NEUROLOGY FOR BACHELORS

INTRODUCTION

Neurology (from Greek νεῦρον, neuron, "nerve"; and -λογία, -logia) is a medical specialty
dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and
treatment of all categories of disease involving the central, peripheral, and autonomic nervous
systems, including their coverings, blood vessels, and all effector tissue, such as muscle.The
corresponding surgical specialty is neurosurgery. A neurologist is a physician who specializes in
neurology, and is trained to investigate, or diagnose and treat, neurological disorders. Pediatric
neurologists treat neurological disease in children.
Neurological disorders are disorders that can affect the central nervous system (brain and spinal
cord), the peripheral nervous system, or the autonomic nervous system.
Conditions can include but are not limited to:
behavioral/cognitive syndromes
headache disorders such as migraine, cluster headache and tension headache
epilepsy
neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's
disease, and Amyotrophic lateral sclerosis (Lou Gehrig's disease).
cerebrovascular disease, such as transient ischemic attack and stroke.
sleep disorders
pediatric cerebral palsy
infections of the brain (encephalitis), brain meninges (meningitis), spinal cord (myelitis)
infections of the peripheral nervous system
movement disorders such as Parkinson's disease, Huntington's disease, hemiballismus, tic
disorder, etc
demyelinating diseases of the central nervous system, such as multiple sclerosis, and of the
peripheral nervous system, such as Guillain-Barré syndrome
disorders of peripheral nerves, muscle (myopathy) and neuromuscular junctions
altered mental higher status, encephalopathy, stupor and coma
speech and language disorders
functional symptoms, having no apparent physiological cause
Neurologists complete, on average, at least 10 years of college education and clinical training.
Many neurologists also have additional subspecialty training (fellowships) after completing their
residency in one area of neurology such as stroke or vascular neurology, interventional
neurology, epilepsy, neuromuscular, neurorehabilitation, behavioral neurology, sleep medicine,
pain management, neuroimmunology, clinical neurophysiology, or movement disorders.
During a neurological examination, the neurologist reviews the patient's health history with
special attention to the current condition. The patient then takes a neurological exam. Typically,
the exam tests mental status, function of the cranial nerves (including vision), strength,
coordination, reflexes and sensation. This information helps the neurologist determine if the
problem exists in the nervous system and the clinical localization. Localization of the pathology
is the key process by which neurologists develop their differential diagnosis. Further tests may
be needed to confirm a diagnosis and ultimately guide therapy and appropriate management.
Neurologists are responsible for the diagnosis, treatment, and management of all the above
conditions. Neurologists frequently care for people with hereditary (genetic) diseases when the
major manifestations are neurological, as is frequently the case. Lumbar punctures are frequently
performed by neurologists. Some neurologists may develop an interest in particular subfields,
such as dementia, movement disorders, headaches, epilepsy, sleep disorders, chronic pain
management, multiple sclerosis or neuromuscular diseases.
Human brain

Illustration of the human brain and skull

The human brain is the center of the human nervous system and is a highly complex organ.
Enclosed in the cranium, it has the same general structure as the brains of other mammals, but is
over three times as large as the brain of a typical mammal with an equivalent body size. Most of
the expansion comes from the cerebral cortex, a convoluted layer of neural tissue that covers the
surface of the forebrain. Especially expanded are the frontal lobes, which are involved in
executive functions such as self-control, planning, reasoning, and abstract thought. The portion
of the brain devoted to vision is also greatly enlarged in human beings.
Brain evolution, from the earliest shrewlike mammals through primates to hominids, is marked
by a steady increase in encephalization, or the ratio of brain to body size. The human brain has
been estimated to contain 50–100 billion (1011) neurons, of which about 10 billion (1010) are
cortical pyramidal cells. These cells pass signals to each other via as many as 1000 trillion (1015)
synaptic connections.
The brain monitors and regulates the body's actions and reactions. It continuously receives
sensory information, and rapidly analyzes this data and then responds, controlling bodily actions
and functions. The brainstem controls breathing, heart rate, and other autonomic processes. The
neocortex is the center of higher-order thinking, learning, and memory. The cerebellum is
responsible for the body's balance, posture, and the coordination of movement.
In spite of the fact that it is protected by the thick bones of the skull, suspended in cerebrospinal
fluid, and isolated from the bloodstream by the blood-brain barrier, the delicate nature of the
human brain makes it susceptible to many types of damage and disease. The most common
forms of physical damage are closed head injuries such as a blow to the head, a stroke, or
poisoning by a wide variety of chemicals that can act as neurotoxins. Infection of the brain is
rare because of the barriers that protect it, but is very serious when it occurs. More common are
genetically based diseases, such as Parkinson's disease, multiple sclerosis, and many others. A
number of psychiatric conditions, such as schizophrenia and depression, are widely thought to be
caused at least partially by brain dysfunctions, although the nature of such brain anomalies is not
well understood.
Structure
Bisection of the head of an adult man, showing the cerebral cortex and underlying white matter
The adult human brain weighs on average about 3 lb (1.5 kg) with a size of around 1130 cubic
centimetres (cm3) in women and 1260 cm3 in men, although there is substantial individual
variation. Men's brains are on average 100g heavier than a woman's, even when corrected for
body size differences. The brain is very soft, having a consistency similar to soft gelatin or firm
tofu. Despite being referred to as "grey matter", the live cortex is pinkish-beige in color and
slightly off-white in the interior. The photo on the right shows a horizontal slice of the head of an
adult man, from the National Library of Medicine's Visible Human Project. In this project, two
human cadavers (from a man and a woman) were frozen and then sliced into thin sections, which
were individually photographed and digitized. The slice here is taken from a small distance
below the top of the brain, and shows the cerebral cortex (the convoluted cellular layer on the
outside) and the underlying white matter, which consists of myelinated fiber tracts traveling to
and from the cerebral cortex. At the age of 20, a man has around 176,000 km and a woman,
about 149,000 km of myelinated axons in their brains.

Drawing of the human brain, showing several important structures

The cerebral hemispheres form the largest part of the human brain and are situated above most
other brain structures. They are covered with a cortical layer with a convoluted topography.
Underneath the cerebrum lies the brainstem, resembling a stalk on which the cerebrum is
attached. At the rear of the brain, beneath the cerebrum and behind the brainstem, is the
cerebellum, a structure with a horizontally furrowed surface that makes it look different from any
other brain area. The same structures are present in other mammals, although the cerebellum is
not so large relative to the rest of brain. As a rule, the smaller the cerebrum, the less convoluted
the cortex. The cortex of a rat or mouse is almost completely smooth. The cortex of a dolphin or
whale, on the other hand, is more convoluted than the cortex of a human.
The dominant feature of the human brain is corticalization. The cerebral cortex in humans is so
large that it overshadows every other part of the brain. A few subcortical structures show
alterations reflecting this trend. The cerebellum, for example, has a medial zone connected
mainly to subcortical motor areas, and a lateral zone connected primarily to the cortex. In
humans the lateral zone takes up a much larger fraction of the cerebellum than in most other
mammalian species. Corticalization is reflected in function as well as structure. In a rat, surgical
removal of the entire cerebral cortex leaves an animal that is still capable of walking around and
interacting with the environment. In a human, comparable cerebral cortex damage produces a
permanent state of coma.

The four lobes of the cerebral cortex The bones of the human skull
The cerebral cortex is nearly symmetric in outward form, with left and right hemispheres.
Anatomists conventionally divide each hemisphere into four "lobes", the frontal lobe, parietal
lobe, temporal lobe, and occipital lobe. It is important to realize that this categorization does not
actually arise from the structure of the cortex itself: the lobes are named after the bones of the
skull that overlie them. There is one exception: the border between the frontal and parietal lobes
is shifted backward to the central sulcus, a deep fold that marks the line where the primary
somatosensory cortex and primary motor cortex come together.
Researchers who study the functions of the cortex divide it into three functional categories of
regions, or areas. One consists of the primary sensory areas, which receive signals from the
sensory nerves and tracts by way of relay nuclei in the thalamus. Primary sensory areas include
the visual area of the occipital lobe, the auditory area in the temporal lobe, and the
somatosensory area in the parietal lobe. A second category is the primary motor area, which
sends axons down to motor neurons in the brainstem and spinal chord. This area occupies the
rear portion of the frontal lobe, directly in front of the somatosensory area. The third category
consists of the remaining parts of the cortex, which are called the association areas. These areas
receive input from the sensory areas and lower parts of the brain and are involved in the complex
process that we call perception, thought, and decision making. The amount of association cortex,
relative to the other two categories, increase dramatically as one goes from simpler mammals,
such as the rat and the cat, to more complex ones, such as the chimpanzee and the human.

Major gyri and sulci on the lateral surface of the cortex

The cerebral cortex is essentially a sheet of neural tissue, folded in a way that allows a large
surface area to fit within the confines of the skull. Each cerebral hemisphere, in fact, has a total
surface area of about 1.3 square feet. Anatomists call each cortical fold a sulcus, and the smooth
area between folds a gyrus. Most human brains show a similar pattern of folding, but there are
enough variations in the shape and placement of folds to make every brain unique. Nevertheless,
the pattern is consistent enough for each major fold to have a name, for example, the "superior
frontal gyrus", "postcentral sulcus", or "trans-occipital sulcus". Deep folding features in brain
such as the inter-hemispheric and lateral fissure, and the insular cortex are present in almost all
normal subjects.

Brodmann's classification of areas of the cortex

Different parts of the cerebral cortex are involved in different cognitive and behavioral functions.
The differences show up in a number of ways: the effects of localized brain damage, regional
activity patterns exposed when the brain is examined using functional imaging techniques,
connectivity with subcortical areas, and regional differences in the cellular architecture of the
cortex. Anatomists describe most of the cortex—the part they call isocortex—as having six
layers, but not all layers are apparent in all areas, and even when a layer is present, its thickness
and cellular organization may vary. Several anatomists have constructed maps of cortical areas
on the basis of variations in the appearance of the layers as seen with a microscope. One of the
most widely used schemes came from Brodmann, who split the cortex into 51 different areas and
assigned each a number (anatomists have since subdivided many of the Brodmann areas). For
example, Brodmann area 1 is the primary somatosensory cortex, Brodmann area 17 is the
primary visual cortex, and Brodmann area 25 is the anterior cingulate cortex.

Topography

Topography of the primary motor cortex, showing which body part is controlled by each zone
Many of the brain areas Brodmann defined have their own complex internal structures. In a
number of cases, brain areas are organized into "topographic maps", where adjoining bits of the
cortex correspond to adjoining parts of the body, or of some more abstract entity. A simple
example of this type of correspondence is the primary motor cortex, a strip of tissue running
along the anterior edge of the central sulcus, shown in the image to the right. Motor areas
innervating each part of the body arise from a distinct zone, with neighboring body parts
represented by neighboring zones. Electrical stimulation of the cortex at any point causes a
muscle-contraction in the represented body part. This "somatotopic" representation is not evenly
distributed, however. The head, for example, is represented by a region about three times as large
as the zone for the entire back and trunk. The size of a zone correlates to the precision of motor
control and sensory discrimination possible. The areas for the lips, fingers, and tongue are
particularly large, considering the proportional size of their represented body parts.
In visual areas, the maps are retinotopic—that is, they reflect the topography of the retina, the
layer of light-activated neurons lining the back of the eye. In this case too the representation is
uneven: the fovea—the area at the center of the visual field—is greatly overrepresented
compared to the periphery. The visual circuitry in the human cerebral cortex contains several
dozen distinct retinotopic maps, each devoted to analyzing the visual input stream in a particular
way. The primary visual cortex (Brodmann area 17), which is the main recipient of direct input
from the visual part of the thalamus, contains many neurons that are most easily activated by
edges with a particular orientation moving across a particular point in the visual field. Visual
areas farther downstream extract features such as color, motion, and shape.
In auditory areas, the primary map is tonotopic. Sounds are parsed according to frequency (i.e.,
high pitch vs. low pitch) by subcortical auditory areas, and this parsing is reflected by the
primary auditory zone of the cortex. As with the visual system, there are a number of tonotopic
cortical maps, each devoted to analyzing sound in a particular way.Within a topographic map
there can sometimes be finer levels of spatial structure. In the primary visual cortex, for example,
where the main organization is retinotopic and the main responses are to moving edges, cells that
respond to different edge-orientations are spatially segregated from one another.

