Enzyme
dissolution of the nucleus pulposus. Nature 198, 1311–1312.
Stern, I. J., and Smith, L. (1967). Dissolution by chymopapain in
vitro of tissue from normal or prolapsed intervertebral disks.
Clin. Orthop. 50, 269–277.
Thomas, L. (1956). Reversible collapse of rabbit ears after
intravenous papain and prevention by cortisone. J. Csp. Med.
104, 245.
van de Belt, H., Franssen, S., and Deutman, R. (1999). Repeat
chemonucleolysis is safe and effective. Clin. Orthop. 363,
121–125.
Chiari Malformations
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN 1891, Hans Chiari, professor of pathological
anatomy at the German University in Prague,
described an anomaly characterized by elongated
‘‘peg-like’’ cerebellar tonsils that projected into the
cervical spinal canal. He described a second type of
hindbrain anomaly in which the vermis, pons, fourth
ventricle, and medulla were displaced inferiorly into
the cervical canal to the level of the fifth cervical
vertebra. Furthermore, he described the presence of a
‘‘cerebellar–cervical hydroencephalocele.’’ When
combined with multiple cerebellar and brainstem
anomalies, this latter condition has been termed the
Chiari type III malformation. Chiari related the
herniation of the contents of the posterior fossa to
excessive intracranial pressure (ICP) from hydroce-
phalus.
Although the initial description of the pathology
originally derived from Chiari, his name became
secondarily associated with the syndrome in con-
temporary terminology. In 1907, Schwalbe and
Gredig attached Arnold’s name to the condition
apparently because their work was done in the
laboratory of the German pathologist Julius Arnold.
Chiari’s most important contribution was the char-
acterization of the different types of this disease
according to the degree of inferior displacement of
the involved structures.
TYPES OF CHIARI MALFORMATIONS
Type I malformations are characterized by cerebellar
tonsils below the foramen magnum. The embryogen-
esis of the Chiari type I malformation is thought to
be related to maldevelopment of the posterior fossa

structures, producing a small posterior fossa and
creating a downward pressure gradient. These
paraxial mesoderm malformations are part of a
disorder that produces basilar invagination and
platybasia, also present in some patients with a
Chiari type I malformation.
Type II malformations are found in almost all
patients (90%) with myelomeningocele. Likewise,
many infants with Chiari type II malformations have
myelomeningoceles. The vermis, fourth ventricle,
and lower brainstem are below the level of the
foramen magnum (Fig. 1). This abnormally low
configuration of the brainstem carries along the
lower cranial nerves, which are compressed,
stretched, and oriented more horizontally than
normal.
Type III malformations are characterized by caudal
displacement of the cerebellum and brainstem into a
high cervical meningocele. This anomaly is usually
incompatible with life and, fortunately, is extremely
rare.
Type IV malformations were not described by
Chiari, but some authors classify this condition
within the rubric of Chiari malformations. It is
Figure 1
Sagittal section of a typical Chiari II malformation (reproduced
with permission from the Barrow Neurological Institute).
CHIARI MALFORMATIONS 693
characterized by severe cerebellar hypoplasia or
cerebellar agenesis but is not a hindbrain herniation.
Usually, these patients have poor functional ability.
ORIGIN OF CHIARI MALFORMATIONS
There are three major theories on the origin of Chiari
malformations. The Gardner theory, also known as
the hydrodynamic theory, proposes a persistent
communication between the central canal and the
fourth ventricle through the obex. Pathologically
occluded or partially occluded lateral and medial
fourth ventricle foramina (Luschka and Magendie,
respectively) cause cerebrospinal fluid (CSF) to flow
abnormally. The persistence of communication be-
tween the fourth ventricle and the central canal, in
concert with CSF pressure pulsation, creates a water
hammer effect that causes progressive dilatation
(syrinx) of the ependymal canal. A major problem
with this theory, however, is the difficulty in locating
a consistent communication between the syrinx and
the fourth ventricle.
Chiari type I malformations and syringomyelia are
associated in approximately 60% of cases. The most
widely accepted theory regarding the growth of the
cyst (syrinx) is that the reduced subarachnoid space
associated with the small posterior fossa causes a
pressure gradient with a vector toward the spine that
enlarges the cyst. Whatever mechanism produces a
cyst inside the spinal cord, tonsillar herniation seems
to play an important role in the pathogenesis of the
syringomyelia.
During a Valsalva maneuver in the normal condi-
tion, the epidural veins engorge. Intraspinal pressure
increases and the pressure gradient favors the skull,
both of which increase ICP. When the Valsalva
maneuver ends, the opposite phenomenon creates a
pressure gradient toward the spine. Adhesions at the
foramen magnum or mechanical obstruction to
normal CSF flow alters the pressure gradient in
association with an altered duration of increased ICP.
Williams’ theory proposes that the equilibration of
pressures may be delayed. The resulting increased
period of increased pressure forces the cerebellar
tonsils progressively downward.
McLone’s theory is a unified theory of the
pathophysiology underlying Chiari type II malforma-
tions. It proposes that the etiology stems from a
defect in the closure of the neural tube and a resultant
subsequent CSF leak. During fetal life, the leak causes
the posterior fossa structures to descend progres-
sively. CSF volume inside the lateral ventricles
694 CHIARI MALFORMATIONS
decreases, and the inductive effect caused by brain
development on the bone is compromised. Osaka
reinforced this theory, finding that the defect in the
neural tube closure occurs before the hindbrain
herniation, suggesting that a difference in pressure
contributes to the migration of the contents of the
posterior fossa down below the foramen magnum.
Chiari malformations may be associated with a
close familial link. In one study, 43 of 275 (12%)
patients with a Chiari malformation had at least one
close relative with a Chiari malformation or syr-
ingomyelia.
CLINICAL MANIFESTATIONS
In 275 patients, the most common symptom was
suboccipital or high cervical pain (81%). In children
who cannot yet speak, this symptomatology may be
manifested as irritability or persistent crying. A
Chiari type I patient may be asymptomatic for long
periods. Usually, patients visit a physician for
symptoms related to brainstem compression: head-
ache, neck pain, nystagmus, ataxia, dizziness, oscil-
lopsia, persistent crying, dysphagia, and cranial
nerve palsies. ‘‘Ménière’s syndrome-like’’ symptoms
and spinal cord disturbances are common even in the
absence of a syrinx. Patients with episodic, severe,
and incapacitating headaches after Valsalva maneu-
vers, coughs, or strains should be evaluated. This
headache is usually self-limited, suboccipital, and
explained by the delay in normalizing ICP after a
Valsalva maneuver (William’s theory).
Osseous anomalies are found in one-fourth of all
patients with a Chiari type I malformation and
include atlanto-occipital assimilation, platybasia,
basilar invagination, and fused cervical vertebrae
(Klippel-Feil). The skull may be especially thin with
areas described as lacunar spaces (Lückenschädel,
meaning lacunar skull).
In Chiari type II patients, the most common
symptoms are those related to the myelomeningocele
and secondarily those related to the Chiari mal-
formation. Typically, these symptoms resolve, but
one-third of such infants die from compromise of
cranial nerves IX and X between 9 and 12 weeks of
age. Respiratory symptoms are common in Chiari
type II patients. Examination of the vocal cords
shows abductor paralysis with intact adduction.
Episodes of apnea, cyanosis, and bradycardia also
occur, likely from compression of the vagus nerve or
its nucleus. Nystagmus (horizontal, rotatory, or
downbeat) is also common. Downbeat nystagmus is
present in the primary position but accentuated when
the patient gazes downward. It may disappear when
the patient looks upward.
DIAGNOSTIC IMAGING
Sagittal magnetic resonance imaging (MRI) of Chiari
type I malformations reveals the descended position
of the cerebellar tonsils without other brain abnor-
malities. Tonsillar position in relation to the foramen
magnum varies with age because the cerebellar
tonsils normally ascend with age. Tonsillar descent
more than 6 mm during the first decade, 5 mm during
second and third decades, 4 mm during the fourth
through eighth decades, and more than 3 mm during
the ninth decade is two standard deviations above
the normal range and must be considered patholo-
gical.
Axial MRI can be used to classify intramedullary
cysts (syrinxes) according to their location inside the
spinal cord. Anomalies related to hindbrain hernia-
tion are basically of the central type. Eccentric cysts
are more commonly related to tumors, infectious
diseases, and trauma. Paracentral cavities grow
toward the posterolateral quadrant of the spinal
cord and produce segmental neurological signs.
Similar to the inductive effect of the supratentorial
ventricles on brain and bone development, the small
fourth ventricle may likewise inhibit brain formation
and bone in the posterior fossa, leading to a small
posterior fossa. The development of the cerebellum
and brainstem within the small posterior fossa leads
to upward herniation, resulting in a large, usually
heart-shaped, tentorial incisura, and downward
displacement of the vermis and brainstem into the
cervical canal. Failure to maintain the inductive
effect of the CSF-filled ventricles, including the third
ventricle, places the thalami in proximity to each
other, resulting in large massa intermedia.
Approximately 75% of patients with type II
malformations have fused superior and inferior
colliculi, creating the appearance of a ‘‘beak’’ on
sagittal MRI. This beaked mesencephalon is likely
responsible for Parinaud’s syndrome in these pa-
tients. Hydrocephalus is a common finding in
patients with a Chiari II malformation, likely related
to the dilatation of the ventricular system.
Chiari type III malformations are extremely rare,
and few imaging descriptions are available. MRI
demonstrates the presence of posterior fossa struc-
tures inside an occipital encephalocele, with a

displaced medulla oblongata, cerebellum, occipital
lobes, and meninges.
TREATMENT
The availability of MRI has resulted in increased
detection of asymptomatic patients with Chiari
malformations. Thus, the decision to operate or
observe such patients must be based on astute
judgment and experience, including open and forth-
right discussion with the patient and family regard-
ing the benefits and risks of the surgery. Predicting
which patients will deteriorate based on clinical
characteristics and imaging studies is difficult.
The most widely accepted method of treatment is
posterior fossa decompression with duraplasty,
which attempts to increase the size of the foramen
magnum, thus allowing a more open and direct
pathway for CSF flow. The posterior rim of the bony
foramen magnum, including the posterior arch of
C1, is removed. Duraplasty (Fig. 2) is controversial
but is supported by studies of tonsillar movement
using intraoperative ultrasonography.
Early (i.e., fetal surgery) closure of myelomenin-
goceles reverses hindbrain herniation and decreases
the frequency of shunt-dependent hydrocephalus.
Currently, however, evidence is insufficient to con-
firm that fetal surgery is definitively beneficial in the
treatment of hindbrain herniation. Hydrocephalus
associated with increased ICP must be treated by
shunting before the suboccipital decompression is
performed.
—L. Fernando Gonzalez, Mark C. Preul,
Robert F. Spetzler, and Patrick Han
See also–Central Nervous System
Malformations; Cerebellum; Inferior Colliculus;
Nystagmus and Saccadic Intrusions and
Oscillations; Superior Colliculus; Syringomyelia;
Valsalva Maneuver
Further Reading
Batzdorf, U. (1996). Syringomyelia, Chiari malformation and
hydromyelia. In Neurological Surgery (J. R. Youmans, Ed.).