Lateralization

Routing of neural signals from the two eyes to the brain

Each hemisphere of the brain interacts primarily with one half of the body, but for reasons that
are unclear, the connections are crossed: the left side of the brain interacts with the right side of
the body, and vice versa. Motor connections from the brain to the spinal cord, and sensory
connections from the spinal cord to the brain, both cross the midline at brainstem levels. Visual
input follows a more complex rule: the optic nerves from the two eyes come together at a point
called the optic chiasm, and half of the fibers from each nerve split off to join the other. The
result is that connections from the left half of the retina, in both eyes, go to the left side of the
brain, whereas connections from the right half of the retina go to the right side of the brain.
Because each half of the retina receives light coming from the opposite half of the visual field,
the functional consequence is that visual input from the left side of the world goes to the right
side of the brain, and vice versa. Thus, the right side of the brain receives somatosensory input
from the left side of the body, and visual input from the left side of the visual field—an
arrangement that presumably is helpful for visuomotor coordination.
The corpus callosum, a nerve bundle connecting the two cerebral hemispheres, with the lateral
ventricles directly below
The two cerebral hemispheres are connected by a very large nerve bundle called the corpus
callosum, which crosses the midline above the level of the thalamus. There are also two much
smaller connections, the anterior commisure and hippocampal commisure, as well as many
subcortical connections that cross the midline. The corpus callosum is the main avenue of
communication between the two hemispheres, though. It connects each point on the cortex to the
mirror-image point in the opposite hemisphere, and also connects to functionally related points
in different cortical areas.
In most respects, the left and right sides of the brain are symmetrical in terms of function. For
example, the counterpart of the left-hemisphere motor area controlling the right hand is the right-
hemisphere area controlling the left hand. There are, however, several very important exceptions,
involving language and spatial cognition. In most people, the left hemisphere is "dominant" for
language: a stroke that damages a key language area in the left hemisphere can leave the victim
unable to speak or understand, whereas equivalent damage to the right hemisphere would cause
only minor impairment to language skills.
A substantial part of our current understanding of the interactions between the two hemispheres
has come from the study of "split-brain patients"—people who underwent surgical transection of
the corpus callosum in an attempt to reduce the severity of epileptic seizures. These patients do
not show unusual behavior that is immediately obvious, but in some cases can behave almost
like two different people in the same body, with the right hand taking an action and then the left
hand undoing it. Most such patients, when briefly shown a picture on the right side of the point
of visual fixation, are able to describe it verbally, but when the picture is shown on the left, are
unable to describe it, but may be able to give an indication with the left hand of the nature of the
object shown.
It should be noted that the differences between left and right hemispheres are greatly overblown
in much of the popular literature on this topic. The existence of differences has been solidly
established, but many popular books go far beyond the evidence in attributing features of
personality or intelligence to the left or right hemisphere dominance.
Sources of information
Information about the structure and function of the human brain comes from a variety of sources.
Most information about the cellular components of the brain and how they work comes from
studies of animal subjects, using techniques described in the brain article. Some techniques,
however, are used mainly in humans, and therefore are described here.
Computed tomography of human brain, from base of the skull to top, taken with intravenous
contrast medium
EEG
By placing electrodes on the scalp it is possible to record the summed electrical activity of the
cortex, in a technique known as electroencephalography (EEG). EEG measures mass changes in
population synaptic activity from the cerebral cortex, but can only detect changes over large
areas of the brain, with very little sensitivity for sub-cortical activity. EEG recordings can detect
events lasting only a few thousandths of a second. EEG recordings have good temporal
resolution, but poor spatial resolution.
Structural and functional imaging

A scan of the brain using fMRI

There are several methods for detecting brain activity changes by three-dimensional imaging of
local changes in blood flow. The older methods are SPECT and PET, which depend on injection
of radioactive tracers into the bloodstream. The newest method, functional magnetic resonance
imaging (fMRI), has considerably better spatial resolution and involves no radioactivity. Using
the most powerful magnets currently available, fMRI can localize brain activity changes to
regions as small as one cubic millimeter. The downside is that the temporal resolution is poor:
when brain activity increases, the blood flow response is delayed by 1–5 seconds and lasts for at
least 10 seconds. Thus, fMRI is a very useful tool for learning which brain regions are involved
in a given behavior, but gives little information about the temporal dynamics of their responses.
A major advantage for fMRI is that, because it is non-invasive, it can readily be used on human
subjects.
Effects of brain damage
A key source of information about the function of brain regions is the effects of damage to them.
In humans, strokes have long provided a "natural laboratory" for studying the effects of brain
damage. Most strokes result from a blood clot lodging in the brain and blocking the local blood
supply, causing damage or destruction of nearby brain tissue: the range of possible blockages is
very wide, leading to a great diversity of stroke symptoms. Analysis of strokes is limited by the
fact that damage often crosses into multiple regions of the brain, not along clear-cut borders,
making it difficult to draw firm conclusions.
Language

Location of two brain areas that play a critical role in language, Broca's area and Wernicke's area
In human beings, it is the left hemisphere that usually contains the specialized language areas.
While this holds true for 97% of right-handed people, about 19% of left-handed people have
their language areas in the right hemisphere and as many as 68% of them have some language
abilities in both the left and the right hemisphere. The two hemispheres are thought to contribute
to the processing and understanding of language: the left hemisphere processes the linguistic
meaning of prosody (or, the rhythm, stress, and intonation of connected speech), while the right
hemisphere processes the emotions conveyed by prosody. Studies of children have shown that if
a child has damage to the left hemisphere, the child may develop language in the right
hemisphere instead. The younger the child, the better the recovery. So, although the "natural"
tendency is for language to develop on the left, human brains are capable of adapting to difficult
circumstances, if the damage occurs early enough.
The first language area within the left hemisphere to be discovered is Broca's area, named after
Paul Broca, who discovered the area while studying patients with aphasia, a language disorder.
Broca's area doesn't just handle getting language out in a motor sense, though. It seems to be
more generally involved in the ability to process grammar itself, at least the more complex
aspects of grammar. For example, it handles distinguishing a sentence in passive form from a
simpler subject-verb-object sentence — the difference between "The boy was hit by the girl" and
"The girl hit the boy."
The second language area to be discovered is called Wernicke's area, after Carl Wernicke, a
German neurologist who discovered the area while studying patients who had similar symptoms
to Broca's area patients but damage to a different part of their brain. Wernicke's aphasia is the
term for the disorder occurring upon damage to a patient's Wernicke's area.
Wernicke's aphasia does not only affect speech comprehension. People with Wernicke's aphasia
also have difficulty recalling the names of objects, often responding with words that sound
similar, or the names of related things, as if they are having a hard time recalling word
associations.
Pathology

A human brain showing frontotemporal lobar degeneration causing frontotemporal dementia

Clinically, death is defined as an absence of brain activity as measured by EEG. Injuries to the
brain tend to affect large areas of the organ, sometimes causing major deficits in intelligence,
memory, personality, and movement. Head trauma caused, for example, by vehicle or industrial
accidents, is a leading cause of death in youth and middle age. In many cases, more damage is
caused by resultant edema than by the impact itself. Stroke, caused by the blockage or rupturing
of blood vessels in the brain, is another major cause of death from brain damage.
Other problems in the brain can be more accurately classified as diseases than as injuries.
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, motor neurone
disease, and Huntington's disease are caused by the gradual death of individual neurons, leading
to diminution in movement control, memory, and cognition.
Mental disorders, such as clinical depression, schizophrenia, bipolar disorder and post-traumatic
stress disorder may involve particular patterns of neuropsychological functioning related to
various aspects of mental and somatic function. These disorders may be treated by
psychotherapy, psychiatric medication or social intervention and personal recovery work; the
underlying issues and associated prognosis vary significantly between individuals.
Some infectious diseases affecting the brain are caused by viruses and bacteria. Infection of the
meninges, the membrane that covers the brain, can lead to meningitis. Bovine spongiform
encephalopathy (also known as "mad cow disease") is deadly in cattle and humans and is linked
to prions. Kuru is a similar prion-borne degenerative brain disease affecting humans. Both are
linked to the ingestion of neural tissue, and may explain the tendency in human and some non-
human species to avoid cannibalism. Viral or bacterial causes have been reported in multiple
sclerosis and Parkinson's disease, and are established causes of encephalopathy, and
encephalomyelitis.
Many brain disorders are congenital, occurring during development. Tay-Sachs disease, Fragile
X syndrome, and Down syndrome are all linked to genetic and chromosomal errors. Many other
syndromes, such as the intrinsic circadian rhythm disorders, are suspected to be congenital as
well. Normal development of the brain can be altered by genetic factors, drug use, nutritional
deficiencies, and infectious diseases during pregnancy.
Ventricular system
Brain: Cerebral ventricles

Scheme showing relations of the ventricles to the surface of

the brain.

Drawing of a cast of the ventricular cavities, viewed from

above.
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is
continuous with the central canal of the spinal cord.
Components
The system comprises four ventricles:
 right and left lateral ventricles
 third ventricle
 fourth ventricle
There are several small holes or foramina that connect these ventricles, though only the first two
of the list below are generally considered part of the ventricular system:
Name From To
right and left interventricular foramina lateral
third ventricle
(Monro) ventricles
cerebral aqueduct (Sylvius) third ventricle fourth ventricle
fourth
Median aperture (Magendie) subarachnoid space/cisterna magna
ventricle
fourth subarachnoid space/cistern of great
right and left Lateral aperture (Luschka)
ventricle cerebral vein
Ventricles
There are four cerebral ventricles: the paired lateral ventricles, and midline the third and fourth
ventricles. The two lateral ventricles, located within the cerebrum, are relatively large and C-
shaped, roughly wrapping around the dorsal aspects of the basal ganglia. It is in the lateral
ventricles of the embryo that the successive generation of neurons gives rise to the 6-layered
structure of the neocortex, constructed from the inside out during development. Each lateral
ventricle extends into the frontal, temporal and occipital lobes via the frontal (anterior), temporal
(inferior), and occipital (posterior) horns, respectively. The "body" and "atrium" are situated
between the anterior and posterior horns.
The lateral ventricles both communicate via the interventricular foramina with the third ventricle,
found centrally within the diencephalon. The third ventricle communicates via the cerebral
aqueduct, located within the midbrain, with the fourth ventricle, found within the hindbrain. The
three foramina to the subarachnoid space are found here, permitting cerebrospinal fluid produced
in the ventricles to surround the brainstem, cerebellum, and cerebral cortex. The fourth ventricle
is also continuous with the central canal, allowing CSF to bathe the inside surface of the spinal
cord as well.
Flow of cerebrospinal fluid
The ventricles are filled with cerebrospinal fluid (CSF) which bathes and cushions the brain and
spinal cord within their bony confines. Cerebrospinal fluid is produced by modified ependymal
cells of the choroid plexus found in all components of the ventricular system except for the
cerebral aqueduct and the occipital and frontal horns of the lateral ventricles. CSF flows from the
lateral ventricles via the foramina of Monro into the third ventricle, and then the fourth ventricle
via the cerebral aqueduct in the brainstem. From there it can pass into the central canal of the
spinal cord or into the cisterns of the subarachnoid space via three small foramina: the central
foramen of Magendie and the two lateral foramina of Luschka.
The fluid then flows around the superior sagittal sinus to be reabsorbed via the arachnoid villi
into the venous system. CSF within the spinal cord can flow all the way down to the lumbar
cistern at the end of the cord around the cauda equina where lumbar punctures are performed.
The aqueduct between the third and fourth ventricles is very small, as are the foramina, which
means that they can be easily blocked, causing high pressure in the lateral ventricles. This is a
common cause of hydrocephalus--otherwise known as water in the brain--and is an extremely
serious condition due to both the damage caused by the pressure as well as nature of whatever
caused the block (possibly a tumour or inflammatory swelling).
Protection of the brain
The brain and spinal cord are covered by a series of tough membranes called meninges, which
protect these organs from rubbing against the bones of the skull and spine. The cerebrospinal
fluid within the skull and spine is found between the pia mater and the arachnoid meninges and
provides further cushioning.
Role in disease or disorder
Diseases of the ventricular system include abnormal enlargement (hydrocephalus) and
inflammation of the CSF spaces (meningitis, ventriculitis) caused by infection or introduction of
blood following trauma or hemorrhage.
Interestingly, scientific study of CT scans of the ventricles in the late 1970s revolutionized the
study of mental disorder. Researchers found that individuals with schizophrenia had (in terms of
group averages) enlarged ventricles compared to healthy subjects.This became the first
"evidence" that mental disorder was biological in origin and led to a reinvigoration of the study
of such conditions via modern scientific techniques. Whether the enlargement of the ventricles is
a cause or a result of schizophrenia has not yet been ascertained, however. Nowadays, magnetic
resonance imaging (MRI) has superseded the use of CT in research into the role of ventricular
abnormalities in psychiatric illness. Ventricle volumes have been found to be "mainly explained
by environmental factors"1 and to be extremely diverse between individuals, such that the
percentage difference in group averages in schizophrenia studies (+16%) has been described as
"not a very profound difference in the context of normal variation."(ranging from 25% to 350%
of the mean average)2
Cerebrospinal fluid

4 vials of CSF
Cerebrospinal fluid (CSF), Liquor cerebrospinalis, is a clear bodily fluid that occupies the
subarachnoid space and the ventricular system around and inside the brain. In essence, the brain
"floats" in it.
The CSF occupies the space between the arachnoid mater (the middle layer of the brain cover,
meninges), and the pia mater (the layer of the meninges closest to the brain). It constitutes the
content of all intra-cerebral (inside the brain, cerebrum) ventricles, cisterns, and sulci (singular
sulcus), as well as the central canal of the spinal cord.
It acts as a "cushion" or buffer for the cortex, providing a basic mechanical and immunological
protection to the brain inside the skull.
It is produced in the choroid plexus.
Circulation
CSF is produced in the brain by modified ependymal cells in the choroid plexus (approx. 50-
70%), and the remainder is formed around blood vessels and along ventricular walls. It circulates
from the choroid plexus through the interventricular foramina (foramen of Monro) into the third
ventricle, and then through the cerebral aqueduct (aqueduct of Sylvius) into the fourth ventricle,
where it exits through two lateral apertures (foramina of Luschka) and one median aperture
(foramen of Magendie). It then flows through the cerebellomedullary cistern down the spinal
cord and over the cerebral hemispheres.
It had been thought that CSF returns to the vascular system by entering the dural venous sinuses
via the arachnoid granulations or villi. However, some1 have suggested that CSF flow along the
cranial nerves and spinal nerve roots allow it into the lymphatic channels; this flow may play a
substantial role in CSF reabsorbtion, in particular in the neonate, in which arachnoid granulations
are sparsely distributed. The flow of CSF to the nasal submucosal lymphatic channels through
the cribiform plaque seems to be specially important2.
Amount and constitution
The CSF is produced at a rate of 500 ml/day. Reference ranges in CSF
Since the brain can contain only from 135 to 150 Substance Lower limit Upper limit Unit
ml, large amounts are drained primarily into the 3
blood through arachnoid granulations in the Glucose 50 803 ng/dL
3 4 3
superior sagittal sinus. Thus the CSF turns over Protein 15 40 - 45 mg/dL
3 3
about 3.7 times a day. This continuous flow into RBCs n/a 0 / negative cells/µL
the venous system dilutes the concentration of WBCs 0 3
33 cells/µL
larger, lipoinsoluble molecules penetrating the
brain and CSF.5
The CSF contains approximately 0.3% plasma proteins, or approximately 15 to 40 mg/dL,
depending on sampling site.4 CSF pressure ranges from 80 to 100 mmH2O (780–980 Pa or 4.4-
7.3 mmHg) in newborns, and < 200 mmH20 (1.94 kPa) in normal children and adults, with most
variations due to coughing or internal compression of jugular veins in the neck.
There are quantitative differences in the distributions of a number of proteins in the CSF. In
general, globular proteins and albumin are in lower concentration in ventricular CSF compared
to lumbar or cisternal fluid.6
Functions
CSF serves four primary purposes:
1. Buoyancy-- The actual mass of the human brain is about 1400 grams; however the net
weight of the brain suspended in the CSF is equivalent to a mass of 25 grams.7 The brain
therefore exists in neutral buoyancy, which allows the brain to maintain its density
without being impaired by its own weight, which would cut off blood supply and kill
neurons in the lower sections without CSF.8
2. Protection-- CSF protects the brain tissue from injury when jolted or hit. In certain
situations such as auto accidents or sports injuries, the CSF cannot protect the brain from
forced contact with the skull case, causing hemorrhaging, brain damage, and sometimes
death.9
3. Chemical Stability-- CSF flows throughout the inner ventricular system in the brain and
is absorbed back into the bloodstream, rinsing the metabolic waste from the central
nervous system through the blood-brain barrier. This allows for homeostatic regulation of
the distribution of neuroendocrine factors, to which slight changes can cause problems or
damage to the nervous system. For example, high glycine concentration disrupts
temperature and blood pressure control, and high CSF pH causes dizziness and
syncope.10
4. Prevention of brain ischemia-- The prevention of brain ischemia is made by decreasing
the amount of CSF in the limited space inside the skull. This decreases total intracranial
pressure and facilitates blood perfusion.
Pathology and laboratory diagnosis

Cerebrospinal fluid (CSF) at glance.