Saunders, Philadelphia.
Brazis, P. W., Masdeu, J. C., and Biller, J. (1996). The localization
of lesions affecting the ocular motor systems. In Localization in
Clinical Neurology (P. W. Brazis, J. C. Masdeu, and J. Biller,
Eds.), pp. 155–250. Little, Brown, Boston.
Bruner, J. P., Tulipan, N., Paschall, R. L., et al. (1999). Fetal
surgery for myelomeningocele and the incidence of shunt-
dependent hydrocephalus. J. Am. Med. Assoc. 282, 1819–1825.
CHICKPEA INTOXICATION 695
Chiari, H. (1987). Concerning alterations in the cerebellum
resulting from cerebral hydrocephalus. Pediatr. Neurosci. 13,
3–8. [Original work published in 1891.]
Gardner, W. J. (1965). Hydrodynamic mechanism of syringomye-
lia: Its relationship to myelocele. J. Neurol. Neurosurg.
Psychiatr. 28, 247–259.
McLone, D. G., and Naidich, T. P. (1992). Developmental
morphology of the subarachnoid space, brain vasculature, and
contiguous structures, and the cause of the Chiari II malforma-
tion. Am. J. Neuroradiol. 13, 463–482.
Mikulis, D. J., Diaz, O., Egglin, T. K., et al. (1992). Variance of the
position of the cerebellar tonsils with age: Preliminary report.
Radiology 183, 725–728.
Milhorat, T. H., Chou, M. W., Trinidad, E. M., et al. (1999).
Chiari I malformation redefined: Clinical and radiographic
findings for 364 symptomatic patients. Neurosurgery 44, 1005–
1017.
Oakes, W. J. (1996). Chiari malformations, hydromyelia, and
syringomyelia. In Neurosurgery (R. H. Wilkins and S. S.
Rengachary, Eds.), pp. 3593–3616. McGraw-Hill, New York.
Oakes, W. J. (1999). Chiari malformations. In Principles and
Practice of Pediatric Neurosurgery (A. Pollack, Ed.). Thieme,
New York.
Osaka, K., Tanimura, T., Hirayama, A., et al. (1978). Myelome-
ningocele before birth. J. Neurosurg. 49, 711–724.
Osborn, A. G. (1994). Disorders of neural tube closure. In
Diagnostic Neuroradiology (A. G. Osborn, Ed.), pp. 15–36.
Mosby/Year Book, St. Louis.
Sutton, L. N., Adzick, N. S., Bilaniuk, L. T., et al. (1999).
Improvement in hindbrain herniation demonstrated by serial
fetal magnetic resonance imaging following fetal surgery for
myelomeningocele. J. Am. Med. Assoc. 282, 1826–1831.
Chickpea Intoxication
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN AREAS in Europe and India, progressive gait
difficulty, usually associated with leg weakness and
spasticity (spastic paraplegia), has developed in
humans and other animals following consumption
of different varieties of the chickpea, Lathyrus. Three
potent neurotoxins, amino-b-oxalylaminopropionic
acid, amino-oxalylaminobutyric acid, and b-N-ox-
alylamino-l-alanine, appear to be involved in the
pathogenesis of human lathyrism. Men are seven
times more likely than women to be affected by
intoxication, possibly as a result of antioxidant
characteristics of female hormones. The onset of
neurotoxic signs can be acute or gradual and
progressive. Low back pain and lower extremity
weakness with stiffness are usually the first effects
and occur after awakening in the morning. A low-
grade fever may accompany these symptoms.

displaced medulla oblongata, cerebellum, occipital
lobes, and meninges.
TREATMENT
The availability of MRI has resulted in increased
detection of asymptomatic patients with Chiari
malformations. Thus, the decision to operate or
observe such patients must be based on astute
judgment and experience, including open and forth-
right discussion with the patient and family regard-
ing the benefits and risks of the surgery. Predicting
which patients will deteriorate based on clinical
characteristics and imaging studies is difficult.
The most widely accepted method of treatment is
posterior fossa decompression with duraplasty,
which attempts to increase the size of the foramen
magnum, thus allowing a more open and direct
pathway for CSF flow. The posterior rim of the bony
foramen magnum, including the posterior arch of
C1, is removed. Duraplasty (Fig. 2) is controversial
but is supported by studies of tonsillar movement
using intraoperative ultrasonography.
Early (i.e., fetal surgery) closure of myelomenin-
goceles reverses hindbrain herniation and decreases
the frequency of shunt-dependent hydrocephalus.
Currently, however, evidence is insufficient to con-
firm that fetal surgery is definitively beneficial in the
treatment of hindbrain herniation. Hydrocephalus
associated with increased ICP must be treated by
shunting before the suboccipital decompression is
performed.
—L. Fernando Gonzalez, Mark C. Preul,
Robert F. Spetzler, and Patrick Han
See also–Central Nervous System
Malformations; Cerebellum; Inferior Colliculus;
Nystagmus and Saccadic Intrusions and
Oscillations; Superior Colliculus; Syringomyelia;
Valsalva Maneuver
Further Reading
Batzdorf, U. (1996). Syringomyelia, Chiari malformation and
hydromyelia. In Neurological Surgery (J. R. Youmans, Ed.).
Saunders, Philadelphia.
Brazis, P. W., Masdeu, J. C., and Biller, J. (1996). The localization
of lesions affecting the ocular motor systems. In Localization in
Clinical Neurology (P. W. Brazis, J. C. Masdeu, and J. Biller,
Eds.), pp. 155–250. Little, Brown, Boston.
Bruner, J. P., Tulipan, N., Paschall, R. L., et al. (1999). Fetal
surgery for myelomeningocele and the incidence of shunt-
dependent hydrocephalus. J. Am. Med. Assoc. 282, 1819–1825.
CHICKPEA INTOXICATION 695
Chiari, H. (1987). Concerning alterations in the cerebellum
resulting from cerebral hydrocephalus. Pediatr. Neurosci. 13,
3–8. [Original work published in 1891.]
Gardner, W. J. (1965). Hydrodynamic mechanism of syringomye-
lia: Its relationship to myelocele. J. Neurol. Neurosurg.
Psychiatr. 28, 247–259.
McLone, D. G., and Naidich, T. P. (1992). Developmental
morphology of the subarachnoid space, brain vasculature, and
contiguous structures, and the cause of the Chiari II malforma-
tion. Am. J. Neuroradiol. 13, 463–482.
Mikulis, D. J., Diaz, O., Egglin, T. K., et al. (1992). Variance of the
position of the cerebellar tonsils with age: Preliminary report.
Radiology 183, 725–728.
Milhorat, T. H., Chou, M. W., Trinidad, E. M., et al. (1999).
Chiari I malformation redefined: Clinical and radiographic
findings for 364 symptomatic patients. Neurosurgery 44, 1005–
1017.
Oakes, W. J. (1996). Chiari malformations, hydromyelia, and
syringomyelia. In Neurosurgery (R. H. Wilkins and S. S.
Rengachary, Eds.), pp. 3593–3616. McGraw-Hill, New York.
Oakes, W. J. (1999). Chiari malformations. In Principles and
Practice of Pediatric Neurosurgery (A. Pollack, Ed.). Thieme,
New York.
Osaka, K., Tanimura, T., Hirayama, A., et al. (1978). Myelome-
ningocele before birth. J. Neurosurg. 49, 711–724.
Osborn, A. G. (1994). Disorders of neural tube closure. In
Diagnostic Neuroradiology (A. G. Osborn, Ed.), pp. 15–36.
Mosby/Year Book, St. Louis.
Sutton, L. N., Adzick, N. S., Bilaniuk, L. T., et al. (1999).
Improvement in hindbrain herniation demonstrated by serial
fetal magnetic resonance imaging following fetal surgery for
myelomeningocele. J. Am. Med. Assoc. 282, 1826–1831.
Chickpea Intoxication
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
IN AREAS in Europe and India, progressive gait
difficulty, usually associated with leg weakness and
spasticity (spastic paraplegia), has developed in
humans and other animals following consumption
of different varieties of the chickpea, Lathyrus. Three
potent neurotoxins, amino-b-oxalylaminopropionic
acid, amino-oxalylaminobutyric acid, and b-N-ox-
alylamino-l-alanine, appear to be involved in the
pathogenesis of human lathyrism. Men are seven
times more likely than women to be affected by
intoxication, possibly as a result of antioxidant
characteristics of female hormones. The onset of
neurotoxic signs can be acute or gradual and
progressive. Low back pain and lower extremity
weakness with stiffness are usually the first effects
and occur after awakening in the morning. A low-
grade fever may accompany these symptoms.
696 CHILD ABUSE, HEAD INJURIES
Decreased strength, often associated with paresthe-
sias or tingling sensations, develops within several
days, and thereafter leg spasticity and jerking move-
ments, called clonic tremor, occur. The muscle tone
in the legs increases so that the severely affected
patient characteristically walks on the balls of the
feet with a lurching, scissoring gait. Extensor plantar
responses are typical and indicative of spinal cord
involvement. If the condition is severe, the upper
extremities may also be involved.
With disease progression, there may also be muscle
atrophy and a marked sensory deficit with paresthe-
sias, lightning pains reminiscent of tabes dorsalis,
and decreased sensitivity to touch, heat, and pain.
Bladder and bowel control are usually retained
unless the involvement is extensive. Within 1 or 2
weeks, the pain and paresthesias usually disappear,
leaving only weakness and the gait problem. There
may be some recovery of muscle power following the
initial attack, but the spastic gait tends to persist. In
some instances, relapses occur. Although spastic
paraplegia is the most common neurotoxic effect,
pure peripheral nerve involvement can occur and
cause isolated nerve damage (mononeuropathies) or
a diffuse (polyneuropathy) damage to the distal
nerves of the body.
—Christopher G. Goetz
See also–Excitotoxins and Excitotoxicity;
Intoxication; Neurotoxicology, Overview
Further Reading
Goetz, C. G., and Meisel, E. (2000). Biological neurotoxins.
Neurol. Clin. 18, 719–740.
Ludolph, A. C., and Spencer, P. S. (1996). Toxic models of upper
motor neuron disease. J. Neurol. Sci. 139, 53–59.
Misra, U. K., and Sharma, V. P. (1994). Peripheral and central
conduction studies in neurolathyrism. J. Neurol. Neurosurg.
Psychiatr. 57, 572–577.
Spencer, P. S. (1995). Lathyrism. In Handbook of Clinical
Neurology (P. J. Vinken and G. W. Bruyn, Eds.), pp. 1–20.
Elsevier, Amsterdam.
Child Abuse, Head Injuries
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHILD MALTREATMENT, including neglect, physical
abuse, and sexual abuse, is a common occurrence in
childhood. For neurologists, head injuries due to
physical abuse are particularly important for several
reasons: their frequency in young children, the
differentiation of abusive from nonabusive injuries,
and the substantial morbidity and mortality. In this
entry, we briefly review the definitions and epide-
miology of child maltreatment and the clinical
characteristics of abusive head injuries.