When CSF pressure is elevated, cerebral blood flow may be constricted. When disorders of CSF
flow occur, they may therefore affect not only CSF movement but also craniospinal compliance
and the intracranial blood flow, with subsequent neuronal and glial vulnerabilities. The venous
system is also important in this equation. Infants and patients shunted as small children may have
particularly unexpected relationships between pressure and ventricular size, possibly due in part
to venous pressure dynamics. This may have significant treatment implications, but the
underlying pathophysiology needs to be further explored.
CSF connections with the lymphatic system have been demonstrated in several mammalian
systems. Preliminary data suggest that these CSF-lymph connections form around the time that
the CSF secretory capacity of the choroid plexus is developing (in utero). There may be some
relationship between CSF disorders, including hydrocephalus and impaired CSF lymphatic
transport.
CSF can be tested for the diagnosis of a variety of neurological diseases.11 It is usually obtained
by a procedure called lumbar puncture. Removal of CSF during lumber puncture can cause a
severe headache after the fluid is removed, because the brain hangs on the vessels and nerve
roots, and traction on them stimulates pain fibers. The pain can be relieved by intrathecal
injection of sterile isotonic saline. Lumbar puncture is performed in an attempt to count the cells
in the fluid and to detect the levels of protein and glucose. These parameters alone may be
extremely beneficial in the diagnosis of subarachnoid hemorrhage and central nervous system
infections (such as meningitis). Moreover, a CSF culture examination may yield the
microorganism that has caused the infection. By using more sophisticated methods, such as the
detection of the oligoclonal bands, an ongoing inflammatory condition (for example, multiple
sclerosis) can be recognized. A beta-2 transferrin assay is highly specific and sensitive for the
detection for, e.g., CSF leakage.
Polymorphonuclear
Cause Appearance Lymphocyte Protein Glucose
cell
Pyogenic Slightly
Yellowish, Markedly
bacterial Markedly increase increase or Decrease
turbid increase
meningitis Normal
Slightly
Viral Slightly increase or Markedly
Clear fluid increase or Normal
meningitis Normal increase
Normal
Tuberculous Yellowish and Slightly increase or Markedly
Increase Decrease
meningitis viscous Normal increase
Slightly
Fungal Yellowish and Slightly increase or Markedly Normal or
increase or
meningitis viscous Normal increase decrease
Normal

Lumbar puncture
Lumbar puncture can also be performed to measure the intracranial pressure, which might be
increased in certain types of hydrocephalus. However a lumbar puncture should never be
performed if increased intracranial pressure is suspected because it could lead to brain herniation
and ultimately death.

A patient undergoes a lumbar puncture at the hands of a neurologist. The reddish-brown swirls
on the patient's back are tincture of iodine (an antiseptic).
In medicine, a lumbar puncture (colloquially known as a spinal tap) is a diagnostic and at times
therapeutic procedure that is performed in order to collect a sample of cerebrospinal fluid (CSF)
for biochemical, microbiological, and cytological analysis, or very rarely as a treatment
("therapeutic lumbar puncture") to relieve increased intracranial pressure.
Indications
The most common purpose for a lumbar puncture is to collect cerebrospinal fluid in a case of
suspected meningitis, since there is no other reliable tool with which meningitis, a life-
threatening but highly treatable condition, can be excluded. Young infants commonly require
lumbar puncture as a part of the routine workup for fever without a source, as they have a much
higher risk of meningitis than older persons and do not reliably show signs of meningeal
irritation (meningismus). In any age group, subarachnoid hemorrhage, hydrocephalus, benign
intracranial hypertension and many other diagnoses may be supported or excluded with this test.
Lumbar punctures may also be done to inject medications into the cerebrospinal fluid
("intrathecally"), particularly for spinal anesthesia or chemotherapy.It may also be used to detect
the presence of malignant cells in the CSF,as in carcinomatous meningitis or medulloblastoma.
Lumbar punctures can be unpleasant for some people, due to increased sensitivity when the
needle is inserted to collect the cerebrospinal fluid.
Contraindications
Lumbar puncture should not be performed when idiopathic (unidentified cause) increased
intracranial pressure (ICP) is present. The exception is therapeutic use of lumbar puncture to
relieve ICP. Ideally, a CT scan should be performed prior to lumbar puncture to rule out space
occupying lesions. Lumbar puncture should not be attempted when there is coagulopathy,
abnormal respiratory pattern,hypertension with bradycardia and deteriorating consciousness or
when there are decreased levels of platelets in the blood (less than 50 x 109/L). Lumbar puncture
in cases of vertebral deformities (scoliosis or kyphosis) is also contraindicated in hands of an
unexperienced physician.12
Procedure

Spinal needles used in lumbar puncture.

In performing a lumbar puncture, first the patient is usually placed in a left (or right) lateral
position with his/her neck bent in full flexion and knees bent in full flexion up to his/her chest,
approximating a fetal position as much as possible. It is also possible to have the patient sit on a
stool and bend his/her head and shoulders forward. The area around the lower back is prepared
using aseptic technique. Once the appropriate location is palpated, local anaesthetic is infiltrated
under the skin and then injected along the intended path of the spinal needle. A spinal needle is
inserted between the lumbar vertebrae L3/L4 or L4/L5 and pushed in until there is a "give" that
indicates the needle is past the dura mater. The stylet from the spinal needle is then withdrawn
and drops of cerebrospinal fluid are collected. The opening pressure of the cerebrospinal fluid
may be taken during this collection by using a simple column manometer. The procedure is
ended by withdrawing the needle while placing pressure on the puncture site. In the past, the
patient would often be asked to lie on his/her back for at least six hours and be monitored for
signs of neurological problems, though there is no scientific evidence that this provides any
benefit. The technique described is almost identical to that used in spinal anesthesia, except that
spinal anesthesia is more often done with the patient in a sitting position.
The upright seated position is advantageous in that there is less distortion of spinal anatomy
which allows for easier withdrawal of fluid. It is preferred by some practitioners when a lumbar
puncture is performed on an obese patient where having them lie on their side would cause a
scoliosis and unreliable anatomical landmarks. On the other hand, opening pressures are
notoriously unreliable when measured on a seated patient and therefore the left or right lateral
(lying down) position is preferred if an opening pressure needs to be measured.
Patient anxiety during the procedure can lead to increased CSF pressure, especially if the person
holds their breath, tenses their muscles or flexes their knees too tightly against their chest.
Diagnostic analysis of changes in fluid pressure during lumbar puncture procedures requires
attention both to the patient's condition during the procedure and to their medical history.
Reinsertion of the stylet may decrease the rate of post lumbar puncture headaches.2
Risks
Headache with nausea is the most common complication; it often responds to analgesics and
infusion of fluids and can often be prevented by strict maintenance of a supine posture for two
hours after the successful puncture. Merritt's Neurology (10th edition), in the section on lumbar
puncture, notes that intravenous caffeine injection is often quite effective in aborting these so-
called "spinal headaches." Contact between the side of the lumbar puncture needle and a spinal
nerve root can result in anomalous sensations (paresthesia) in a leg during the procedure; this is
harmless and patients can be warned about it in advance to minimize their anxiety if it should
occur. A headache that is persistent despite a long period of bedrest and occurs only when sitting
up may be indicative of a CSF leak from the lumbar puncture site. It can be treated by more
bedrest, or by an epidural blood patch, where the patient's own blood is injected back into the site
of leakage to cause a clot to form and seal off the leak.
Serious complications of a properly performed lumbar puncture are extremely rare. They include
spinal or epidural bleeding, and trauma to the spinal cord or spinal nerve roots resulting in
weakness or loss of sensation, or even paraplegia. The latter is exceedingly rare, since the level
at which the spinal cord ends (normally the inferior border of L1, although it is slightly lower in
infants) is several vertebral spaces above the proper location for a lumbar puncture (L3/L4).
There are case reports of lumbar puncture resulting in perforation of abnormal dural arterio-
venous malformations, resulting in catastrophic epidural hemorrhage; this is exceedingly rare.
The procedure is not recommended when epidural infection is present or suspected, when topical
infections or dermatological conditions pose a risk of infection at the puncture site or in patients
with severe psychosis or neurosis with back pain. Some authorities believe that withdrawal of
fluid when initial pressures are abnormal could result in spinal cord compression or cerebral
herniation; others believe that such events are merely coincidental in time, occurring
independently as a result of the same pathology that the lumbar puncture was performed to
diagnose. In any case, computed tomography of the brain is often performed prior to lumbar
puncture if an intracranial mass is suspected.
Removal of cerebrospinal fluid resulting in reduced fluid pressure has been shown to correlate
with greater reduction of cerebral blood flow among patients with Alzheimer's disease. Its
clinical significance is uncertain.
Diagnostics
Increased CSF pressure can indicate congestive heart failure, cerebral edema, subarachnoid
hemorrhage, hypo-osmolality resulting from hemodialysis, meningeal inflammation, purulent
meningitis or tuberculous meningitis, hydrocephalus, or pseudotumor cerebri.
Decreased CSF pressure can indicate complete subarachnoid blockage, leakage of spinal fluid,
severe dehydration, hyperosmolality, or circulatory collapse. Significant changes in pressure
during the procedure can indicate tumors or spinal blockage resulting in a large pool of CSF, or
hydrocephalus associated with large volumes of CSF. Lumbar puncture for the purpose of
reducing pressure is performed in some patients with idiopathic intracranial hypertension (also
called pseudotumor cerebri.)
The presence of white blood cells in cerebrospinal fluid is called pleocytosis. A small number of
monocytes can be normal; the presence of granulocytes is always an abnormal finding. A large
number of granulocytes often heralds bacterial meningitis. White cells can also indicate reaction
to repeated lumbar punctures, reactions to prior injections of medicines or dyes, central nervous
system hemorrhage, leukemia, recent epileptic seizure, or a metastatic tumor. When peripheral
blood contaminates the withdrawn CSF, a common procedural complication, white blood cells
will be present along with erythrocytes, and their ratio will be the same as that in the peripheral
blood.
Several substances found in cerebrospinal fluid are available for diagnostic measurement.
 Measurement of chloride levels may aid in detecting the presence of tuberculous
meningitis.
 Glucose is usually present in the CSF; the level is usually about 60% that in the
peripheral circulation. A fingerstick or venipuncture at the time of lumbar puncture may
therefore be performed to assess peripheral glucose levels in order to determine a
predicted CSF glucose value. Decreased glucose levels can indicate fungal, tuberculous
or pyogenic infections; lymphomas; leukemia spreading to the meninges;
meningoencephalitic mumps; or hypoglycemia. A glucose level of less than one third of
blood glucose levels in association with low CSF lactate levels is typical in hereditary
CSF glucose transporter deficiency also know as De Vivo disease.
 Increased glucose levels in the fluid can indicate diabetes, although the 60% rule still
applies.
 Increased levels of glutamine are often involved with hepatic encephalopathies, Reye's
syndrome, hepatic coma, cirrhosis and hypercapnia.
 Increased levels of lactate can occur the presence of cancer of the CNS, multiple
sclerosis, heritable mitochondrial disease, low blood pressure, low serum phosphorus,
respiratory alkalosis, idiopathic seizures, traumatic brain injury, cerebral ischemia, brain
abscess, hydrocephalus, hypocapnia or bacterial meningitis.
 The enzyme lactate dehydrogenase can be measured to help distinguish meningitides of
bacterial origin, which are often associated with high levels of the enzyme, from those of
viral origin in which the enzyme is low or absent.
 Changes in total protein content of cerebrospinal fluid can result from pathologically
increased permeability of the blood-cerebrospinal fluid barrier, obstructions of CSF
circulation, meningitis, neurosyphilis, brain abscesses, subarachnoid hemorrhage, polio,
collagen disease or Guillain-Barré syndrome, leakage of CSF, increases in intracranial
pressure or hyperthyroidism. Very high levels of protein may indicate tuberculous
meningitis or spinal block.
 IgG synthetic rate is calculated from measured IgG and total protein levels; it is elevated
in immune disorders such as multiple sclerosis, transverse myelitis, and neuromyelitis
optica of Devic.
 Numerous antibody-mediated tests for CSF are available in some countries: these include
rapid tests for antigens of common bacterial pathogens, treponemal titers for the
diagnosis of neurosyphilis and Lyme disease, Coccidioides antibody, and others.
 The India ink test is still used for detection of meningitis caused by Cryptococcus
neoformans, but the cryptococcal antigen (CrAg) test has a higher sensitivity.
 CSF can be sent to the microbiology lab for various types of smears and cultures to
diagnose infections.
 Polymerase chain reaction (PCR) has been a great advance in the diagnosis of some types
of meningitis. It has high sensitivity and specificity for many infections of the CNS, is
fast, and can be done with small volumes of CSF. Even though testing is expensive, it
saves cost of hospitalization.
History
The first technique for accessing the dural space was described by the London physician Dr
Walter Essex Wynter. In 1889, he developed a crude cut down with cannulation in 4 patients
with tuberculous meningitis. The main purpose was the treatment of raised intracranial pressure
rather than for diagnosis.3 The technique for needle lumbar puncture was then introduced by the
German physician Heinrich Quincke, who credits Wynter with the earlier discovery; he first
reported his experiences at an internal medicine conference in Wiesbaden in 1891.4 He
subsequently published a book on the subject.56
The lumbar puncture procedure was taken to the United States by Arthur H. Wentworth M.D., an
assistant professor at the Harvard Medical School, based at Children's Hospital. In 1893, he
published a long paper on diagnosing cerebro-spinal meningitis by examining spinal fluid. His
career took a nosedive, however, when the antivivisectionists prosecuted him for having
obtained spinal fluid from children. He was acquitted, but he was disinvited from the then
forming Johns Hopkins Medical School where he would have been the first professor of
pediatrics.
Hydrocephalus
Hydrocephalus

Hydrocephalus seen on a CT scan of the brain.