DEFINITIONS
Maltreatment of children includes neglect, physical
abuse, sexual abuse, and emotional maltreatment.
Neglect is defined as an act of omission, such as the
failure to provide appropriate levels of shelter,
nutrition, clothing, or supervision or the failure to
ensure that the child receives adequate health care or
education. Neglect can be a single event, such as in
leaving a young child unsupervised in an unsafe
setting, but often is a pattern of inadequate and/or
unsafe care, such as the provision of inadequate food
because of the parents’ substance abuse. Physical
abuse is defined as an act of commission that results
in harm or intended harm to the child. It can include
scald burns that occur when a caretaker punishes the
child, intentional cigarette burns, broken bones,
brain injury from the shaking of a young child, or
even death. Often, injuries that are suspicious for
physical abuse or neglect must be distinguished from
‘‘unintentional’’ or accidental injures. Neglect should
also be distinguished from less serious lapses in
parental supervision, such as when a 9-month-old
rolls off of a bed, or less serious lapses in attending to
a child’s health care needs, such as poor adherence to
a prescribed medication or missing a few appoint-
ments for immunizations.
Sexual abuse is defined as the involvement of
children or adolescents in sexual activities that they
do not fully comprehend, to which they cannot give
informed consent because of their developmental
understanding, and that break family or social
taboos. Sexual abuse includes behaviors such as
genital fondling and sexual intercourse.
Emotional maltreatment is the most difficult form
of maltreatment to define. It includes verbal abuse,
denigration, belittling, scapegoating, or even ignor-
ing so that the child develops a sense of low self-
esteem, worthlessness, and helplessness. Emotional
maltreatment often occurs with other forms of
maltreatment. Because of the difficulty in recognizing
and substantiating this form of maltreatment, emo-
tional maltreatment is underreported.
696 CHILD ABUSE, HEAD INJURIES
Decreased strength, often associated with paresthe-
sias or tingling sensations, develops within several
days, and thereafter leg spasticity and jerking move-
ments, called clonic tremor, occur. The muscle tone
in the legs increases so that the severely affected
patient characteristically walks on the balls of the
feet with a lurching, scissoring gait. Extensor plantar
responses are typical and indicative of spinal cord
involvement. If the condition is severe, the upper
extremities may also be involved.
With disease progression, there may also be muscle
atrophy and a marked sensory deficit with paresthe-
sias, lightning pains reminiscent of tabes dorsalis,
and decreased sensitivity to touch, heat, and pain.
Bladder and bowel control are usually retained
unless the involvement is extensive. Within 1 or 2
weeks, the pain and paresthesias usually disappear,
leaving only weakness and the gait problem. There
may be some recovery of muscle power following the
initial attack, but the spastic gait tends to persist. In
some instances, relapses occur. Although spastic
paraplegia is the most common neurotoxic effect,
pure peripheral nerve involvement can occur and
cause isolated nerve damage (mononeuropathies) or
a diffuse (polyneuropathy) damage to the distal
nerves of the body.
—Christopher G. Goetz
See also–Excitotoxins and Excitotoxicity;
Intoxication; Neurotoxicology, Overview
Further Reading
Goetz, C. G., and Meisel, E. (2000). Biological neurotoxins.
Neurol. Clin. 18, 719–740.
Ludolph, A. C., and Spencer, P. S. (1996). Toxic models of upper
motor neuron disease. J. Neurol. Sci. 139, 53–59.
Misra, U. K., and Sharma, V. P. (1994). Peripheral and central
conduction studies in neurolathyrism. J. Neurol. Neurosurg.
Psychiatr. 57, 572–577.
Spencer, P. S. (1995). Lathyrism. In Handbook of Clinical
Neurology (P. J. Vinken and G. W. Bruyn, Eds.), pp. 1–20.
Elsevier, Amsterdam.
Child Abuse, Head Injuries
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHILD MALTREATMENT, including neglect, physical
abuse, and sexual abuse, is a common occurrence in
childhood. For neurologists, head injuries due to
physical abuse are particularly important for several
reasons: their frequency in young children, the
differentiation of abusive from nonabusive injuries,
and the substantial morbidity and mortality. In this
entry, we briefly review the definitions and epide-
miology of child maltreatment and the clinical
characteristics of abusive head injuries.
DEFINITIONS
Maltreatment of children includes neglect, physical
abuse, sexual abuse, and emotional maltreatment.
Neglect is defined as an act of omission, such as the
failure to provide appropriate levels of shelter,
nutrition, clothing, or supervision or the failure to
ensure that the child receives adequate health care or
education. Neglect can be a single event, such as in
leaving a young child unsupervised in an unsafe
setting, but often is a pattern of inadequate and/or
unsafe care, such as the provision of inadequate food
because of the parents’ substance abuse. Physical
abuse is defined as an act of commission that results
in harm or intended harm to the child. It can include
scald burns that occur when a caretaker punishes the
child, intentional cigarette burns, broken bones,
brain injury from the shaking of a young child, or
even death. Often, injuries that are suspicious for
physical abuse or neglect must be distinguished from
‘‘unintentional’’ or accidental injures. Neglect should
also be distinguished from less serious lapses in
parental supervision, such as when a 9-month-old
rolls off of a bed, or less serious lapses in attending to
a child’s health care needs, such as poor adherence to
a prescribed medication or missing a few appoint-
ments for immunizations.
Sexual abuse is defined as the involvement of
children or adolescents in sexual activities that they
do not fully comprehend, to which they cannot give
informed consent because of their developmental
understanding, and that break family or social
taboos. Sexual abuse includes behaviors such as
genital fondling and sexual intercourse.
Emotional maltreatment is the most difficult form
of maltreatment to define. It includes verbal abuse,
denigration, belittling, scapegoating, or even ignor-
ing so that the child develops a sense of low self-
esteem, worthlessness, and helplessness. Emotional
maltreatment often occurs with other forms of
maltreatment. Because of the difficulty in recognizing
and substantiating this form of maltreatment, emo-
tional maltreatment is underreported.

Although the mistreatment of children has oc-
curred since there have been families, the clinical
recognition and reporting of child abuse did not
occur until the1960s. In 1962, Kempe and colleagues
coined the term the ‘‘battered child syndrome’’
describing children who presented with recurrent
injuries but with no history of major trauma and
who had been physically abused by their parents. In
the mid-1960s, state reporting statutes were passed
requiring physicians to report suspected abuse, and
child protective service agencies were established to
investigate reports, help provide services to families,
and arrange for alternative placements such as foster
care to keep children safe.
Since 1976, annual reports to each state’s child
protective service agency have been tabulated. In the
most recent survey (1998), there were approximately
2.8 million reports of maltreatment of children
younger than 18 years of age and approximately
1100 deaths in the United States. The types of
maltreatment were neglect (56%), abuse (23%),
sexual abuse (12%), emotional maltreatment (6%),
and other (3%). The rates of maltreatment were
highest in children younger than 7 years of age. In
cases of abuse or neglect, reports were approximately
equal for males and females, but in cases of sexual
abuse more than 75% of the victims were female.
Of the approximately 3 million reports, approxi-
mately 30% were ‘‘substantiated,’’ meaning that the
protective service agency had enough evidence to
believe that maltreatment occurred. The failure of
the agency to substantiate does not, of course, mean
that maltreatment did not occur. The absence of clear
statements from an abused child or the absence of a
clear diagnosis from a physician may result in the
protective service agency classifying the report as
unsubstantiated.
ABUSIVE HEAD INJURIES
Abusive head injuries can result from a variety of
mechanisms, including direct blows to the head from
an object or a hand; the child’s head being forced or
slammed against a wall, floor, or other surface, such
as a mattress or crib railing; violent shaking; and
strangulation. Although soft tissue injuries of the
face or head are probably the most common injury
and can occur at any age, children younger than 2
years of age are at the highest risk of suffering severe
intracranial injuries.
The most common mechanism of injury in these
young children is shaking or shaking with impact,
CHILD ABUSE, HEAD INJURIES 697
and this has been called the shaken baby syndrome
or the shaken-impact syndrome. The injuries occur
when the child is grabbed under the axillae or by the
upper arms and is vigorously shaken, resulting in
rotational injuries of the head from acceleration–
deceleration. Because of the proportionately large
head size and relatively weak neck muscles, infants
are believed to be more susceptible to rotational
injuries. These injuries include tearing of the bridging
veins, subdural hematomas, subarachnoid hemor-
rhage, diffuse axonal injury, and other intracranial
abnormalities as well as retinal hemorrhages. Often,
the head injuries are associated with rib fractures
from squeezing of the chest or with other signs of
physical abuse. In some children, there may be
cranial injuries due to impact when the child is also
slammed or thrown against a surface. In addition,
since there may be a delay in seeking care because the
perpetrator hopes that the child will recover, the
brain-injured child may have a period of poor
respiratory effort and even periods of apnea that
can result in hypoxic or anoxic brain injury.
EPIDEMIOLOGY
Head injury from abuse is the most common cause of
death due to trauma in young children. Although
accidental head injuries in young children can result
in death, such as when a child is in a motor vehicle
accident, most serious head injuries are due to
physical abuse. For example, in 84 children younger
than 1 year of age with head injuries, Billmire and
Myers found that 64% of these injuries (excluding
those with uncomplicated skull fractures) and 95%
of serious intracranial injuries were due to child
abuse.
Two recent population-based studies in the United
Kingdom examined the incidence of subdurals due to
abuse. A retrospective examination of all children
younger than 2 years of age in South Wales and south
England during a 3-year period identified 33 cases of
subdural hemorrhage; 28 cases occurred in the first
year of life. Of the 33 cases, 82% were highly
suggestive of physical abuse; the incidence of abuse
was 17 per 100,000 children younger than 1 year of
age per year. In a prospective study conducted in
1998 and 1999 in Scotland, other investigators found
a similar annual incidence of shaken-impact syn-
drome—25 per 100,000 children younger than 1
year of age.
In a recent hospital-based study, Feldman and
colleagues prospectively identified and evaluated
698 CHILD ABUSE, HEAD INJURIES
children younger than 36 months of age with
subdural hematoma and used criteria to classify
children into one of three categories: intentional
injury, indeterminate, and unintentional. Of the 66
children, 59% of injuries were due to abuse, 23%
were unintentional, and 18% were indeterminate.
All the children who were unintentionally injured
had clear histories of major trauma, such as motor
vehicle accidents or falls of more than 10 ft.
The abuser is most often an adult living in the
home. In a study by Starling, 60% of the perpetrators
were males, including fathers, mothers’ boyfriends,
or stepfathers. Female perpetrators included mothers
and baby-sitters. Abuse can occur when the caretaker
becomes frustrated with the infant’s behaviors, such
as crying or spitting up, which may be viewed as
excessive and intentional.