Hydrocephalus1, also known as Water on the Brain, is a medical condition. People with
hydrocephalus have an abnormal accumulation of cerebrospinal fluid (CSF) in the ventricles, or
cavities, of the brain. This may cause increased intracranial pressure inside the skull and
progressive enlargement of the head, convulsion, and mental disability. Hydrocephalus can also
cause death.
History
Hydrocephalus was first described by the ancient Greek physician Hippocrates, but it remained
an intractable condition until the 20th century, when shunts and other neurosurgical treatment
modalities were developed. It is a lesser-known medical condition; relatively small amounts of
research are conducted to improve treatments for hydrocephalus, and to this day there remains no
cure for the condition.
Epidemiology
Hydrocephalus affects both pediatric and adult patients. According to the NIH website, there are
an estimated 700,000 children and adults living with hydrocephalus.
Pediatric hydrocephalus affects one in every 500 live births,2 making it one of the most common
developmental disabilities, more common than Down syndrome or deafness.3 It is the leading
cause of brain surgery for children in the United States. There are over 180 different causes of
the condition, one of the most common acquired etiologies being brain hemorrhage associated
with premature birth. Pediatric hydrocephalus may also be a heritable condition and runs in
certain families mostly affecting boys.
One of the most performed treatments for hydrocephalus, the cerebral shunt, has not changed
much since it was developed in 1960. The shunt must be implanted through neurosurgery into
the patient's brain, a procedure which itself may cause brain damage. An estimated 50% of all
shunts fail within two years, requiring further surgery to replace the shunts. In the past 25 years,
death rates associated with hydrocephalus have decreased from 54% to 5% and the occurrence of
intellectual disability has decreased from 62% to 30%.
Pathology
Hydrocephalus is usually due to blockage of cerebrospinal fluid (CSF) outflow in the ventricles
or in the subarachnoid space over the brain. In a person without hydrocephalus, CSF
continuously circulates through the brain, its ventricles and the spinal cord and is continuously
drained away into the circulatory system. Alternatively, the condition may result from an
overproduction of the CSF fluid, from a congenital malformation blocking normal drainage of
the fluid, or from complications of head injuries or infections.4
Compression of the brain by the accumulating fluid eventually may cause convulsions and
mental retardation. These signs occur sooner in adults, whose skulls no longer are able to expand
to accommodate the increasing fluid volume within. Fetuses, infants, and young children with
hydrocephalus typically have an abnormally large head, excluding the face, because the pressure
of the fluid causes the individual skull bones — which have yet to fuse — to bulge outward at
their juncture points. Another medical sign, in infants, is a characteristic fixed downward gaze
with whites of the eyes showing above the iris, as though the infant were trying to examine its
own lower eyelids.5 Hydrocephalus occurs in about one out of every 500 live births2 and was
routinely fatal until surgical techniques for shunting the excess fluid out of the central nervous
system and into the blood or abdomen were developed. Hydrocephalus is detectable during
prenatal ultrasound examinations.
Usually, hydrocephalus does not cause any intellectual disability if recognized and properly
treated. A massive degree of hydrocephalus rarely exists in typically functioning people, though
such a rarity may occur if onset is gradual rather than sudden.6

Spontaneous intracerebral and intraventricular hemorrhage with hydrocephalus shown on CT

scan7
The elevated intracranial pressure may cause compression of the brain, leading to brain damage
and other complications. Conditions among affected individuals vary widely. Children who have
had hydrocephalus may have very small ventricles, and presented as the "normal case".
If the foramina (pl.) of the fourth ventricle or the cerebral aqueduct are blocked, cereobrospinal
fluid (CSF) can accumulate within the ventricles. This condition is called internal
hydrocephalus and it results in increased CSF pressure. The production of CSF continues, even
when the passages that normally allow it to exit the brain are blocked. Consequently, fluid builds
inside the brain causing pressure that compresses the nervous tissue and dilates the ventricles.
Compression of the nervous tissue usually results in irreversible brain damage. If the skull bones
are not completely ossified when the hydrocephalus occurs, the pressure may also severely
enlarge the head. The cerebral aqueduct may be blocked at the time of birth or may become
blocked later in life because of a tumor growing in the brainstem.
Internal hydrocephalus can be successfully treated by placing a drainage tube (shunt) between
the brain ventricles and abdominal cavity to eliminate the high internal pressures. There is some
risk of infection being introduced into the brain through these shunts, however, and the shunts
must be replaced as the person grows. A subarachnoid hemorrhage may block the return of CSF
to the circulation. If CSF accumulates in the subarachnoid space, the condition is called external
hydrocephalus. In this condition, pressure is applied to the brain externally, compressing neural
tissues and causing brain damage. Thus resulting in further damage of the brain tissue and
leading to necrotization.
Classification
Hydrocephalus can be caused by impaired cerebrospinal fluid (CSF) flow, reabsorption, or
excessive CSF production.
 The most common cause of hydrocephalus is CSF flow obstruction, hindering the free
passage of cerebrospinal fluid through the ventricular system and subarachnoid space
(e.g., stenosis of the cerebral aqueduct or obstruction of the interventricular foramina -
foramina of Monro secondary to tumors, hemorrhages, infections or congenital
malformations).
  Hydrocephalus can also be caused by overproduction of cerebrospinal fluid (relative
obstruction) (e.g., papilloma of choroid plexus).
Based on its underlying mechanisms, hydrocephalus can be classified into communicating and
non-communicating (obstructive). Both forms can be either congenital or acquired.
Communicating
Communicating hydrocephalus, also known as non-obstructive hydrocephalus, is caused by
impaired cerebrospinal fluid resorption in the absence of any CSF-flow obstruction between the
ventricles and subarachnoid space. It has been theorized that this is due to functional impairment
of the arachnoid granulations, which are located along the superior sagittal sinus and is the site of
cerebrospinal fluid resorption back into the venous system. Various neurologic conditions may
result in communicating hydrocephalus, including subarachnoid/intraventricular hemorrhage,
meningitis, Chiari malformation, and congenital absence of arachnoidal granulations
(Pacchioni's granulations). Scarring and fibrosis of the subarachnoid space following
infectious, inflammatory, or hemorrhagic events can also prevent resorption of CSF, causing
diffuse ventricular dilatation.
 Normal pressure hydrocephalus (NPH) is a particular form of communicating
hydrocephalus, characterized by enlarged cerebral ventricles, with only intermittently
elevated cerebrospinal fluid pressure. The diagnosis of NPH can be established only with
the help of continuous intraventricular pressure recordings (over 24 hours or even
longer), since more often than not instant measurements yield normal pressure values.
Dynamic compliance studies may be also helpful. Altered compliance (elasticity) of the
ventricular walls, as well as increased viscosity of the cerebrospinal fluid, may play a role
in the pathogenesis of normal pressure hydrocephalus.
Main article: normal pressure hydrocephalus
 Hydrocephalus ex vacuo also refers to an enlargement of cerebral ventricles and
subarachnoid spaces, and is usually due to brain atrophy (as it occurs in dementias),
post-traumatic brain injuries and even in some psychiatric disorders, such as
schizophrenia. As opposed to hydrocephalus, this is a compensatory enlargement of the
CSF-spaces in response to brain parenchyma loss - it is not the result of increased CSF
pressure.
Non-communicating
Non-communicating hydrocephalus, or obstructive hydrocephalus, is caused by a CSF-flow
obstruction ultimately preventing CSF from flowing into the subarachnoid space (either due to
external compression or intraventricular mass lesions).
 Foramen of Monro obstruction may lead to dilation of one or, if large enough (e.g., in
colloid cyst), both lateral ventricles.
 The aqueduct of Sylvius, normally narrow to begin with, may be obstructed by a
number of genetically or acquired lesions (e.g., atresia, ependymitis, hemorrhage, tumor)
and lead to dilation of both lateral ventricles as well as the third ventricle.
 Fourth ventricle obstruction will lead to dilatation of the aqueduct as well as the lateral
and third ventricles.
 The foramina of Luschka and foramen of Magendie may be obstructed due to
congenital failure of opening (e.g., Dandy-Walker malformation).
Congenital
The cranial bones fuse by the end of the third year of life. For head enlargement to occur,
hydrocephalus must occur before then. The causes are usually genetic but can also be acquired
and usually occur within the first few months of life, which include 1) intraventricular matrix
hemorrhages in premature infants, 2) infections, 3) type II Arnold-Chiari malformation, 4)
aqueduct atresia and stenosis, and 5) Dandy-Walker malformation.
In newborns and toddlers with hydrocephalus, the head circumference is enlarged rapidly and
soon surpasses the 97th percentile. Since the skull bones have not yet firmly joined together,
bulging, firm anterior and posterior fontanelles may be present even when the patient is in an
upright position.
The infant exhibits fretfulness, poor feeding, and frequent vomiting. As the hydrocephalus
progresses, torpor sets in, and the infant shows lack of interest in his surroundings. Later on, the
upper eyelids become retracted and the eyes are turned downwards (due to hydrocephalic
pressure on the mesencephalic tegmentum and paralysis of upward gaze). Movements become
weak and the arms may become tremulous. Papilledema is absent but there may be reduction of
vision. The head becomes so enlarged that the child may eventually be bedridden.
About 80-90% of fetuses or newborn infants with spina bifida—often associated with
meningocele or myelomeningocele—develop hydrocephalus.8
Acquired
This condition is acquired as a consequence of CNS infections, meningitis, brain tumors, head
trauma, intracranial hemorrhage (subarachnoid or intraparenchymal) and is usually extremely
painful.
Symptoms
Symptoms of increased intracranial pressure may include headaches, vomiting, nausea,
papilledema, sleepiness, or coma. Elevated intracranial pressure may result in uncal and/or
cerebellar tonsill herniation, with resulting life threatening brain stem compression. For details
on other manifestations of increased intracranial pressure:
The triad (Hakim triad) of gait instability, urinary incontinence and dementia is a relatively
typical manifestation of the distinct entity normal pressure hydrocephalus (NPH). Focal
neurological deficits may also occur, such as abducens nerve palsy and vertical gaze palsy
(Parinaud syndrome due to compression of the quadrigeminal plate, where the neural centers
coordinating the conjugated vertical eye movement are located).
Effects
Because hydrocephalus can injure the brain, thought and behavior may be adversely affected.
Learning disabilities including short-term memory loss are common among those with
hydrocephalus, who tend to score better on verbal IQ than on performance IQ, which is thought
to reflect the distribution of nerve damage to the brain. However the severity of hydrocephalus
can differ considerably between individuals and some are of average or above-average
intelligence. Someone with hydrocephalus may have motion and visual problems, problems with
coordination, or may be clumsy. They may reach puberty earlier than the average child (see
precocious puberty). About one in four develops epilepsy.
Treatment
Hydrocephalus treatment is surgical. It involves the placement of a ventricular catheter (a tube
made of silastic), into the cerebral ventricles to bypass the flow obstruction/malfunctioning
arachnoidal granulations and drain the excess fluid into other body cavities, from where it can be
resorbed. Most shunts drain the fluid into the peritoneal cavity (ventriculo-peritoneal shunt), but
alternative sites include the right atrium (ventriculo-atrial shunt), pleural cavity (ventriculo-
pleural shunt), and gallbladder. A shunt system can also be placed in the lumbar space of the
spine and have the CSF redirected to the peritoneal cavity (Lumbar-peritoneal shunt). An
alternative treatment for obstructive hydrocephalus in selected patients is the endoscopic third
ventriculostomy (ETV), whereby a surgically created opening in the floor of the third ventricle
allows the CSF to flow directly to the basal cisterns, thereby shortcutting any obstruction, as in
aqueductal stenosis. This may or may not be appropriate based on individual anatomy.
Shunt complications
Examples of possible complications include shunt malfunction, shunt failure, and shunt
infection. Although a shunt generally works well, it may stop working if it disconnects, becomes
blocked (clogged), infected, or it is outgrown. If this happens the cerebrospinal fluid will begin
to accumulate again and a number of physical symptoms will develop (headaches, nausea,
vomiting, photophobia/light sensitivity), some extremely serious, like seizures. The shunt failure
rate is also relatively high (of the 40,000 surgeries performed annually to treat hydrocephalus,
only 30% are a patient's first surgery) 9 and it is not uncommon for patients to have multiple
shunt revisions within their lifetime.
The diagnosis of cerebrospinal fluid buildup is complex and requires specialist expertise.
Another complication can occur when CSF drains more rapidly than it is produced by the
choroid plexus, causing symptoms -listlessness, severe headaches, irritability, light sensitivity,
auditory hyperesthesia (sound sensitivity), nausea, vomiting, dizziness, vertigo, migraines,
seizures, a change in personality, weakness in the arms or legs, strabismus, and double vision - to
appear when the patient is vertical. If the patient lies down, the symptoms usually vanish in a
short amount of time. A CT scan may or may not show any change in ventricle size, particularly
if the patient has a history of slit-like ventricles. Difficulty in diagnosing overdrainage can make
treatment of this complication particularly frustrating for patients and their families.
Resistance to traditional analgesic pharmacological therapy may also be a sign of shunt
overdrainage or failure. Diagnosis of the particular complication usually depends on when the
symptoms appear - that is, whether symptoms occur when the patient is upright or in a prone
position, with the head at roughly the same level as the feet.
Corticospinal tract
Brain: Corticospinal tract

Deep dissection of brain-stem. Lateral view. ("pyramidal tract" visible in red, and "pyramidal decussation"
labeled at lower right.)