CLINICAL MANIFESTATIONS
The clinical manifestations of abusive head injury
range from mild to life threatening. Typically, a child
younger than 1 year of age is brought to a physician’s
office or emergency department because of a severe
alteration in mental status, difficulty breathing, and/
or seizures or because of less serious abnormalities,
such as vomiting and lethargy. Since the initial
history provided by the caretaker does not mention
the abusive behavior, the diagnosis of abuse is
sometimes only suspected because of the discrepancy
between the child’s serious condition and the history,
which might not include any mention of trauma or
might include a history of a minor fall or minor
bump to the head. In some circumstances, other signs
of abuse, such as fresh bruises, will lead to the correct
diagnosis.
In other circumstances, the correct diagnosis of
abuse may be missed and the child sent home where
further abuse can occur. In a study conducted by
Jenny et al. of 173 children diagnosed with abusive
head trauma, in 31% of the cases the correct
diagnosis was not made at the first visit to the
clinician, which took place after the head trauma had
occurred. Incorrect diagnoses included otitis media,
colic, gastroenteritis, and accidental injury. Children
who were Caucasian and who lived with two parents
were more likely to have the diagnosis of abusive
head trauma missed at the first medical evaluation.
This finding highlights the importance of considering
the diagnosis in all types of families, not just
those with certain ethnic or socioeconomic charac-
teristics.
On physical examination, the child may have
marked lethargy or hypotonia. The anterior fonta-
nelle may be full. Seizures may be present. In children
with recurrent injuries or chronic subdurals there can
be a marked increase in the growth of the child’s
head and splitting of the sutures.
A general physical examination may reveal other
signs indicating abuse, such as acute or old bruises
or burns. It is important that even a child who is
mechanically ventilated in an intensive care unit
have a careful examination to search for injuries on
the back of the head or on the back or buttocks. In
some cases, even careful examinations may fail to
detect external signs of blunt trauma, which can
be noted at autopsy. In a study of children with
abusive head injuries, at autopsy 13 children had
signs of impact injury to the head, but in 7 of
these cases such signs were not detected prior to
death.
A dilated examination of the retina should be
performed by an ophthalmologist in any child when
there is suspicion of an abusive head injury. In one
study of children with retinal hemorrhages, non-
ophthalmologists failed to detect the hemorrhages in
29% of the cases. Retinal hemorrhages occur in 60–
90% of children with shaken-impact syndrome. In
approximately 15% of cases, these hemorrhages can
be unilateral. The hemorrhages seen with shaken-
impact syndrome are usually diffuse and extend to
the periphery and may involve all layers of the retina.
There may be traumatic retinoschisis or vitreal
hemorrhages as well. Although the mechanism
of how these injuries occur is not certain, the
most likely explanation is that rotational accelera-
tion and deceleration results in traction at the
junction between the vitreous and retina with
resultant splitting of the layers and tears in blood
vessels.
Retinal hemorrhages can occur in accidental head
injuries as well, but the occurrence is markedly less
(5% or less) and the hemorrhages are usually few
and located in the posterior pole. When retinal
hemorrhages do occur in children with accidental
injuries, these children usually have sustained a
major injury. There have been a few case reports of
children having retinal hemorrhages after accidents
that occur in homes, but the occurrence of diffuse
retinal hemorrhages after falls from objects, such as
chairs or beds, would be distinctly unusual. Retinal
hemorrhages also rarely, if ever, occur after cardio-
pulmonary resuscitation or seizures. The most
common cause of retinal hemorrhages is the delivery

of healthy newborns. In a study of 149 healthy
newborns, in 34% retinal hemorrhages were de-
tected within the first 30 hr of life. The incidence was
highest for vacuum-assisted deliveries (75%) com-
pared with spontaneous vaginal deliveries (33%) and
deliveries by cesarean section (7%). By 2 weeks after
birth, the hemorrhages resolved in 86% of eyes.
At 4 weeks, no intraretinal hemorrhage was seen; a
single subretinal hemorrhage persisted until 6 weeks
of age.
With intracranial bleeding, the child’s hemoglobin
may be decreased. When parenchymal brain injury
occurs (in either abusive or nonabusive head
injuries), there may be release of tissue factor
resulting in active coagulation, a prolonged pro-
thrombin time, and even disseminated intravascular
coagulation.
Some infants may undergo a lumbar puncture as
part of an evaluation for suspected sepsis. If the
spinal fluid is bloody, it should not be assumed to be
a traumatic tap and should be checked for xantho-
chromia, the presence of which suggests bleeding
that is at least several hours old.
A skeletal survey should be obtained to search for
evidence of acute or healing fractures. Rib fractures
occur in approximately 20% of infants with abusive
head trauma. These fractures occur when the chest is
squeezed during violent shaking and the rib cage
bends posteriorly. Posterior rib fractures, which
occur just lateral to the spine, are considered
diagnostic of child abuse. When a child’s chest is
squeezed during shaking, fractures can occur later-
ally and at other places along the rib. Recent rib
fractures are difficult to see on chest x-rays in infants;
such fractures are usually not visible until bony callus
can be seen on x-ray 10–14 days after an acute
fracture. Therefore, the presence of healing rib
fractures and an acute head injury indicates that
the child has been injured on more than one
occasion. If the skeletal survey is negative, many
clinicians either obtain a bone scan to search for
acute rib fractures that can be missed on x-ray or
repeat the skeletal survey 2 weeks later so that
if healed rib fractures are present, they will be
visible.
INTRACRANIAL INJURIES
Diagnostic imaging should include a computed
tomography (CT) scan to search for acute injuries,
including skull fractures, and magnetic resonance
imaging (MRI) 2 or 3 days later to help determine the
CHILD ABUSE, HEAD INJURIES 699
timing of the injury. The MRI can also help
distinguish the location of the bleeding and is more
sensitive to small intraparenchymal bleeds.
The most common finding is the presence of a
subdural hematoma (SDH) or subarachnoid hemor-
rhage (SAH). Such injuries are usually acute, but
some children have evidence of old bleeding as well,
indicative of previous trauma. In Feldman’s prospec-
tive study of 66 young children with subdurals, of the
39 classified as abusive, 56% were considered acute,
31% chronic, and 13% acute and chronic. The
hemorrhage, which may be bilateral or unilateral, is
usually seen over the convexities and extends into the
interhemispheric fissure. Although the subdurals are
usually thin, they can occasionally be more extensive
and create mass effects, and this may require
intermittent drainage through the anterior fontanel.
In some children, the subdurals may become chronic
and require the placement of a shunt. Subarachnoid
hemorrhage may also be present with the subdurals.
Kleinman highlighted the fact that SAHs are
frequently noted at autopsy of children who died of
shaken-impact syndrome, but often SAHs are not
detected on imaging studies.
Since the SDH and/or SAH are usually small and
not life threatening, the cortical injuries suffered by
the child have the major impact on the clinical course
and prognosis. In abusive head injury, the most
common cortical injuries are shear injuries of the
white matter (diffuse axonal injury) and contusions.
Contusions may occur beneath the site of impact or
fracture or may occur as contrecoup lesions opposite
the site of the impact.
Diffuse cerebral edema may occur as a secondary
injury in children with shaken-impact syndrome. The
extent of the cerebral edema and swelling greatly
influences the child’s prognosis. In a study by
Duhaime and colleagues of 48 children with abuse
head trauma, all 13 fatalities were due to uncontrol-
lable swelling of the brain.
Hypoxic–ischemic cortical injuries may be second-
ary to the depressed respirations or apnea that can
occur after a brain injury or may be due to
smothering or strangulation of an infant. Several
authors have highlighted a unique pattern of edema
in abused infants called the reversal sign in which the
cerebral cortex and subcortical white matter are
hypodense on CT compared with the basal ganglia,
thalami, and cerebellum, which are relatively spared
and thus hyperdense. Autopsies in infants with these
findings have demonstrated hypoxic–ischemic
changes.
700 CHILD ABUSE, HEAD INJURIES
The evaluation of an infant who has only a
subdural hemorrhage (and no other intracranial
injuries, retinal hemorrhages, or fractures on skeletal
survey) can be especially challenging. Morris and
colleagues presented the clinical features of nine such
infants 11 days to 15 months of age who had chronic
(2), subacute (5), or acute (2) subdurals. After a
thorough investigation of the past medical history,
the investigators concluded that two children were
clearly abused, four were in dangerous social
situations but shaking or inflicted injury could not
be proved, and three were in situations with risk
factors for abuse but the cause of the subdural was
not clear. This study is a reminder of the importance
of gathering past medical information and extensive
social data (often with the help of a hospital social
worker and an investigator from the local child
protective service agency) when trying to determine
the cause of a subdural hemorrhage.
The prognosis of infants with shaken-impact
syndrome clearly depends on the extent and location
of the injuries. In most series, approximately 10–
30% of the children die, 30–50% have a serious
neurological deficit, and the remaining children are
either normal or have more subtle deficits. Retinal
hemorrhages usually resolve without visual impair-
ment. When blindness does occur, it is almost always
due to a cortical defect.
LEGAL RESPONSIBILITIES
In many countries, including the United States, if a
physician suspects that a child’s condition is due to
physical abuse, a report must be made to the child
protective service agency. In some countries, report-
ing is strongly recommended but not mandated. In
the United States, reporting is usually done by
calling a statewide hot line number. To file a
report, the physician does not have to be 100%
certain that the child has been abused; rather,
the physician has to have ‘‘a reasonable medical
suspicion.’’
In cases of abusive head injury, investigations will
be conducted by both child protective services (CPS)
and the police. Important aspects of the investigation
focus on when the injury was likely to have occurred
and on the suspected perpetrator. In part, clinical
data, such as when the child became lethargic and
who was caring for the child when the symptoms
occurred, can be helpful; also, the age of the injuries
as determined by CT and MRI can provide helpful
information. In our experience, estimating the age of
the injury on a single CT scan has resulted in
erroneous information. We therefore try to have all
the clinicians caring for the child and a neuroradiol-
ogist meet to review all the imaging studies before
offering a conclusion about the extent and timing of
the injuries and whether it is likely that both old and
acute injuries are present.
When a child with an abusive head injury is
identified, it is important that CPS investigates the
health and safety of the siblings. All siblings should
be examined for signs of abuse. A skeletal survey
should be obtained in siblings younger than 36
months of age, and an examination by an ophthal-
mologist and a CT or MRI of the head should be
considered in siblings younger than 12 months of
age. MRI is a more sensitive (and more expensive)
test than CT. When one twin has been abused, the
other is at increased risk and should be investigated
thoroughly (including an eye exam).
CPS may request an affidavit of a physician. The
purpose of such an affidavit is to describe the child’s
injuries and to indicate to the court whether these
injuries are consistent with the diagnosis of abusive
head injury and whether the child would be safe
returning to the home. If the child is removed from
the home and placed in the temporary custody of
CPS, the physician may be subpoenaed to testify in
juvenile or family court about the injuries and the
child’s clinical course and prognosis. In such a trial,
the focus is on the child’s safety. If an abuser is
arrested, the physician may also testify in criminal
court.