Diagram of the principal fasciculi of the spinal cord.

The corticospinal or pyramidal tract is a collection of axons that travel between the cerebral
cortex of the brain and the spinal cord.
The corticospinal tract mostly contains motor axons. It actually consists of two separate tracts
in the spinal cord: the lateral corticospinal tract and the medial corticospinal tract. An
understanding of these tracts leads to an understanding of why for the most part, one side of the
body is controlled by the opposite side of the brain.
Also the corticobulbar tract is considered to be a pyramidal tract. The corticobulbar tract carries
signals that control motor neurons located in cranial nerve brain nuclei rather than motor neurons
located in the spinal cord.1
The neurons of the pyramidal tracts are pyramidal neurons, but that is not how the pyramidal
tract got its name, as most of the pyramidal neurons send their axons elsewhere.2 Instead, it got
its name from the shape of the corticospinal axon tracts: when the pyramidal tract passes the
medulla, it forms a dense bundle of nerve fibres that is shaped somewhat like a pyramid.3
The corticospinal tract is concerned specifically with discrete voluntary skilled movements,
especially of the distal parts of the limbs. (Sometimes called "fractionated" movements)
 The motor pathway
The corticospinal tract originates from pyramidal cells in layer V of the cerebral cortex. About
half of its fibres arise from the primary motor cortex. Other contributions come from the
supplementary motor area, premotor cortex, somatosensory cortex, parietal lobe, and cingulate
gyrus. The average fibre diameter is in the region of 10μm; around 3% of fibres are extra-large
(20μm) and arise from Betz cells, mostly in the leg area of the primary motor cortex.
Upper motor neurons
The motor neuron cell bodies in the motor cortex, together with their axons that travel down
through the brain stem and spinal cord, are referred to as upper motor neurons.

Decussation and synapses

The neuronal cell bodies in the motor cortex send long axons to the motor cranial nerve nuclei
mainly of the contralateral side of the midbrain (cortico-mesencephalic tract), pons (cortico-
pontine tract), medulla oblongata (cortico-bulbar tract); the bulk of these fibers, however, extend
all the way down to the spinal cord (corticospinal tract).
 Most of the cortico-spinal fibers (about 80%) cross over to the contralateral side in the
medulla oblongata (pyramidal decussation). Those that cross in the medulla oblongata
travel in the lateral corticospinal tract.
 10% enter the lateral corticospinal tract on the same side.
 The remainder of them (10%) cross over at the level that they exit the spinal cord, and
these travel in the anterior corticospinal tract.
Whichever of these two tracts it travels in, a cortico-spinal axon will synapse with another
neuron in the ventral horn. This ventral horn neuron is considered a second-order neuron in this
pathway, but is not part of the corticospinal tract itself.

From cerebral to motor neurons

The motor axons move closer together as they travel down through the cerebral white matter,
and form part of the posterior limb of the internal capsule.
The motor fibers continue down into the brainstem. The bundle of corticospinal axons is visible
as two column-like structures ("pyramids") on the ventral surface of medulla oblongata - this is
where the name pyramidal tract comes from.
After the decussation, the axons travel down the spinal cord as the lateral corticospinal tract.
Fibers that do not cross over in the medulla oblongata travel down the separate anterior
corticospinal tract, and most of them cross over to the contralateral side in the spinal cord,
shortly before reaching the lower motor neurons.
Lower motor neurons
In the spinal cord, the axons of the upper motor neuron connect (most of them via interneurons,
but to a lesser extent also via direct synapses) with the lower motor neurons, located in the
ventral horn of the spinal cord.
In the brain stem, the lower motor neurons are located in the motor cranial nerve nuclei
(oculomotor, trochlear, motor nucleus of the trigeminal nerve, abducens, facial, accessory,
hypoglossal). The lower motor neuron axons leave the brain stem via motor cranial nerves and
the spinal cord via anterior roots of the spinal nerves respectively, end-up at the neuromuscular
plate and provide motor innervation for voluntary muscles.
Sensory pathways
 Spinothalamic tract
 Spinocerebellar tract
 Visual pathway
 Olfactory system
 Posterior column pathway
Upper motor neuron
Upper motor neuron

The motor tract

Upper motor neurons are motor neurons that originate in the motor region of the cerebral
cortex or the brain stem and carry motor information down to the final common pathway, that is,
any motor neurons that are not directly responsible for stimulating the target muscle. The main
effector neurons for voluntary movement lie within layer V of the primary motor cortex and are
called Betz cells. The cell bodies of these neurons are some of the largest in the brain,
approaching nearly 100μm in diameter.
These neurons connect the brain to the appropriate level in the spinal cord, from which point
nerve signals continue to the muscles by means of the lower motor neurons. The
neurotransmitter glutamate transmits the nerve impulses from upper to lower motor neurons
where it is detected by glutamatergic receptors.
Pathways
Upper motor neurons travel in several pathways through the CNS:
Tract Pathway Function
from the motor cortex to The major function of this pathway is fine
lower motor neurons in the voluntary motor control of the limbs. The
corticospinal tract
ventral horn of the spinal pathway also controls voluntary body
cord posture adjustments.
from the motor cortex to Involved in control of facial and jaw
corticobulbar tract several nuclei in the pons musculature, swallowing and tongue
and medulla oblongata movements.
tectospinal
from the superior colliculus Involved in involuntary adjustment of head
tract/colliculospinal
to lower motor neurons position in response to visual information.
tract
Involved in involuntary adjustment of arm
from red nucleus to lower
rubrospinal tract position in response to balance
motor neurons
information; support of the body.
 from vestibular nuclei,
It is responsible for adjusting posture to
vestibulospinal tract which processes stimuli
maintain balance.
from semicircular canals
Regulates various involuntary motor
reticulospinal tract from reticular formation
activities and assists in balance.
Lesions
Upper motor neuron lesions are indicated by spasticity, muscle weakness, exaggerated reflexes,
clonus, and an out toeing (flaring) of toes and extensor plantar response known as the Babinski
sign.

Lower motor neuron

Lower motor neurons (LMNs) are the motor neurons connecting the brainstem and spinal cord
to muscle fibers, bringing the nerve impulses from the upper motor neurons out to the muscles.
A lower motor neuron's axon terminates on an effector (muscle).
Classification
Lower motor neurons are classified based on the type of muscle fiber they innervate:
 Alpha motor neurons (α-MNs) innervate extrafusal muscle fibers, the most numerous
type of muscle fiber and the one involved in muscle contraction.
 Gamma motor neurons (γ-MNs) innervate intrafusal muscle fibers, which together with
sensory afferents compose muscle spindles. These are part of the system for sensing body
position (proprioception).
Physiology
Glutamate released from the upper motor neurons triggers depolarization in the lower motor
neurons in the ventral horn which in turn causes an action potential to propagate the length of the
axon to the neuromuscular junction where acetylcholine is released to carry the signal across the
synaptic cleft to the postsynaptic receptors of the muscle cell membrane, signaling the muscle to
contract.
Consequences of lesions
Damage to lower motor neurons, lower motor neuron lesions (LMNL) cause decreased tone,
decreased strength and decreased reflexes in affected areas. These findings are in contrast to
findings in upper motor neuron lesions. LMNL is indicated by abnormal EMG potentials,
fasciculations, paralysis, weakening of muscles, and neurogenic atrophy of skeletal muscle.
Sensory system
Sensory system

Typical sensory system: the visual system, illustrated by the classic Gray's
FIG. 722– This scheme shows the flow of information from the eyes to the Medulla spinalis. (Extrapyramidal tracts
central connections of the optic nerves and optic tracts, to the visual cortex. labeled "2" in red, at left.)
Area V1 is the region of the brain which is engaged in vision.

A sensory system is a part of the nervous system responsible for processing sensory
information. A sensory system consists of sensory receptors, neural pathways, and parts of the
brain involved in sensory perception. Commonly recognized sensory systems are those for
vision, hearing, somatic sensation (touch), taste and olfaction (smell). In short, senses are
transducers from the physical world to the realm of the mind.
The receptive field is the specific part of the world to which a receptor organ and receptor cells
respond. For instance, the part of the world an eye can see, is its receptive field; the light that
each rod or cone can see, is its receptive field.1 Receptive fields have been identified for the
visual system, auditory system and somatosensory system, so far.
Stimulus
Sensory systems code for four aspects of a stimulus; type (modality), intensity, location, and
duration. Arrival time of a sound pulse and phase differences of continuous sound are used for
localization of sound sources. Certain receptors are sensitive to certain types of stimuli (for
example, different mechanoreceptors respond best to different kinds of touch stimuli, like sharp
or blunt objects). Receptors send impulses in certain patterns to send information about the
intensity of a stimulus (for example, how loud a sound is). The location of the receptor that is
stimulated gives the brain information about the location of the stimulus (for example,
stimulating a mechanoreceptor in a finger will send information to the brain about that finger).
The duration of the stimulus (how long it lasts) is conveyed by firing patterns of receptors.
Modality
A stimulus modality (sensory modality) is a type of physical phenomenon that can be sensed.
Examples are temperature, taste, sound, and pressure. The type of sensory receptor activated by a
stimulus plays the primary role in coding the stimulus modality.
In the memory-prediction framework, Jeff Hawkins mentions a correspondence between the six
layers of the cerebral cortex and the six layers of the optic tract of the visual system. The visual
cortex has areas labelled V1, V2, V3, V4, V5, MT, IT, etc. Thus Area V1 mentioned below, is
meant to signify only one class of cells in the brain, for which there can be many other cells
which are also engaged in vision.
Hawkins lays out a scheme for the analogous modalities of the sensory system. Note that there
can be many types of senses, some not mentioned here. In particular, for humans, there will be
cells which can be labelled as belonging to V1, V2 A1, A2, etc.:
V1 (vision)
The human eye is the first element of a sensory system: in this case, vision, for the visual
system.
Visual Area 1, or V1, is used for vision, via the visual system to the primary visual cortex.
A1 (auditory - hearing)
Auditory Area 1, or A1, is for hearing, via the auditory system, the primary auditory cortex.
S1 (somatosensory - touch and proprioception)
Somatosensory Area 1, or S1, is for touch and proprioception in the somatosensory system. The
somatosensory system feeds the Brodmann Areas 3, 1 and 2 of the primary somatosensory
cortex. But there are also pathways for proprioception (via the cerebellum), and motor control
(via Brodmann area 4).
G1 (gustatory - taste)
Gustatory Area 1, or G1, is used for taste.
O1 (olfactory - smell)
Olfactory Area 1, or O1, is used for smell. In contrast to vision and hearing, the olfactory bulbs
are not cross-hemispheric; the right bulb connects to the right hemisphere and the left bulb
connects to the left hemisphere.
Human sensory system
The Human sensory system consists of the following sub-systems:
 Visual system consists of the photoreceptors, optic nerve, and V1.
 Auditory system
 Somatosensory system consists of the receptors, transmitters (pathways) leading to S1,
and S1 that experiences the sensations labelled as touch or pressure, temperature (warm
or cold), pain (including itch and tickle), and the sensations of muscle movement and
joint position including posture, movement, and facial expression (collectively also called
proprioception).
 Gustatory system
 Olfactory system
Human sensory receptors are:
 Chemosensor
 Mechanoreceptor
 Nociceptor
 Photoreceptor
 Thermoreceptor