DIFFERENTIAL DIAGNOSIS
The major differential diagnosis to be considered is
an unintentional or accidental head injury. Acciden-
tal events, such as major falls (which can be due to
neglect) or motor vehicle accidents, can result in
serious head injuries including subdural hematomas
or even death. The history clearly describes the event
so that there is usually no confusion with the
diagnosis of abuse. In these types of unintentional
injuries, retinal hemorrhages occur rarely (o5%),
and when they do occur the pattern is different from
that seen for abusive injuries.
A common unintentional event for many infants is
a fall from a couch, bed, or changing table. Such a
fall can result in a short, linear, usually parietal skull
fracture. A small percentage of such children may
have a small contact subdural hematoma beneath the
fracture. It would be distinctly unusual for a child

either to have major intracranial injuries or to die
after a short fall. Such cases would clearly need to be
evaluated for suspected abuse.
An epidural hematoma may also occur after a
relatively short fall onto a hard surface. The epidural
is usually located beneath an associated skull
fracture. Most epidurals are due to accidental
injuries. In a study of 33 children with epidurals
who were younger than 4 years of age, two of the
injuries (6%) were due to abuse and the rest due to
nonabusive circumstances.
Other possible diagnoses to be considered are
extremely rare. Children with congenital bleeding
disorders or infants with vitamin K deficiency can
have intracranial hemorrhages. An intracranial an-
eurysm can bleed and result in a SDH. Children with
glutaric aciduria type I can have subdural hemor-
rhages, but they also have other signs of the disease,
including developmental delay, hypotonia, and cor-
tical atrophy.
—John M. Leventhal and Kirsten Bechtel
See also–Brain Injury, Traumatic:
Epidemiological Issues; Head Trauma, Overview;
Sudden Infant Death Syndrome (SIDS)
Further Reading
Billmire, M. E., and Myers, P. A. (1985). Serious head injury in
infants: Accident or abuse? Pediatrics 75, 340–342.
Committee on Child Abuse and Neglect, American Academy of
Pediatrics (2001). Shaken baby syndrome: Rotational cranial
injuries—Technical report. Pediatrics 108, 206–210.
Duhaime, A. C., Gennarelli, T. A., Thibault, L. E., et al. (1987).
The shaken baby syndrome. A clinical, pathological, and
biomechanical study. J. Neurosurg. 66, 409–415.
Duhaime, A. C., Christian, C. W., Rorke, L. B., et al. (1998).
Nonaccidental head injury in infants: The ‘‘shaken-baby
syndrome.’’ N. Engl. J. Med. 338, 1822–1829.
Emerson, M. V., Pieramici, D. J., Stoessel, K. M., et al. (2001).
Incidence and rate of disappearance of retinal hemorrhage in
newborns. Ophthalmology 108, 36–39.
Feldman, K. W., Bethel, R., Shugerman, R. P., et al. (2001). The
cause of infant and toddler subdural hemorrhage: A prospective
study. Pediatrics 108, 636–646.
Jenny, C., Hymel, K. P., Ritzen, A., et al. (1999). Analysis of
missed cases of abusive head trauma. J. Am. Med. Assoc. 281,
621–626.
Kempe, C. H., Silverman, F. N., Steele, B., et al. (1962).
The battered child syndrome. J. Am. Med. Assoc. 18,
17–24.
Kivlin, J. D., Simons, K. B., Lazoritz, S., et al. (2000). Shaken baby
syndrome. Ophthalmology 107, 1246–1254.
Kleinman, P. K., and Barnes, P. D. (1998). Head trauma. In
Diagnostic Imaging of Child Abuse (P. K. Kleinman, Ed.), 2nd
ed., pp. 285–342. Mosby, St Louis.
CHILDHOOD BRAIN TUMORS 701
Levin, A. V. (2000). Retinal hemorrhages: A review. Recent Adv.
Paediatr. (T. J. David, Ed.) 18, 151–219.
Morris, M. W., Smith, S., Cressman, J., et al. (2000). Evaluation of
infants with subdural hematoma who lack external evidence of
abuse. Pediatrics 105, 549–553.
Shugerman, R. P., Paez, A., Grossman, D. C., et al. (1996).
Epidural hemorrhage: Is it abuse? Pediatrics 97, 664–668.
Starling, S. P., Holden, J. R., and Jenny, C. (1995). Abusive head
trauma: The relationship of perpetrators to their victims.
Pediatrics 95, 259–262.
Childhood Brain Tumors
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN TUMORS are the most common form of solid
tumor of childhood and are exceeded only by
leukemia in incidence of all cancers in patients
younger than 15 years of age. The reported incidence
of childhood tumors increased from 2.4 cases per
100,000 children under age 15 at risk per year in
1973 to 3.5 cases per 100,000 children at risk in
1994. It is unclear whether this reported increase in
incidence is representative of an actual increase in the
number of tumors occurring in childhood or whether
it is due to improved diagnosis and reporting. The
incidence of central nervous system tumors is
inversely proportional to age, with 3.5 to 4 cases
per 100,000 children in children younger than 5
years of age compared to 2.5 cases per 100,000 at
risk for children between 10 and 15 years of age. In
the United States each year, approximately 2200
children are diagnosed with central nervous system
tumors. The incidence of brain tumors is higher in
boys than in girls, with a ratio of approximately
55:45. This gender difference is primarily accounted
for by a male predominance of primitive neuroecto-
dermal tumors and ependymomas.
Approximately 50% of all childhood brain tumors
arise in the posterior fossa. In this region of brain, the
most common tumors are cerebellar astrocytomas,
medulloblastomas, ependymomas, and brainstem
gliomas. Up to 20% of childhood tumors will arise
in the suprasellar region; craniopharyngiomas, visual
pathway gliomas, and germinomas comprise the
majority of lesions. The majority of childhood
cortical tumors are gliomas, with a predominance
of low-grade tumors.
Most childhood brain tumors are not linked to
known genetic conditions. Children with neurofibro-
matosis type 1 are 50 times more likely than other
710 CHILD NEUROLOGY, HISTORY OF
Child Neurology, History of
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
THERE IS NO SPECIFIC TIME that can be identified as
the beginning of child neurology because adult and
child neurology share the same rich heritage of
contributions of numerous physicians, anatomists,
and physiologists to our knowledge of the nervous
system. Despite the initial use of the word brain and
reference to the underlying membranes and fluid in
3500 bc, the recorded history of diseases of the
nervous system thereafter has been sparse. Fielding
Garrison, librarian to the Surgeon General, wrote
The History of Medicine in 1925 and followed up
with a historical chapter on neurology in Charles
Dana’s Textbook of Nervous Diseases later that same
year. McHenry revised and enlarged Garrison’s
original chapter on the history of neurology in
1969, culminating in the text Garrisons’s History
of Neurology, a trove of neurological history from
antiquity to the 20th century. Unfortunately, there is
little reference to child neurology in the text.
It was not until the latter part of the 19th and early
20th centuries that an occasional allusion was made
to children being affected with neurological disor-
ders, but no attention was directed to encompassing
the body of neurological disorders of childhood.
During this period, physicians with a specific interest
in clinical neurology could be identified in France,
Germany, Great Britain, and the United States. A
primary figure of the French school was Jean-Martin
Charcot, who, following graduation from medical
school, became interested in chronic and senile
diseases. His interests were then directed to the
nervous system, and at the age of 36 he became chief
physician of one of the sections of the Salpetriere in
Paris. Within a short period of time, he developed a
clinical neurology service that was not found in other
hospitals of that period, and his clinics and published
lessons, Lecon de Mardi, soon attracted numerous
physicians from not only France but also other areas
of Europe and the United States.
In Germany, neurology began to flourish following
the work of Romberg and the publications of Erb,
Oppenheim, Friedreich, Foerster, and many others.
British neurology also blossomed at approximately
the same time in the 19th century after the establish-
ment in 1859 of the National Hospital for the
Paralyzed and Epileptic in London, and clinical
neurology thrived with the enormous productivity
of Jackson, Ferrier, Gowers, Holmes, Collier, Buz-
zard, and Kinnier Wilson. In the United States,
neurology was just beginning to develop during and
after the Civil War, primarily because of the
forcefulness of William Hammond, Weir Mitchell,
and, later, Spiller, Dercum, Seguin, Putnam, and
Dana.
AMERICAN CHILD NEUROLOGY
The first text regarding diseases of the nervous
system in children was that of Bernard Sachs. Born
in the United States in 1858, he completed Harvard
College and then attended medical school at Stras-
bourg in Alsace. To enhance his training, he went to
Vienna to work with Theodor Meynert and Carl
Frederick Westphal and then to Paris, where he
attended the clinics of Charcot for several months.
Following his studies in Paris, he spent time with
John Hughlings Jackson at the National Hospital in
London and then returned to the United States in
1884. He was subsequently appointed to the Poly-
clinic Hospital in 1885, the neurology staff at the
Montefiore Home, and then consulting neurologist at
Mt. Sinai Hospital. He opened one of the first
neurology services at Mt. Sinai and remained there
for 31 years.
Sachs published numerous papers on neurological
disorders, but it is the report(s) of his findings
of amaurotic familial idiocy (Tay–Sachs disease)
in 1887 for which he is remembered. He later
recorded his observations of this disease in
Osler’s Principles and Practice of Medicine in 1910.
Because of Sachs’ interest in pediatrics, Charles
Dana suggested that Sachs write a book on the
neurology of children, which resulted in the publica-
tion of the first textbook of child neurology, A
Treatise on the Nervous Diseases of Children, in
1885. He later established the first pediatric neurol-
ogy service at the New York Neurological Institute in
1935.
For several decades thereafter, little interest was
expressed in diseases of children, particularly dis-
eases of the nervous system, until medical schools
began to employ full-time, salaried academic faculty
as part of training programs. Clinical specialty
training programs and clinical research programs
were established that attracted patients with a variety
of diseases. New methods of diagnosis and treatment
were introduced, and the number of patients attend-
ing the various pediatric specialty clinics increased

greatly. It was during this period of change that the
discipline of child neurology began to develop, not
only in the United States but also throughout the
world. It was slow to develop in the United States
because there were only a few physicians who had
expertise in diseases of the nervous system of
children, namely Frank Ford at Johns Hopkins
Hospital, Douglas Buchanan at the University of
Chicago, and Bronson Crothers at Boston Children’s
Hospital.
Douglas Buchanan, born in Glasgow, Scotland, in
1901, received his undergraduate and medical train-
ing at Glasgow. He remained there after receiving a
fellowship for the physiology of the nervous system.
Then, he proceeded to Trinity College, Cambridge,
England, where he was an investigator and lecturer
for the Medical Research Council. He was then
registrar at the National Hospital, Queen Square,
London, where he met Paul Bucy from the University
of Chicago. Through Bucy, Buchanan accepted an
invitation to come to the University of Chicago to
develop child neurology and he moved to Chicago in
1931. He ultimately rose to the rank of professor of
pediatrics and neurology and became a consultant in
neurology at the Children’s Memorial Hospital,
Chicago. He published a number of papers on
neurological diseases of childhood and particularly
on intracranial tumors of children, the latter of
which were gathered and, in collaboration with
Pearce Bailey and Paul Bucy, were published in the
classic text Intracranial Tumors of Childhood.
Recognized for his great clinical and teaching skills
as well as his personal warmth, he was endeared by
students, resident physicians, and his many child
patients and their parents.
Frank Ford, a native Baltimorean born in 1892,
completed undergraduate studies and attended med-
ical school at Johns Hopkins University. He accepted
a position as house officer in psychiatry under
Adolph Meyers and then began training in clinical
neurology under Foster Kennedy at Bellevue Hospi-
tal in New York. He returned to Johns Hopkins in
1923, was soon recognized as a superlative clinical
neurologist, and was appointed head of neurology.
His incisive thinking and ability to formulate a
diagnosis without particular effort were monumental
and recognized by all, and he became known as ‘‘the
judge.’’ His close association with Dr. Frank Walsh
and his regular participation in the Saturday morning
neuroophthalmology conference at the Wilmer In-
stitute became legendary. As noted by Dr. David
Clark,
CHILD NEUROLOGY, HISTORY OF 711
Despite the fact that Ford was averse to travel, attended no
national meetings, and infrequently published papers, he was
widely recognized as one of the foremost neurologists of his
time and one of the premier child neurologists in the United
States.
In collaboration with Marian Putnam and Bronson
Crothers, he published his first book, Birth Injuries
of the Nervous System, in 1927. His meticulous
record keeping of clinical reports resulted in the
publication of Diseases of the Nervous System in
Infancy, Childhood, and Adolescence, which ap-
peared in six editions. Although he had no trainees
and no official child neurology service, Frank Ford
was one of the major forces in creating the specialty
of child neurology.
David Clark, born in 1913 in Glen Ellyn, Illinois,
began undergraduate study as a veterinary student at
Michigan State College, during which time he
became fascinated by the nervous system. He
transferred to the University of Chicago Graduate
School of Medicine, where he worked in the
neuroscience program with Heinrich Kluver and C.
Judson Herrick and received his PhD in anatomy in
1939. Following World War II, he resumed medical
studies at the University of Chicago and from 1942
to 1946 worked part-time as neuropathologist at the
Children’s Memorial Hospital, receiving his MD in
1946. During his time in Chicago, Clark developed a
close relationship with Douglas Buchanan that lasted
throughout Buchanan’s lifetime.
He had an internship in medicine and 1 year of
residency in neurology at Johns Hopkins, followed
by his selection as a Fulbright lecturer in neurology at
the National Hospital, Queen Square, London. He
returned to Johns Hopkins as an instructor and rose
through the academic ranks. While at Johns Hop-
kins, he developed a very close relationship with
Frank Ford and he proved to be a favorite among
students and the house staff. He had a most
interesting, if not exciting, manner of presenting a
CPC that endeared him to students and staff alike,
and he particularly enjoyed relating clinical stories of
patients and the consultant staff from his time at the
National Hospital in London. His contributions to
the pediatric and child neurology literature are vast,
and he was one of the staunch supporters of
establishing child neurology as a distinct neurologi-
cal subspecialty. He was one of the first child
neurology consultants to Pearce Bailey, then director
of the National Institute of Neurological Diseases
and Blindness, and he later became an adviser to the
National Collaborative Perinatal Project.
712 CHILD NEUROLOGY, HISTORY OF
As one of the directors of the American Board of
Psychiatry and Neurology, he was often the head of
one of the sections on child neurology, making the
examination experience pleasantly memorable not
only for the candidates but also for the examiners. In
1965, Clark became the first professor and chairman
of the department of neurology at the University of
Kentucky, where he introduced and continued the
traditions of the University of Chicago as well the
National Hospital, Queen Square, and Johns Hop-
kins. Clark was a warm and decent man who made
major contributions to child neurology and its
establishment as a distinct discipline, and he made
a lasting mark on the history of child neurology in
the United States.
The Boston area was an early center of develop-
ment of the new pediatric subspecialty, child
neurology. One of the first physicians to have an
academic career in child neurology in the United
States was Bronson Crothers. He attended Harvard
College, completed Harvard Medical School, and
had a residency at the Massachusetts General
Hospital (MGH) and Children’s Hospital in Boston.
Following World War I, he studied at the New York
Neurological Institute and was then appointed
neurologist at the Boston Children’s Hospital and
to the Harvard Medical School faculty, remaining
there until his retirement in 1952. His years at
Boston Children’s Hospital were very productive,
and he and his colleagues made numerous contribu-
tions to our understanding of brachial plexus palsies
and spinal cord injuries, noting their relationship to
birth trauma. These data were published with
coauthor Marian Putnam in Medicine and later in
collaboration with Frank Ford as the text, Birth
Injuries of the Central Nervous System.
Crothers paid particular attention to the complete
assessment and treatment of the child with cerebral
palsy and other neurological disabilities, including
the psychological support required, the role of the
family, and educational needs. His vast experience
with children with these kinds of disabilities was
published in 1959 with Richmond Paine in the text,
The Natural History of Cerebral Palsy. He was the
stimulus for collaboration with a variety of pediatric
specialists, including Randolph Byers, C. A. Smith,
and Elizabeth Lord.
Randolph Byers, a pediatrician who had a
particular interest in child neurology, was greatly
influenced by his mentor and colleague, Bronson
Crothers, and headed the neurology service at the
Boston Children’s Hospital from 1951 to 1962.
Although not formally trained in neurology, he made
major contributions to neurological aspects of
pediatrics, particularly with regard to lead poisoning,
chronic encephalopathies of childhood, neonatal
kernicterus, dural sinus thrombosis, and the evolu-
tion of infantile hemiplegia. In collaboration with
Betty Banker, he carefully delineated the spectrum of
infantile muscular atrophy and steroid myopathy in
children.
Following graduation from the University of
Oregon, Raymond Adams became interested in
experimental psychology and while working on a
doctorate in psychology was introduced to experi-
mental sensory neurophysiology. He enrolled in
medical school at Duke University, after which
he received a Rockefeller fellowship to study
neurology at the MGH. During these fruitful
years, he met Charles Kubik, chief of neurology at
MGH, who introduced Adams to neuropathology.
Ultimately, Adams was given a position in neuro-
pathology at the Boston City Hospital. As lecturer
and consultant neurologist, he gained much experi-
ence in child neurology, which, aside from the
work of Crothers and Byers, was limited in
the Boston area. He realized the importance of a
training program in child neurology, and a child
neurology service was established and Philip Dodge,
a resident in neurology, was selected to develop the
service.
Dodge represents the beginning of contemporary
child neurology and its training programs in the
United States. Following graduation from medical
school at the University of Rochester, he worked as a
research assistant in neuroanatomy and neurosurgery
for Wilbur Smith. He interned at Strong Memorial
Hospital in Rochester and returned to Boston
for residency training in neurology and neuropathol-
ogy at the Boston City Hospital with Derek
Denny-Brown. After several years in the Army, he
returned to MGH in 1956 and developed a child
neurology service that attracted fellows from
throughout the world. Dodge was recognized as an
outstanding clinician/teacher and he made seminal
contributions to the pediatric and child neurology
literature. Following his move to St. Louis Children’s
Hospital to take the position of professor and
head of pediatrics, and as a result of his enthusiastic
support, the teaching and research programs
flourished. The division of child neurology also
blossomed, and he trained many of the present-day
chiefs of child neurology services throughout the
country.

Following retirement as chairman of pediatrics at
St. Louis Children’s Hospital, he became director of
the National Institute of Child Health and Human
Development but also spent part of his time
contributing to the division of child neurology at
St. Louis Children’s Hospital, where he continues to
contribute to the teaching and research programs.
Sidney Carter, born 1912 in Winthrop, Massachu-
setts, completed Dartmouth College and then entered
Boston University School of Medicine, from which
he graduated in 1938. He then interned at St. Mary’s
Hospital in Waterbury, Connecticut; became a
psychiatry resident at Westboro State Hospital in
Westboro, Massachusetts; and the following year
began his neurology residency at the Boston City
Hospital. During this time, he was exposed to the
teaching and clinical methods of H. Houston
Merritt, Raymond Adams, and Derek Denny-Brown.
He was Merritt’s last resident at the Boston City
Hospital and the first chief resident of Denny-Brown.
In 1943, he enlisted in the U.S. Army and became
the assistant chief of the neuropsychiatry section in
England; he later became chief of neuropsychiatry at
the 116th General Hospital in Nurnberg, Germany.
Following his military experience, he had a fellow-
ship with Merritt, chief of neurology at the
Montefiore Hospital in New York. Merritt became
director of neurology at Columbia-Presbyterian
Neurological Institute, and Carter followed to
become assistant attending neurologist. In 1951,
Carter was appointed chief of pediatric neurology
following the retirement of Louis Casamajor, and
because of Carter’s enthusiastic interest in developing
an active teaching service and his willingness to
consult and attend the conferences at Babies Hospi-
tal, Rustin McIntosh, the director of Babies Hospital,
thought it more appropriate to transfer the child
neurology patients from the Neurological Institute to
Babies Hospital. This was a new concept of pediatric
care in that child neurologists would now manage
not only the neurological aspects of the child’s
problem but also the total pediatric care.
In 1957, following discussions of Pearce Bailey, the
director of the National Institute of Neurological
Disease and Blindness, with Houston Merritt, Philip
Dodge, and David Clark, it was decided that there
would be federal funding for training fellowships in
child neurology. At that time, Carter formally
established a training program in child neurology
and accepted two fellows for each year of a 3-year
program. The fellows accepted for the program had
already completed their pediatric training. Questions
CHILD NEUROLOGY, HISTORY OF 713
arose, however, regarding where the child neurolo-
gists would belong—in pediatrics or neurology. After
much consideration and discussion among members
of the American Board of Pediatrics and the
American Board of Psychiatry and Neurology
(ABPN), it was ultimately decided that there would
be a new category of the ABPN, namely that
following successfully passing of examinations,
candidates would be certified by the ABPN with
special competence in child neurology.
Carter was soon recognized for his inordinate
skills as clinician/teacher and he soon attracted not
only numerous applicants for his training program
but also patients from throughout the world. He
contributed greatly to the child neurology literature
and facilitated collaboration with numerous talented
faculty and fellows who were encouraged to utilize
the vast clinical experience of the neurological
institute. Subsequently, numerous landmark reports
were published and these are still referred to today,
decades after they first appeared in the literature. At
the fourth annual meeting of the Child Neurology
Society in Monterey, California, he received the
prestigious Hower Award and at that time his
trainees were asked to stand. Approximately half of
the audience had been trained by Sidney Carter—
truly a testament to his stature and role in the history
of American child neurology.
He was a director and later president of the ABPN,
a member of the board of trustees and later president
of the American Academy of Neurology, and
president of the American Neurological Association.
Carter retired from Columbia University in 1978 and
became chief of neurology at the Blythedale Chil-
dren’s Hospital in Valhalla, New York.