Somatosensory system
The somatosensory system is a diverse sensory system comprising the receptors and processing
centres to produce the sensory modalities such as touch, temperature, proprioception (body
position), and nociception (pain). The sensory receptors cover the skin and epithelia, skeletal
muscles, bones and joints, internal organs, and the cardiovascular system. While touch is
considered one of the five traditional senses, the impression of touch is formed from several
modalities; In medicine, the colloquial term touch is usually replaced with somatic senses to
better reflect the variety of mechanisms involved.
The system reacts to diverse stimuli using different receptors: thermoreceptors,
mechanoreceptors and chemoreceptors. Transmission of information from the receptors passes
via sensory nerves through tracts in the spinal cord and into the brain. Processing primarily
occurs in the primary somatosensory area in the parietal lobe of the cerebral cortex.
At its simplest, the system works when a sensory neuron is triggered by a specific stimulus such
as heat; this neuron passes to an area in the brain uniquely attributed to that area on the body—
this allows the processed stimulus to be felt at the correct location. The mapping of the body
surfaces in the brain is called a homunculus and is essential in the creation of a body image.
Anatomy
The somatosensory system is spread through all major parts of a mammal's body (and other
vertebrates). It consists both of sensory receptors and sensory (afferent) neurones in the
periphery (skin, muscle and organs for example), to deeper neurones within the central nervous
system.
General somatosensory pathway
A somatosensory pathway will typically have three long neurons1: primary, secondary and
tertiary (or first, second, and third).
 The first neuron always has its cell body in the dorsal root ganglion of the spinal nerve
(if sensation is in head or neck, it will be the trigeminal nerve ganglia or the ganglia of
other sensory cranial nerves).
 The second neuron has its cell body either in the spinal cord or in the brainstem. This
neuron's ascending axons will cross (decussate) to the opposite side either in the spinal
cord or in the brainstem. The axons of many of these neurones terminate in the thalamus
(for example the ventral posterior nucleus, VPN), others terminate in the reticular system
or the cerebellum.
 In the case of touch and certain types of pain, the third neuron has its cell body in the
VPN of the thalamus and ends in the postcentral gyrus of the parietal lobe.
Periphery
In the periphery, the somatosensory system detects various stimuli by sensory receptors, e.g. by
mechanoreceptors for tactile sensation and nociceptors for pain sensation. The sensory
information (touch, pain, temperature etc.,) is then conveyed to the central nervous system by
afferent neurones. There are a number of different types of afferent neurones which vary in their
size, structure and properties. Generally there is a correlation between the type of sensory
modality detected and the type of afferent neurone involved. For example, slow, thin,
unmyelinated neurones conduct pain whereas faster, thicker, myelinated neurones conduct casual
touch.
Spinal cord
In the spinal cord, the somatosensory system 2 includes ascending pathways from the body to the
brain. One major target within the brain is the postcentral gyrus in the cerebral cortex. This is the
target for neurones of the Dorsal Column Medial Lemniscal pathway and the Ventral
Spinothalamic pathway. Note that many ascending somatosensory pathways include synapses in
either the thalamus or the reticular formation before they reach the cortex. Other ascending
pathways, particularly those involved with control of posture are projected to the cerebellum.
These include the ventral and dorsal spinocerebellar tracts. Another important target for afferent
somatosensory neurones which enter the spinal cord are those neurones involved with local
segmental reflexes.
Brain
The primary somatosensory area in the human cortex is located in the postcentral gyrus of the
parietal lobe. The postcentral gyrus is the location of the primary somatosensory area, the main
sensory receptive area for the sense of touch. Like other sensory areas, there is a map of sensory
space called a homunculus at this location. For the primary somatosensory cortex, this is called
the sensory homunculus. Areas of this part of the human brain map to certain areas of the body,
dependent on the amount or importance of somatosensory input from that area. For example,
there is a large area of cortex devoted to sensation in the hands, while the back has a much
smaller area. Interestingly, one study showed somatosensory cortex was found to be 21% thicker
in 24 migraine sufferers, on average than in 12 controls3, although we do not yet know what the
significance of this is. Somatosensory information involved with proprioception and posture also
targets an entirely different part of the brain, the cerebellum.
Physiology
Initiation of "somatosensation" begins with activation of a physical "receptor". These
somatosensory receptors tend to lie in skin, organs or muscle. The structure of these receptors is
broadly similar in all cases, consisting of either a "free nerve ending" or a nerve ending
embedded in a specialised capsule. They can be activated by movement (mechanoreceptor),
pressure (mechanoreceptor), chemical (chemoreceptor) and/or temperature. Another activation is
by vibrations generated as a finger scans across a surface. This is the means by which we can
sense fine textures in which the spatial scale is less than 200 µm. Such vibrations are around
250 Hz, which is the optimal frequency sensitivity of Pacinian corpuscles.4 In each case, the
general principle of activation is similar; the stimulus causes depolarisation of the nerve ending
and then an action potential is initiated. This action potential then (usually) travels inward
towards the spinal cord.
Technology
The new research area of haptic technology can provide touch sensation in virtual and real
environments. This new discipline has started to provide critical insights into touch capabilities.
Internal capsule
Brain: Internal capsule

Horizontal section of right cerebral hemisphere.

The motor tract.
(Capsula interna labeled at upper left.)
The internal capsule is an area of white matter in the brain that separates the caudate nucleus
and the thalamus from the lenticular nucleus. The internal capsule contains both ascending and
descending axons.
It consists of axonal fibres that run between the cerebral cortex and the pyramids of the medulla.
Components
The internal capsule is V-shaped when cut both coronally (on the same plane as the face) and
horizontally/transversely (the same plane as the brim of a top hat).
When cut horizontally:
 the bend in the V is called the "genu".
 the part in front of the genu is the "anterior limb". or crus anterius.
 the part behind the genu is called the "posterior limb" or crus posterius.
There is also a retrolenticular and a sublenticular part to the internal capsule.
Fibers
 The posterior limb of the internal capsule contains corticospinal fibers, sensory fibers
(including the medial lemniscus and the anterolateral system) from the body and a few
corticobulbar fibers.
 The genu contains corticobulbar fibers, which run between the cortex and the brainstem.
 The anterior limb of the internal capsule contains:
o 1) frontopontine (corticofugal) fibers project from frontal cortex to pons;
o 2) thalamocortico fibers connect the medial and anterior nuclei of the thalamus to
the frontal lobes (these are severed during a prefrontal lobotomy).
 The retrolenticular part contains fibers from the optic system, coming from the lateral
geniculate nucleus of the thalamus. More posteriorly, this becomes the optic radiation.
Some fibers from the medial geniculate nucleus (which carry auditory information) also
pass in the retrolenticular internal capsule, but most are in the sublenticular part.
Blood supply
The superior parts of both the anterior and posterior limbs and the genu of the internal capsule
are supplied by the lenticulostriate arteries, which are branches off of the M1 segment of the
middle cerebral artery.
The inferior half of the anterior limb is supplied via the recurrent artery of Heubner, which is a
branch of the anterior cerebral artery.
The inferior half of the posterior limb is supplied by the anterior choroidal artery, which is a
branch of the internal carotid artery.
In summary, the blood supply of the internal capsule is
Anterior limb: lenticulostriate branches of middle cerebral artery (superior half) & recurrent
artery of Heubner off of the anterior cerebral artery (inferior half)
Genu: lenticulostriate branches of middle cerebral artery
Posterior limb: lenticulostriate branches of middle cerebral artery (superior half) & anterior
choroidal artery (inferior half)
As in many parts of the body, some degree of variation in the blood supply exists. For example,
thalamoperforator arteries, which are branches of the basilar artery, occasionally supply the
inferior half of the posterior limb.
Pathology
The lenticulostriate arteries supply a substantial amount of the internal capsule. These small
vessels are particularly vulnerable to narrowing in the setting of chronic hypertension and can
result in small, punctate infarctions or intraparenchymal hemorrhage due to vessel rupture.
Lesions of the genu of the internal capsule affect fibers of the corticobulbar tract.
The primary motor cortex sends its axons through the posterior limb of the internal capsule.
Lesions, therefore, result in a contralateral hemiparesis or hemiplegia. While symptoms of
weakness due to an isolated lesion of the posterior limb can initially be severe, recovery of motor
function is sometimes possible due to spinal projections of premotor cortical regions that are
contained more rostrally in the internal capsule.
Thalamus
Brain: Thalamus

MRI cross-section of human brain, with thalamus

marked.
The thalamus (from Greek θάλαμος = room, chamber) is a midline paired symmetrical structure
within the brains of vertebrates, including humans. It is situated between the cerebral
cortex and midbrain, both in terms of location and neurological connections. Its function
includes relaying sensation, spatial sense and motor signals to the cerebral cortex, along with the
regulation of consciousness, sleep and alertness. The thalamus surrounds the third ventricle. It is
the main product of the embryonic diencephalon.
Location and topography
The thalamus is the largest structure in the diencephalon, the part of the brain situated between
the midbrain (mesencephalon) and forebrain (telencephalon). Anatomically, the thalamus is
perched on top of the brainstem, near the center of the brain, in a position to send nerve fibers
out to the cerebral cortex in all directions. The diencephalon includes also the dorsally
locatedepithalamus (essentially the habenula and annexes) and the perithalamus
(prethalamusformerly described as ventral thalamus) containing the zona incerta and the
"reticulate nucleus" (not the reticular, term of confusion). Due to their
different ontogenetic origins, the epithalamus and the perithalamus are formally distinguished
from the thalamus proper.
In humans, the two halves of the thalamus are prominent bulb-shaped masses, about 5.7 cm in
length, located obliquely (about 30°) and symmetrically on each side of the third ventricle.
Anatomy
The thalamus comprises a system of lamellae (made up of myelinated fibers) separating different
thalamic subparts. Other areas are defined by distinct clusters of neurons, such as the
periventricular gray, the intralaminar elements, the "nucleus limitans", and others.[1] These latter
structures, different in structure from the major part of the thalamus, have been grouped together
into the allothalamus as opposed to the isothalamus.[2] This distinction simplifies the global
description of the thalamus.
See also List of thalamic nuclei.
Arterial supply
The thalamus derives its blood supply from four arteries including the polar artery(posterior
communicating artery), paramedian thalamic-subthalamic arteries, inferolateral
(thalamogeniculate) arteries, and posterior (medial and lateral) choroidal arteries.[3] These are
all derived from the vertebrobasilar arterial system except the polar artery.
Function
The thalamus has multiple functions. It is generally believed to act as a relay between a variety
of subcortical areas and the cerebral cortex. In particular, every sensory system (with the
exception of the olfactory system) includes a thalamic nucleus that receives sensory signals and
sends them to the associated primary cortical area. For the visual system, for example, inputs
from the retina are sent to the lateral geniculate nucleus of the thalamus, which in turn projects to
the primary visual cortex (area V1) in the occipital lobe. The thalamus is believed to both
process sensory information as well as relaying it—each of the primary sensory relay areas
receives strong "back projections" from the cerebral cortex. Similarly the medial geniculate
nucleus acts as a key auditory relay between the inferior colliculus of the midbrain and
the primary auditory cortex, and the ventral posterior nucleus is a key somatosensoryrelay, which
sends touch and proprioceptive information to the primary somatosensory cortex.
The thalamus also plays an important role in regulating states of sleep and
wakefulness.[4] Thalamic nuclei have strong reciprocal connections with the cerebral cortex,
forming thalamo-cortico-thalamic circuits that are believed to be involved with consciousness.
The thalamus plays a major role in regulating arousal, the level of awareness, and activity.
Damage to the thalamus can lead to permanent coma.
Many different functions are linked to various regions of the thalamus. This is the case for many
of the sensory systems (except for the olfactory system), such as
the auditory, somatic,visceral, gustatory and visual systems where localized lesions provoke
specific sensory deficits. A major role of the thalamus is devoted to "motor" systems. This has
been and continues to be a subject of interest for investigators. VIm, the relay of cerebellar
afferences, is the target of stereotactians particularly for the improvement of tremor. The role of
the thalamus in the more anterior pallidal and nigral territories in the basal ganglia system
disturbances is recognized but still poorly understood. The contribution of the thalamus to
vestibular or to tectal functions is almost ignored. The thalamus has been thought of as a "relay"
that simply forwards signals to the cerebral cortex. Newer research suggests that thalamic
function is more selective.[5]
Pathology
Cerebrovascular events (strokes) can cause thalamic syndrome,[6] which results in a
contralateral hemianaesthesia, burning or aching sensation on one half of a body (painful
anaesthesia) often accompanied by mood swings. Ischemia of the territory of the paramedian
artery, if bilateral, causes serious troubles including akinetic mutism accompanied or not by
oculomotor troubles. It is also related to Thalamocortical Dysrhythmia.
Korsakoff's Syndrome stems from mammillary bodies, mammilothalamic, or thalamic lesions.
Fatal familial insomnia is a hereditary prion disease in which degeneration of the thalamus
occurs, causing the patient to gradually lose his ability to sleep, progressing to a state of total
insomnia, which invariably leads to death.
Basal ganglia
Brain: Basal ganglia

Basal ganglia labeled at top right.

The basal ganglia (or basal nuclei) are a group of nuclei in the brains of vertebrates, situated at
the base of the forebrain and strongly connected with the cerebral cortex, thalamus and other
areas. The basal ganglia are associated with a variety of functions, including motor control and
learning. Currently popular theories implicate the basal ganglia primarily in action selection, that
is, the decision of which of several possible behaviors to execute at a given time. Experimental
studies show that the basal ganglia exert an inhibitory influence on a number of motor systems,
and that a release of this inhibition permits a motor system to become active. The "behavior
switching" that takes place within the basal ganglia is influenced by signals from many parts of
the brain, including the prefrontal cortex, which is widely believed to play a key role in
executive functions.
The main components of the basal ganglia are the striatum, pallidum, substantia nigra, and
subthalamic nucleus. The largest component, the striatum, receives input from many brain areas
but sends output only to other components of the basal ganglia. The pallidum receives its most
important input from the striatum (either directly or indirectly), and sends inhibitory output to a
number of motor-related areas, including the part of the thalamus that projects to the motor-
related areas of the cortex. The substantia nigra consists of two parts, one that functions similarly
to the pallidum, and another that provides the source of dopamine input to the striatum. The
subthalamic nucleus receives input mainly from the striatum and cortex, and projects to the
pallidum. Each of these areas has a complex internal anatomical and neurochemical
organization.
The basal ganglia play a central role in a number of neurological conditions, including several
movement disorders. The most notable are Parkinson's disease, which involves degeneration of
the dopamine cells in the substantia nigra, and Huntington's disease, which primarily involves
damage to the striatum. Basal ganglia disfunction is also implicated in some other disorders of
behavior control such as Tourette's syndrome and obsessive–compulsive disorder, although the
neural mechanisms underlying these are not well understood.
The basal ganglia have a limbic sector whose components are assigned distinct names: the
nucleus accumbens (NA), ventral pallidum, and ventral tegmental area (VTA). The VTA
provides dopamine to the nucleus accumbens in the same way that the substantia nigra provides
dopamine to the striatum. The VTA→NA dopaminergic projection has attracted a great deal of
attention, because there is much evidence that it plays a central role in reward learning. A
number of highly addictive drugs, including cocaine, amphetamines, and nicotine, are thought to
work by increasing the efficacy of the VTA→NA dopamine signal. There is also evidence
implicating overactivity of the VTA dopaminergic projection in schizophrenia.
Anatomy
Coronal slices of human brain showing the basal ganglia. White matter is shaded darkly, gray
matter lightly.
ANTERIOR: striatum, globus pallidus (GPe and GPi)
POSTERIOR: subthalamic nucleus (STN), substantia nigra (SN)
Main article: Anatomical subdivisions and connections of the basal ganglia
The basal ganglia form a fundamental component of the vertebrate telencephalon (forebrain). In
contrast to the pallial or cortical layer that lines the surface of the forebrain, the basal ganglia are
a collection of distinct masses of gray matter lying in the interior, not far from the junction with
the thalamus. Like most parts of the brain, the basal ganglia consist of left and right sides that are
virtual mirror images of each other.
At the highest level, the basal ganglia are divided by anatomists into four distinct structures. Two
of them, the striatum and pallidum, are relatively large; the other two, the substantia nigra and
subthalamic nucleus, are smaller. In the illustration to the right, two coronal sections of the
human brain show the location of the basal ganglia. The subthalamic nucleus and substantia
nigra lie farther back in the brain than the striatum and pallidum.
Connections

Connectivity diagram showing excitatory glutamatergic pathways as red, inhibitory GABAergic

pathways as blue, and modulatory dopaminergic as magenta.
The flow of neural signals through the basal ganglia is strongly directional. The striatum is the
primary recipient of input from other brain areas, most notably the cerebral cortex. The internal
segment of the globus pallidus (GPi), together with the reticular part of the substantia nigra
(SNr), give rise to the primary output, most notably to the thalamus. The striatum projects to the
pallidum both directly and indirectly via the subthalamic nucleus, which also receives cortical
input. The substantia nigra consists of two parts, one of which functions similarly to the
pallidum, the other of which sends a modulatory dopaminergic input to the striatum and other
structures.
The adjoining figure shows some of the most important connections between components. On
the largest scale, the basal ganglia form a loop that begins and ends in the cortex. Anatomists
have distinguished two main circuits, known as the "direct" and "indirect" pathways. The direct
pathway runs cortex→striatum→GPi→thalamus→cortex. Two of these links are excitatory, and
two inhibitory, so the net effect of the whole sequence is excitatory: the cortex excites itself via
the direct pathway. The indirect pathway runs
cortex→striatum→GPe→STN→GPi→thalamus→cortex. Three of these links are inhibitory and
two excitatory, so the net effect of the sequence is inhibitory: the cortex inhibits itself via the
indirect pathway. The total effect of basal ganglia upon the cortex is believed to result from a
complex interplay between these two pathways.
Striatum
The striatum is the largest component of the basal ganglia. The term "striatum" comes from the
observation that this structure has a striped appearance when sliced in certain directions, arising
from numerous large and small bundles of nerve fibers (white matter) that traverse it. Early
anatomists, examining the human brain, perceived the striatum as two distinct masses of gray
matter separated by a large tract of white matter called the internal capsule. They named these
two masses the "caudate nucleus" and "putamen". More recent anatomists have concluded, on
the basis of microscopic and neurochemical studies, that it is more appropriate to consider these
masses as two separated parts of a single entity, the "striatum", in the same way that a city may
be separated into two parts by a river. Numerous functional differences between the caudate and
putamen have been identified, but these are taken to be consequences of the fact that each sector
of the striatum is preferentially connected to specific parts of the cerebral cortex.
The internal organization of the striatum is extraordinarily complex. The great majority of
neurons (about 96%) are of a type called "medium spiny neurons". These are GABAergic cells
(meaning that they inhibit their targets) with small cell bodies and dendrites densely covered
with dendritic spines, which receive synaptic input primarily from the cortex and thalamus.
Medium spiny neurons can be divided into subtypes in a number of ways, on the basis of
neurochemistry and connectivity. The next most numerous type (around 2%) are a class of large
cholinergic interneurons with smooth dendrites. There are also several other types of
interneurons making up smaller fractions of the neural population.
Numerous studies have shown that the connections between cortex and striatum are generally
topographic; that is, each part of the cortex sends stronger input to some parts of the striatum
than to others. The nature of the topography has been difficult to understand, however—perhaps
in part because the striatum is organized in three dimensions whereas the cortex, as a layered
structure, is organized in two. This dimensional discrepancy entails a great deal of distortion and
discontinuity in mapping one structure to the other.
Pallidum
The pallidum consists of a large structure called the globus pallidus ("pale globe") together with
a smaller ventral extension called the ventral pallidum. The globus pallidus appears as a single
neural mass, but can be divided into two functionally distinct parts, called the internal
(sometimes "medial") and external (sometimes "lateral") segments, abbreviated GPi and GPe.
Both segments contain primarily GABAergic neurons, which therefore have inhibitory effects on
their targets. The two segments participate in distinct neural circuits. The external segment, or
GPe, receives input mainly from the striatum, and projects to the subthalamic nucleus. The
internal segment, or GPi, receives signals from the striatum via two pathways, called "direct" and
"indirect". The direct pathway consists of direct projections from the striatum to the GPi. The
indirect pathway consists of projections from the striatum to the GPe, followed by projections
from the GPe to the subthalamic nucleus (STN), followed by projections from the STN to the
GPi. These pathways have opposite net effects: striatal activity inhibits the GPi via the direct
pathway because striatal outputs are GABAergic, but has a net excitatory effect on the GPi via
the indirect pathway because this three-link pathway consists of two inhibitory links plus one
excitatory link.
Pallidal neurons operate using a "disinhibition" principle. These neurons fire at steady high rates
in the absence of input, and signals from the striatum cause them to "pause". Because pallidal
neurons themselves have inhibitory effects on their targets, the net effect of striatal input to the
pallidum is a reduction of the tonic inhibition exerted by pallidal cells on their targets.
Function
Information about the functions of the basal ganglia comes from anatomical studies, from
physiological studies carried out mainly in rats and monkeys, and from the study of diseases that
damage them.
The greatest source of insight into the functions of the basal ganglia has come from the study of
two neurological disorders, Parkinson's disease and Huntington's disease. For both of these
disorders, the nature of the neural damage is well understood and can be correlated with the
resulting symptoms. Parkinson's disease involves major loss of dopaminergic cells in the
substantia nigra; Huntington's disease involves massive loss of medium spiny neurons in the
striatum. The symptoms of the two diseases are virtually opposite: Parkinson's disease is
characterized by gradual loss of the ability to initiate movement, while Huntington's disease is
characterized by an inability to prevent parts of the body from moving unintentionally. It is
noteworthy that although both diseases have cognitive symptoms, especially in their advanced
stages, the most salient symptoms relate to the ability to initiate and control movement. Thus,
both are classified primarily as movement disorders. A different movement disorder, called
hemiballismus, may result from damage restricted to the subthalamic nucleus. Hemiballismus is
characterized by violent and uncontrollable flinging movements of the arms and legs.
Eye movements
One of the most intensively studied functions of the BG is their role in controlling eye
movements.5 Eye movement is influenced by an extensive network of brain regions that
converge on a midbrain area called the superior colliculus (SC). The SC is a layered structure
whose layers form two-dimensional retinotopic maps of visual space. A "bump" of neural
activity in the deep layers of the SC drives an eye movement directed toward the corresponding
point in space.
The SC receives a strong inhibitory projection from the BG, originating in the substantia nigra
pars reticulata (SNr).5 Neurons in the SNr usually fire continuously at high rates, but at the onset
of an eye movement they "pause", thereby releasing the SC from inhibition. Eye movements of
all types are associated with "pausing" in the SNr; however, individual SNr neurons may be
more strongly associated with some types of movements than others. Neurons in some parts of
the caudate nucleus also show activity related to eye movements. Since the great majority of
caudate cells fire at very low rates, this activity almost always shows up as an increase in firing
rate. Thus, eye movements begin with activation in the caudate nucleus, which inhibits the SNr
via the direct GABAergic projections, which in turn disinhibits the SC.
Role in motivation
Although the role of the basal ganglia in motor control is clear, there are also many indications
that it is involved in the control of behavior in a more fundamental way, at the level of
motivation. In Parkinson's disease, the ability to execute the components of movement is not
greatly affected, but motivational factors such as hunger fail to cause movements to be initiated
or switched at the proper times. The immobility of Parkinsonian patients has sometimes been
described as a "paralysis of the will".6 These patients have occasionally been observed to show a
phenomenon called kinesia paradoxica, in which a person who is otherwise immobile responds
to an emergency in a coordinated and energetic way, then lapses back into immobility once the
emergency has passed.
The role in motivation of the "limbic" part of the basal ganglia—the nucleus accumbens (NA),
ventral pallidum, and ventral tegmental area (VTA)—is particularly well established. Thousands
of experimental studies combine to demonstrate that the dopaminergic projection from the VTA
to the NA plays a central role in the brain's reward system. Animals with stimulating electrodes
implanted along this pathway will bar-press very energetically if each press is followed by a
brief pulse of electrical current. Numerous things that people find rewarding, including addictive
drugs, good-tasting food, and sex, have been shown to elicit activation of the VTA dopamine
system. Damage to the NA or VTA can produce a state of profound torpor.
Although it is not universally accepted, some theorists have proposed a distinction between
"appetitive" behaviors, which are initiated by the basal ganglia, and "consummatory" behaviors,
which are not. For example, an animal with severe basal ganglia damage will not move toward
food even if it is placed a few inches away, but if the food is placed directly in the mouth, the
animal will chew it and swallow it.
Comparative anatomy and naming
The basal ganglia form one of the basic components of the forebrain, and can be recognized in
all species of vertebrates.7 Even in the lamprey (generally considered one of the most primitive
of vertebrates), striatal, pallidal, and nigral elements can be identified on the basis of anatomy
and histochemistry.8
A clear emergent issue in comparative anatomy of the basal ganglia is the development of this
system through phylogeny as a convergent cortically re-entrant loop in conjunction with the
development and expansion of the cortical mantle. There is controversy, however, regarding the
extent to which convergent selective processing occurs versus segregated parallel processing
within re-entrant closed loops of the basal ganglia. Regardless, the transformation of the basal
ganglia into a cortically re-entrant system in mammalian evolution occurs through a re-direction
of pallidal (or "paleostriatum primitivum") output from midbrain targets such as the superior
colliculus, as occurs in sauropsid brain, to specific regions of the ventral thalamus and from there
back to specified regions of the cerebral cortex that form a subset of those cortical regions
projecting into the striatum. The abrupt rostral re-direction of the pathway from the internal
segment of the globus pallidus into the ventral thalamus—via the path of the ansa lenticularis--
could be viewed as a footprint of this evolutionary transformation of basal ganglia outflow and
targeted influence. The evolutionary emergence of cortical re-entrant systems in the brain has
been postulated by Gerald Edelman as a critical basis for the emergence of primary
consciousness in the theory of Neural Darwinism.
Neurotransmitters
In most regions of the brain, the predominant classes of neurons use glutamate as
neurotransmitter and have excitatory effects on their targets. In the basal ganglia, however, the
great majority of neurons use GABA as neurotransmitter and have inhibitory effects on their
targets. The inputs from the cortex and thalamus to the striatum and STN are glutamatergic, but
the outputs from the striatum, pallidum, and substantia nigra pars reticulata all use GABA.
Thus, following the initial excitation of the striatum, the internal dynamics of the basal ganglia
are dominated by inhibition and disinhibition.
Other neurotransmitters have important modulatory effects. The most intensively studied is
dopamine, which is used by the projection from the substantia nigra pars compacta to the
striatum, and also in the analogous projection from the ventral tegmental area to the nucleus
accumbens. Acetylcholine also plays an important role, being used both by several external
inputs to the striatum, and by a group of striatal interneurons. Although cholinergic cells make
up only a small fraction of the total population, the striatum has one of the highest acetylcholine
concentrations of any brain structure.
Spinal cord