EUROPEAN/ASIAN CHILD NEUROLOGY
Johannes Melchior, born in 1913, began his higher
education at Horsens and later attended Aarhus and
the University of Copenhagen, where he graduated in
1950. His first appointment in pediatrics was at the
Sundby Hospital in 1952, and following further
training in neurology he was appointed to the
University Clinic of Pediatrics Rigshospitalet, Co-
penhagen in 1956. He moved to the United States
and received additional training in pediatric neuro-
pathology and neurology at Harvard Medical School
and the Fernald State School and also attended
clinical teaching sessions at the Massachusetts
General Hospital with Raymond Adams, Philip
Dodge, and Paul Yakovlev. He became professor of
714 CHILD NEUROLOGY, HISTORY OF
pediatrics at the Copenhagen County Hospital and
was later named professor of pediatrics at the
University of Copenhagen.
Melchior published more than 100 papers relating
to his primary interest in progressive encephalopa-
thies, seizure disorders, and cerebral palsy. With
Bengt Hagberg of Gothenburg, Sweden, he was
founder and one of the presidents of the Scandina-
vian Neuropaediatric Society in 1963 and later
facilitated the development of the European Federa-
tion of Child Neurology with the assistance of
Ronald MacKeith.
Sven Brandt was born in 1913 in Fredriksberg,
Denmark, and spent part of his early life in Cairo,
where his father was consul. He began the study of
medicine at the University of Copenhagen, graduat-
ing in 1939, but continued his training because of his
particular interest in neurology and especially the
neurology of children.
Brandt qualified for both pediatrics and neurology,
an unusual circumstance at that time, and early in his
career began to study Werdnig–Hoffmann disease.
During these studies, he noted that it was not
possible to corroborate the existence of ‘‘amyotonia
congenita’’ as described by Oppenheim in 1900, a
fact that is now well recognized. He further noted
that muscle ‘‘flabbiness’’ (hyopotonia) was a com-
mon sign observed in a number of conditions of
varied etiology.
During a visit to the United States, he made many
contacts with American neurologists and he was
encouraged to return as a visiting scholar. He did so
and spent time studying neurophysiology and elec-
trophysiology at the University of Illinois with Erna
and Frederik Gibbs. He returned to Denmark and
concentrated on electroencephalography of children
and cerebral palsy. He received his medical degree in
1950 following the publication of his classic mono-
graph, Werdnig–Hoffmann’s Infantile Progressive
Muscular Atrophy, and went on to start the first
Danish pediatric neurophysiology/electroencephalo-
graphy laboratory. In 1977, he was appointed
pediatric neurologist at the Rigshospitalet in Copen-
hagen. During his professional career, Brandt had
numerous medical publications, primarily on pedia-
tric neurology topics, and he is remembered for his
paper, ‘‘The Parentage of Child Neurology,’’ pre-
sented at the First International Congress of Child
Neurology in 1977.
Bengt Hagberg was born in 1923 in Gothenburg,
Sweden. He enrolled as a medical student at the
University of Uppsala and graduated in 1950, after
which he began the study of pediatrics in Uppsala
with Bo Vahlquist, a prominent Swedish academic
pediatrician. He spent several years in the field of
pediatric hematology but became interested in the
neurological diseases of children. The field of
pediatric neurology was new at the time, and he
enrolled in a 3-year program of adult neurology and
medicine. He received training from Karl Ekbom in
Uppsala, Wohlfahrt in Lund, and Waldenstrom in
Malmo. He also spent some time with Sven Brandt,
the only child neurologist in Scandinavia at the time.
Hagberg was essentially self taught in child neurol-
ogy, and as member of the department of pediatrics
at the University of Uppsala, training in pediatric
subspecialties was encouraged.
He was appointed professor of pediatrics at
Gothenburg in 1971 and soon thereafter developed
a neuropediatric center that became very successful.
Multiple fellows from Scandinavia and Europe were
trained in child neurology, and he began collabora-
tion with Ingemar Olow, with whom he completed
multiple epidemiological studies of patients with
cerebral palsy. He was also performed numerous
studies with Sourander and Svennerholm and pub-
lished cardinal studies on Rett’s syndrome.
In collaboration with Johannes Melchior, Hagberg
formed the Scandinavian Neuropaediatric Society in
1963, and he was also one of the founders, along
with Melchior and MacKeith, of the European
Federation of Child Neurologists. He has received
numerous awards and his notable enthusiasm in
presenting a lecture or discussing a clinical problem
has endeared him to the many trainees and visiting
scholars who have spent time with him. Bengt
Hagberg has contributed greatly to the foundation
of child neurology.
Paul Sandifer, born in 1908, studied law before he
began the study of medicine at the Middlesex
Hospital Medical School, University of London,
after which he was house physician to Douglas
MacAlpine and Sir Alan Moncrieff in the department
of pediatrics. He held subsequent positions at the
Brompton and Middlesex hospitals in 1936, and
after a residency at the Maudsley Hospital he
received a diploma in psychological medicine.
Sandifer was appointed house physician and later
senior medical officer at the National Hospital,
Queen Square. Following World War II, he was
appointed assistant physician at the Maida Vale
Hospital for Nervous Disorders and at the Royal
National Orthopedic Hospital. In 1953, he was
appointed child neurologist at the Hospital for Sick

Children Great Ormond Street and, as noted by
Macdonald Critchley, this was the ‘‘greatest hour in
his professional sense. This achievement led to his
appearance on the scene as the premier pediatric
neurologist—a remote successor of Frederick Bat-
ten.’’
Recognized early for his keen clinical and teaching
skills, Sandifer was sought after for consultation for
difficult clinical problems as well as to provide
second opinions. He attracted fellows and patients
from throughout the world, and his clinics were
always well attended not only by resident physicians
but also by visiting physicians. Despite enormous
clinical demands, he was always readily available to
discuss clinical problems with house officers, a
characteristic that endeared him to all who knew
him. Among his numerous publications, Sandifer is
remembered for his description of an unusual
syndrome, ‘‘hiatus hernia with contortions of the
neck,’’ which became known as Sandifer’s syndrome,
a manifestation of gastroesophageal reflux. He also
described ‘‘dancing eye syndrome,’’ distinguishing it
from other acquired ataxic syndromes and demon-
strating its responsiveness to treatment with ACTH.
He was preparing material for a textbook at the time
of his premature death. It is well recognized that Paul
Sandifer was one of the early founders of child
neurology in Great Britain.
Neil Gordon was born in 1908, and after
attending the Charterhouse School he enrolled in
the University of Edinburgh and graduated in 1940.
He received his medical degree in 1943 and became a
member of the Edinburgh College of Physicians in
1946 and a member of the London College in 1947.
He was registrar at the Royal Edinburgh Infirmary,
followed by an appointment at the National Hospi-
tal, Queen Square. He then worked at the Physicians’
Clinic at Moorfield’s Eye Hospital. Gordon was
senior registrar at St. Mary’s Hospital from 1955 to
1958.
His work at the Royal Manchester Children’s
Hospital was notable for his help in the establish-
ment of neurophysiological laboratories, the practi-
cal application of anticonvulsant serum levels, and
providing pathological facilities for investigation of
neuromuscular disorders. He enlarged the scope of
clinical services available to children with neurolo-
gical disabilities, including learning disabilities and
‘‘developmental apraxia.’’ He collaborated with
Ronald MacKeith on the international meetings of
the Spastics Society from their first meeting in
Oxford in 1958 and from which emerged the British
CHILD NEUROLOGY, HISTORY OF 715
Group of Pediatric Neurologists, later known as the
British Pediatric Neurology Association. At the time
of his retirement, Thomas Ingram noted that his
‘‘greatest achievement was to encourage adult
neurologists to accept pediatric neurology as a
distinct and respectable discipline—by example as
well as by words.’’
Thomas Ingram was born in Carlisle, England, in
1927. He completed medical studies at the University
of Edinburgh in 1949, during which time he became
interested in pediatrics, and while under the influence
of Richard Ellis he developed a particular interest in
child neurology. After receiving a diploma in child
health, he went on to complete research on the
neurological aspects of cerebral palsy, for which he
received a doctorate of medicine with a gold medal in
1961. He trained in pediatrics and neonatology at
Edinburgh and then pursued his interest in neurology
and cerebral palsy. Ingram spent 1 year with Derek
Denny-Brown at the Boston City Hospital, where he
had the opportunity to study neuropathology with
Paul Yakovlev and electroencephalography with
Margaret Lennox. He returned to London for further
study at the National Hospital, Queen Square, after
which he returned to Edinburgh, where he was
appointed senior lecturer and, later, reader in
pediatrics.
Ingram was an academic child neurologist, em-
phasizing that research and scholarship were the
basis of good practice. Moreover, he strongly
believed that all diseases of the brain, spinal cord,
and peripheral nervous system are the domain of the
child neurologist and that one should not be nihilistic
about treating children with neurological diseases.
In addition to his great interest in cerebral palsy, he
was also interested in the acquisition of speech and
language as well as learning disabilities. He was the
founding editor of Neuropaediatrie and was also on
the editorial board of Developmental Medicine and
Child Neurology. His prodigious effort in attempting
to understand the nature of cerebral palsy culmi-
nated in the text, Paediatric Aspects of Cerebral
Palsy.
Jean Aicardie was born in Rambouillet, France, in
1926. He completed studies at the Paris Medical
School and was then appointed Interne des Hopitaux
de Paris in 1951. He became interested in neurology
while at the Hopital de la Salpetriere, and he became
interested in child neurology while at the Hopital des
Enfants Malades in Paris. There was no recognized
discipline of child neurology in France until the first
unit of child neurology opened at the Hopital des
716 CHILD NEUROLOGY, HISTORY OF
Enfants Malades in 1952, emerging from a clinical
unit that had been dedicated to the care of children
with poliomyelitis. Aicardie became interested in
convulsive disorders of children, an interest that
continued throughout his life. While a research
fellow at the Boston Children’s Hospital, his knowl-
edge and interest in seizure disorders flourished.
Following his return to Paris, he became pediatrician
at the Hopital des Enfants Malades, where he
remained until 1964. In 1968, he joined the Institut
de la Sante et de la Recherche Medicale, and he
returned to Hopital des Enfants Malades in 1979.
Aicardie has been a very active member of multiple
European child neurology activities and was involved
in the development of the European Federation of
Child Neurology Societies. He has published numer-
ous scientific papers, described several new syn-
dromes, and has published several standard texts
relating to neurological diseases of childhood.
The development of child neurology in Japan had
its origin in the 1950s, approximately the time at
which Japanese pediatrics was recognized as an
independent medical specialty. Visiting professors of
neurology from Germany and France had a signifi-
cant impact on medical teaching at the Tokyo
Imperial University, and Japanese physicians in turn
traveled to Germany and France for additional
training in neurology. Moreover, following World
War II and the influence of American medical
teaching, there was a growing awareness in Japan
of the importance of neurology as a medical specialty
as well as a subspecialty of pediatrics. Yukio
Fukuyama was actively involved in the early devel-
opment of child neurology and was one of its
founders. In 1960, he facilitated the establishment
of the Society of Pediatric Psychiatry and Neurology.
Born in 1928, he enrolled as a medical student at
Tokyo University, where he was influenced by Shigeo
Okinaka, professor of medicine and founder of
neurology in Japan, and he graduated in 1962.
Following his internship, he began pediatric training
at the University of Tokyo Hospital and then
undertook graduate studies and clinical research in
child neurology. Tadao Takatsu, chairman of the
department of pediatrics, suggested that Fukuyama
direct his studies to child neurology and its develop-
ment at the University of Tokyo, and within a short
period of time he developed pediatric electrophysiol-
ogy laboratories and gathered a group of other
physicians who had similar interests in child neurol-
ogy. His contributions to the child neurology
literature and our knowledge of neurological diseases
of infancy and childhood are remarkable for their
scope and depth. Fukuyama was one of the founding
members of the Japanese Society of Child Neurology,
and in 1979 he established Brain and Development
as an international journal. He has served on the
editorial boards of numerous other journals and has
remained actively involved in the Japanese Society of
Child Neurology, the International Child Neurology
Association, and the Asian Oceanic Association of
Child Neurology. Fukuyama is one of the major
founders of child neurology not only in Japan but
also throughout Asia.
CONCLUSION
There has been a gradual increase in interest in the
nervous system from the time of the earliest known
portrayal of neurological diseases on the Syrian stele
of the 19th Egyptian dynasty. The contributions of
physicians to our knowledge of the nervous system
from antiquity to the present time have been
enormous, but not until the 20th century and
particularly beginning in the 1950s was there notable
interest in child neurology. Only a few individual
neurologists had an interest in children with diseases
of the nervous system in the United States, Great
Britain, Scandinavia, and Japan, and it is this group
of physicians who stimulated and promoted the
training of younger physicians in child neurology.
By the late 1960s, there were several training
programs in child neurology throughout the United
States, most of which were directed by those trained
in adult neurology but who were either appointed to
or had special interest in neurological diseases of
children. There were no formal guidelines for
training in child neurology; therefore, the National
Advisory Neurological Diseases and Blindness Coun-
cil appointed an ad hoc committee to provide advice
in this regard. The committee was chaired by Dr.
Rustin McIntosh and was composed of senior
neurologists, pediatricians, neuropathologists, and a
neuroanatomist, all primarily from the East Coast.
The recommendations of this ad hoc committee were
published, and revisions of their suggestions have
been made during subsequent years. A workshop on
training in pediatric neurology, chaired by Dr. Sidney
Carter, was held in 1967, and agreement was reached
regarding the qualifications of the core training
program and who should be identified as a child
neurologist. During the ensuing years, there have
been several meetings of the Accreditation Council
for Graduate Medical Education and the Residency

Review Committee (ACGME), and there is now
greater flexibility of training programs in child
neurology. However, to be accredited by the
ACGME each neurology training program must
have a defined period dedicated to training in child
neurology.
Child neurologists from the north central United
States began regular meetings to consider clinical
problems of interest, and in 1972 this group became
the nucleus of the Child Neurology Society, which
has grown from several hundred members in the
mid-1970s to 1171 members and 96 junior members
in 2002. Several years after the establishment of the
Child Neurology Society (CNS), it became apparent
that child neurologists in academic settings had
certain problems that were different from those in
clinical practice, and a society of directors of the
various training programs was formed called Profes-
sors of Child Neurology. These two child neurology
societies were able to present and discuss training
problems with the ABPN, but child neurologists had
no official representation on the ABPN. In 1982,
representatives of the CNS met with a committee of
past and present directors of the ABPN, and the
following year one of the director’s positions was
given to a child neurologist. A year later, a second
director’s position was held for a child neurologist.
During the past 50 years, the importance of child
neurology as a discipline has been recognized
throughout the Western world and Asia, and major
advances have been made in our understanding of
the developing nervous system and every area of
neuroscience. What began as an interest of a small
number of physicians has resulted in major contribu-
tions to our knowledge of the nervous system by
many child neurologists.
—Bruce Berg
See also–Charcot, Jean-Martin; Little, William
John; Nervous System, Neuroembryology of;
Sachs, Bernard
Further Reading
Aki, M. (1980). The history of neurology in Japan, with special
reference to its postwar period. In Historical Aspects of
Neurosciences (F. C. Rose and F. Bynum, Eds.). Raven Press,
New York.
Ashwal, S. (Ed.) (1990). The Founders of Child Neurology.
Norman, San Francisco.
Barlow, C. F. (1988). Memorium: Randolph K. Byers (1896–
1988). Harvard Med. Alum. Bull. 62, 67–68.
Berg, B. O. (1999). Reminisences of a child neurologist. J. Child
Neurol. 14, 736–744.
CHOREA 717
Byers, R. K. (1961). Pediatric profiles. J. Pediatr. 58, 438–444.
Critchley, M. (1965). P. H. Sandifer, F.R.C.P., D.P.M. Br. Med. J.
1, 131.
Garrison, F. A. (1929). An Introduction to the History of
Medicine, 4th ed. Saunders, Philadelphia.
Hagberg, B., Ingram, T. T. S., and MacKeith, R. (1970).
Development of paediatric neurology. Lancet 1, 940–942.
Haymaker, W., and Schiller, F. (Eds.) (1970). The Founders of
Neurology, 2nd ed. Thomas, Springfield, IL.
McHenry, L. C. (1969). Garrison’s History of Neurology. Thomas,
Springfield, IL.
Melchior, J. C. (1985). The Scandinavian Neuropaediatric Society.
The society’s history and present status. Brain Dev. 7, 545–548.
Obituary (1965). Paul Harmer Sandifer, F.R.C.P., D.P.M. Lancet
1, 113.
Riese, W. (1959). A History of Neurology. MD Publications, New
York.
Stumpf, D. A. (1981). The founding of pediatric neurology in
America. Bull. N. Y. Acad. Med. 57, 804–816.
Chorea
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
CHOREA, derived from the Latin choreus, meaning
dance, describes abnormal, purposeless, involuntary
movements that are brief. The causes of chorea are
many. In all cases, there is disruption of the function
of the brain region known as the basal ganglia and its
connection to the thalamus and cerebral cortex
(thalamocortical pathways). This disruption may be
due to anatomical damage, selective neuronal degen-
eration, imbalance of several chemicals of the brain,
or metabolic or immunological causes. In general,
mild chorea should not require any treatment
because the consequences of therapy may be worse
than any short-term relief. If chorea is severe and
disabling, it can be reduced by antidopaminergic
drugs.
Senile chorea (essential chorea) begins after age 60
and is not accompanied by any particular behavioral
symptoms or a family history of chorea. Subjects
usually have basal ganglia degeneration as seen on
neuroimaging studies. Currently, with many genetic
studies available, many subjects with this diagnosis
are found to have Huntington’s disease.
INHERITED CHOREAS
Table 1 lists inherited conditions for which chorea
may be the prominent feature. The most prototypic is
seen in Huntington’s disease.

either to have major intracranial injuries or to die
after a short fall. Such cases would clearly need to be
evaluated for suspected abuse.
An epidural hematoma may also occur after a
relatively short fall onto a hard surface. The epidural
is usually located beneath an associated skull
fracture. Most epidurals are due to accidental
injuries. In a study of 33 children with epidurals
who were younger than 4 years of age, two of the
injuries (6%) were due to abuse and the rest due to
nonabusive circumstances.
Other possible diagnoses to be considered are
extremely rare. Children with congenital bleeding
disorders or infants with vitamin K deficiency can
have intracranial hemorrhages. An intracranial an-
eurysm can bleed and result in a SDH. Children with
glutaric aciduria type I can have subdural hemor-
rhages, but they also have other signs of the disease,
including developmental delay, hypotonia, and cor-
tical atrophy.
—John M. Leventhal and Kirsten Bechtel
See also–Brain Injury, Traumatic:
Epidemiological Issues; Head Trauma, Overview;
Sudden Infant Death Syndrome (SIDS)
Further Reading
Billmire, M. E., and Myers, P. A. (1985). Serious head injury in
infants: Accident or abuse? Pediatrics 75, 340–342.
Committee on Child Abuse and Neglect, American Academy of
Pediatrics (2001). Shaken baby syndrome: Rotational cranial
injuries—Technical report. Pediatrics 108, 206–210.
Duhaime, A. C., Gennarelli, T. A., Thibault, L. E., et al. (1987).
The shaken baby syndrome. A clinical, pathological, and
biomechanical study. J. Neurosurg. 66, 409–415.
Duhaime, A. C., Christian, C. W., Rorke, L. B., et al. (1998).
Nonaccidental head injury in infants: The ‘‘shaken-baby
syndrome.’’ N. Engl. J. Med. 338, 1822–1829.
Emerson, M. V., Pieramici, D. J., Stoessel, K. M., et al. (2001).
Incidence and rate of disappearance of retinal hemorrhage in
newborns. Ophthalmology 108, 36–39.
Feldman, K. W., Bethel, R., Shugerman, R. P., et al. (2001). The
cause of infant and toddler subdural hemorrhage: A prospective
study. Pediatrics 108, 636–646.
Jenny, C., Hymel, K. P., Ritzen, A., et al. (1999)
CHILDHOOD BRAIN TUMORS 701
Levin, A. V. (2000). Retinal hemorrhages: A review. Recent Adv.
Paediatr. (T. J. David, Ed.) 18, 151–219.
Morris, M. W., Smith, S., Cressman, J., et al. (2000). Evaluation of
infants with subdural hematoma who lack external evidence of
abuse. Pediatrics 105, 549–553.
Shugerman, R. P., Paez, A., Grossman, D. C., et al. (1996).
Epidural hemorrhage: Is it abuse? Pediatrics 97, 664–668.
Starling, S. P., Holden, J. R., and Jenny, C. (1995). Abusive head
trauma: The relationship of perpetrators to their victims.
Pediatrics 95, 259–262.
Childhood Brain Tumors
Encyclopedia of the Neurological Sciences
Copyright 2003, Elsevier Science (USA). All rights reserved.
BRAIN TUMORS are the most common form of solid
tumor of childhood and are exceeded only by
leukemia in incidence of all cancers in patients
younger than 15 years of age. The reported incidence
of childhood tumors increased from 2.4 cases per
100,000 children under age 15 at risk per year in
1973 to 3.5 cases per 100,000 children at risk in
1994. It is unclear whether this reported increase in
incidence is representative of an actual increase in the
number of tumors occurring in childhood or whether
it is due to improved diagnosis and reporting. The
incidence of central nervous system tumors is
inversely proportional to age, with 3.5 to 4 cases
per 100,000 children in children younger than 5
years of age compared to 2.5 cases per 100,000 at
risk for children between 10 and 15 years of age. In
the United States each year, approximately 2200
children are diagnosed with central nervous system
tumors. The incidence of brain tumors is higher in
boys than in girls, with a ratio of approximately
55:45. This gender difference is primarily accounted
for by a male predominance of primitive neuroecto-
dermal tumors and ependymomas.
Approximately 50% of all childhood brain tumors
arise in the posterior fossa. In this region of brain, the
most common tumors are cerebellar astrocytomas,
medulloblastomas, ependymomas, and brainstem