The spinal cord nested in the vertebral column

A closer look at the spinal cord

Cross-section through cervical spinal cord

Spinal cord tracts

The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends
from the brain (the medulla specifically). The brain and spinal cord together make up the central
nervous system. The spinal cord extends down to the space between the first and second lumbar
vertebrae; it does not extend the entire length of the vertebral column. It is around 45 cm long
(18 inches) in men and around 43 cm (17 inches)long in women. The enclosing bony vertebral
column protects the relatively shorter spinal cord. The spinal cord functions primarily in the
transmission of neural signals between the brain and the rest of the body but also contains neural
circuits that can independently control numerous reflexes and central pattern generators. The
spinal cord has three major functions: A. Serve as a conduit for motor information, which travels
down the spinal cord. B. Serve as a conduit for sensory information, which travels up the spinal
cord. C. Serve as a center for coordinating certain reflexes.
Structure
The spinal cord is the main pathway for information connecting the brain and peripheral nervous
system. The length of the spinal cord is much shorter than the length of the bony spinal column.
The human spinal cord extends from the medulla oblongata and continues through the conus
medullaris near the first or second lumbar vertebra, terminating in a fibrous extension known as
the filum terminale.
It is about 45 cm long in men and 43 cm long in women, ovoid-shaped, and is enlarged in the
cervical and lumbar regions. The cervical enlargement, located from C4 to T1, is where sensory
input comes from and motor output goes to the arms. The lumbar enlargement,located between
T9 and T12, handles sensory input and motor output coming from and going to the legs. You
should notice that the name is somewhat misleading. However, this region of the cord does
indeed have branches that extend to the lumbar region.
In cross-section, the peripheral region of the cord contains neuronal white matter tracts
containing sensory and motor neurons. Internal to this peripheral region is the gray, butterfly-
shaped central region made up of nerve cell bodies. This central region surrounds the central
canal, which is an anatomic extension of the spaces in the brain known as the ventricles and, like
the ventricles, contains cerebrospinal fluid.
The spinal cord has a shape that is compressed dorso-ventrally, giving it an elliptical shape. The
cord has grooves in the dorsal and ventral sides. The posterior median sulcus is the groove in the
dorsal side, and the anterior median fissure is the groove in the ventral side. Running down the
center of the spinal cord is a cavity, called the central canal.
The three meninges that cover the spinal cord—the outer dura mater, the arachnoid mater, and
the innermost pia mater—are continuous with that in the brainstem and cerebral hemispheres.
Similarly, cerebrospinal fluid is found in the subarachnoid space. The cord is stabilized within
the dura mater by the connecting denticulate ligaments, which extend from the enveloping pia
mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of
the second sacral vertebra.
The spinal cord is protected by three layers of tissue, called spinal meninges, that surround the
cord. The dura mater is the outermost layer, and it forms a tough protective coating. Between the
dura mater and the surrounding bone of the vertebrae is a space, called the epidural space. The
epidural space is filled with adipose tissue (why is this relevant to protection of the spinal cord?),
and it contains a network of blood vessels. The arachnoid is the middle protective layer. Its name
comes from the fact that the tissue has a spiderweb-like appearance. The space between the
arachnoid and the underlyng pia mater is called the subarachnoid space. The subarachnoid space
contains cerebrospinal fluid (CSF). The medical procedure known as a “spinal tap” involves use
of a needle to withdraw CSF from the subarachnoid space, usually from the lumbar region of the
spine. The pia mater is the innermost protective layer. It is very delicate and it is tightly
associated with the surface of the spinal cord.
Spinal cord segments
The animal spinal cord is divided into 31 different segments. At every segment, right and left
pairs of spinal nerves (mixed; sensory and motor) form. Six to eight motor nerve rootlets branch
out of right and left ventro lateral sulci in a very orderly manner. Nerve rootlets combine to form
nerve roots. Likewise, sensory nerve rootlets form off right and left dorsal lateral sulci and form
sensory nerve roots. The ventral (motor) and dorsal (sensory) roots combine to form spinal
nerves (mixed; motor and sensory), one on each side of the spinal cord. Spinal nerves, with the
exception of C1 and C2, form inside intervertebral foramen (IVF). Note that at each spinal
segment, the border between the central and peripheral nervous system can be observed. Rootlets
are a part of the peripheral nervous system.
In the upper part of the vertebral column, spinal nerves exit directly from the spinal cord,
whereas in the lower part of the vertebral column nerves pass further down the column before
exiting. The terminal portion of the spinal cord is called the conus medullaris. The pia mater
continues as an extension called the filum terminale, which anchors the spinal cord to the
coccyx. The cauda equina (“horse’s tail”) is the name for the collection of nerves in the vertebral
column that continue to travel through the vertebral column below the conus medullaris. The
cauda equina forms as a result of the fact that the spinal cord stops growing in length at about
age four, even though the vertebral column continues to lengthen until adulthood. This results in
the fact that sacral spinal nerves actually originate in the upper lumbar region. The spinal cord
can be anatomically divided into 31 spinal segments based on the origins of the spinal nerves.
Each segment of the spinal cord is associated with a pair of ganglia, called dorsal root ganglia,
which are situated just outside of the spinal cord. These ganglia contain cell bodies of sensory
neurons. Axons of these sensory neurons travel into the spinal cord via the dorsal roots.
Ventral roots consist of axons from motor neurons, which bring information to the periphery
from cell bodies within the CNS. Dorsal roots and ventral roots come together and exit the
intervertebral foramina as they become spinal nerves.
The gray matter, in the center of the cord, is shaped like a butterfly and consists of cell bodies of
interneurons and motor neurons. It also consists of neuroglia cells and unmyelinated axons.
Projections of the gray matter (the “wings”) are called horns. Together, the gray horns and the
gray commissure form the “gray H.”
The white matter is located outside of the gray matter and consists almost totally of myelinated
motor and sensory axons. “Columns” of white matter carry information either up or down the
spinal cord.
Within the CNS, nerve cell bodies are generally organized into functional clusters, called nuclei.
Axons within the CNS are grouped into tracts.
There are 37 (some EMS text say 25, counting the sacral as one solid piece) spinal cord nerve
segments in a human spinal cord:
• 8 cervical segments forming 8 pairs of cervical nerves (C1 spinal nerves exit spinal
column between occiput and C1 vertebra; C2 nerves exit between posterior arch of C1 vertebra
and lamina of C2 vertebra; C3-C8 spinal nerves through IVF above corresponding cervica
vertebra, with the exception of C8 pair which exit via IVF between C7 and T1 vertebra)
• 12 thoracic segments forming 12 pairs of thoracic nerves (exit spinal column through IVF
below corresponding vertebra T1-T12)
• 5 lumbar segments forming 5 pairs of lumbar nerves (exit spinal column through IVF,
below corresponding vertebra L1-L5)
• 5 (or 1) sacral segments forming 5 pairs of sacral nerves (exit spinal column through IVF,
below corresponding vertebra S1-S5)
• 3 coccygeal segments joined up becoming a single segment forming 1 pair of coccygeal
nerves (exit spinal column through the sacral hiatus).
Because the vertebral column grows longer than the spinal cord, spinal cord segments do not
correspond to vertebral segments in adults, especially in the lower spinal cord. In the fetus,
vertebral segments do correspond with spinal cord segments. In the adult, however, the spinal
cord ends around the L1/L2 vertebral level, forming a structure known as the conus medullaris.
For example, lumbar and sacral spinal cord segments are found between vertebral levels T9 and
L2.
Although the spinal cord cell bodies end around the L1/L2 vertebral level, the spinal nerves for
each segment exit at the level of the corresponding vertebra. For the nerves of the lower spinal
cord, this means that they exit the vertebral column much lower (more caudally) than their roots.
As these nerves travel from their respective roots to their point of exit from the vertebral column,
the nerves of the lower spinal segments form a bundle called the cauda equina.
There are three regions where the spinal cord enlarges:
• Cervical enlargement - corresponds roughly to the brachial plexus nerves, which
innervate the upper limb. It includes spinal cord segments from about C4 to T1. The vertebral
levels of the enlargement are roughly the same (C4 to T1).
• Lumbosacral enlargement - corresponds to the lumbosacral plexus nerves, which
innervate the lower limb. It comprises the spinal cord segments from L2 to S3 and is found about
the vertebral levels of T9 to T12.
Embryology
The spinal cord is made from part of the neural tube during development. As the neural tube
begins to develop, the notochord begins to secrete a factor known as Sonic hedgehog or SHH. As
a result, the floor plate then also begins to secrete SHH, and this will induce the basal plate to
develop motor neurons. Meanwhile, the overlying ectoderm secretes bone morphogenetic protein
(BMP). This induces the roof plate to begin to secrete BMP, which will induce the alar plate to
develop sensory neurons. The alar plate and the basal plate are separated by the sulcus limitans.
Additionally, the floor plate also secretes netrins. The netrins act as chemoattractants to
decussation of pain and temperature sensory neurons in the alar plate across the anterior white
commissure, where they then ascend towards the thalamus.
Lastly, it is important to note that the past studies of Viktor Hamburger and Rita Levi-Montalcini
in the chick embryo have been further proven by more recent studies which demonstrated that
the elimination of neuronal cells by programmed cell death (PCD) is necessary for the correct
assembly of the nervous system.
Overall, spontaneous embryonic activity has been shown to play a role in neuron and muscle
development but is probably not involved in the initial formation of connections between spinal
neurons.
Somatosensory organization
Somatosensory organization is divided into the dorsal column-medial lemniscus tract (the
touch/proprioception/vibration sensory pathway) and the anterolateral system, or ALS (the
pain/temperature sensory pathway). Both sensory pathways use three different neurons to get
information from sensory receptors at the periphery to the cerebral cortex. These neurons are
designated primary, secondary and tertiary sensory neurons. In both pathways, primary sensory
neuron cell bodies are found in the dorsal root ganglia, and their central axons project into the
spinal cord.
In the dorsal column-medial leminiscus tract, a primary neuron's axon enters the spinal cord and
then enters the dorsal column. If the primary axon enters below spinal level T6, the axon travels
in the fasciculus gracilis, the medial part of the column. If the axon enters above level T6, then it
travels in the fasciculus cuneatus, which is lateral to the fasiculus gracilis. Either way, the
primary axon ascends to the lower medulla, where it leaves its fasiculus and synapses with a
secondary neuron in one of the dorsal column nuclei: either the nucleus gracilis or the nucleus
cuneatus, depending on the pathway it took. At this point, the secondary axon leaves its nucleus
and passes anteriorly and medially. The collection of secondary axons that do this are known as
internal arcuate fibers. The internal arcuate fibers decussate and continue ascending as the
contralateral medial lemniscus. Secondary axons from the medial lemniscus finally terminate in
the ventral posterolateral nucleus (VPL) of the thalamus, where they synapse with tertiary
neurons. From there, tertiary neurons ascend via the posterior limb of the internal capsule and
end in the primary sensory cortex.
The anterolateral system works somewhat differently. Its primary neurons enter the spinal cord
and then ascend one to two levels before synapsing in the substantia gelatinosa. The tract that
ascends before synapsing is known as Lissauer's tract. After synapsing, secondary axons
decussate and ascend in the anterior lateral portion of the spinal cord as the spinothalamic tract.
This tract ascends all the way to the VPL, where it synapses on tertiary neurons. Tertiary
neuronal axons then travel to the primary sensory cortex via the posterior limb of the internal
capsule.
It should be noted that some of the "pain fibers" in the ALS deviate from their pathway towards
the VPL. In one such deviation, axons travel towards the reticular formation in the midbrain. The
reticular formation then projects to a number of places including the hippocampus (to create
memories about the pain), the centromedian nucleus (to cause diffuse, non-specific pain) and
various parts of the cortex. Additionally, some ALS axons project to the periaqueductal gray in
the pons, and the axons forming the periaqueductal gray then project to the nucleus raphe
magnus, which projects back down to where the pain signal is coming from and inhibits it. This
helps control the sensation of pain to some degree.
Motor organization
The corticospinal tract serves as the motor pathway for upper motor neuronal signals coming
from the cerebral cortex and from primitive brainstem motor nuclei.
Cortical upper motor neurons originate from Brodmann areas 1, 2, 3, 4, and 6 and then descend
in the posterior limb of the internal capsule, through the crus cerebri, down through the pons, and
to the medullary pyramids, where about 90% of the axons cross to the contralateral side at the
decussation of the pyramids. They then descend as the lateral corticospinal tract. These axons
synapse with lower motor neurons in the ventral horns of all levels of the spinal cord. The
remaining 10% of axons descend on the ipsilateral side as the ventral corticospinal tract. These
axons also synapse with lower motor neurons in the ventral horns. Most of them will cross to the
contralateral side of the cord (via the anterior white commissure) right before synapsing.
The midbrain nuclei include four motor tracts that send upper motor neuronal axons down the
spinal cord to lower motor neurons. These are the rubrospinal tract, the vestibulospinal tract, the
tectospinal tract and the reticulospinal tract. The rubrospinal tract descends with the lateral
corticospinal tract, and the remaining three descend with the anterior corticospinal tract.
The function of lower motor neurons can be divided into two different groups: the lateral
corticospinal tract and the anterior cortical spinal tract. The lateral tract contains upper motor
neuronal axons which synapse on dorsal lateral (DL) lower motor neurons. The DL neurons are
involved in distal limb control. Therefore, these DL neurons are found specifically only in the
cervical and lumbosaccral enlargements within the spinal cord. There is no decussation in the
lateral corticospinal tract after the decussation at the medullary pyramids.
The anterior corticospinal tract descends ipsilaterally in the anterior column, where the axons
emerge and either synapse on lower ventromedial (VM) motor neurons in the ventral horn
ipsilaterally or descussate at the anterior white commissure where they synapse on VM lower
motor neurons contralaterally . The tectospinal, vestibulospinal and reticulospinal descend
ipsilaterally in the anterior column but do not synapse across the anterior white commissure.
Rather, they only synapse on VM lower motor neurons ipsilaterally. The VM lower motor
neurons control the large, postural muscles of the axial skeleton. These lower motor neurons,
unlike those of the DL, are located in the ventral horn all the way throughout the spinal cord.
Spinocerebellar tracts
Proprioceptive information in the body travels up the spinal cord via three tracts. Below L2, the
proprioceptive information travels up the spinal cord in the ventral spinocerebellar tract. Also
known as the anterior spinocerebellar tract, sensory receptors take in the information and travel
into the spinal cord. The cell bodies of these primary neurons are located in the dorsal root
ganglia. In the spinal cord, the axons synapse and the secondary neuronal axons decussate and
then travel up to the superior cerebellar peduncle where they decussate again. From here, the
information is brought to deep nuclei of the cerebellum including the fastigial and interposed
nuclei.
From the levels of L2 to T1, proprioceptive information enters the spinal cord and ascends
ipsilaterally, where it synapses in Clarke's nucleus. The secondary neuronal axons continue to
ascend ipsilaterally and then pass into the cerebellum via the inferior cerebellar peduncle. This
tract is known as the dorsal spinocerebellar tract.
From above T1, proprioceptive primary axons enter the spinal cord and ascend ipsilaterally until
reaching the accessory cuneate nucleus, where they synapse. The secondary axons pass into the
cerebellum via the inferior cerebellar peduncle where again, these axons synapse on cerebellar
deep nuclei. This tract is known as the cuneocerebellar tract.
Motor information travels from the brain down the spinal cord via descending spinal cord tracts.
Descending tracts involve two neurons: the upper motor neuron (UMN) and lower motor neuron
(LMN) . A nerve signal travels down the upper motor neuron until it synapses with the lower
motor neuron in the spinal cord. Then, the lower motor neuron conducts the nerve signal to the
spinal root where efferent nerve fibers carry the motor signal toward the target muscle. The
descending tracts are composed of white matter. There are several descending tracts serving
different functions. The corticospinal tracts (lateral and anterior) are responsible for coordinated
limb movements.
Brown-Séquard syndrome
Brown-Séquard syndrome

Brown-Séquard syndrome is bottom diagram

Brown-Séquard syndrome, also known as Brown-Séquard's hemiplegia and Brown-
Séquard's paralysis, is a loss of sensation and motor function (paralysis and ataxia) that is
caused by the lateral hemisection (cutting) of the spinal cord. Other synonyms are crossed
hemiplegia, hemiparaplegic syndrome, hemiplegia et hemiparaplegia spinalis and spinal
hemiparaplegia.
Classification
Any presentation of spinal injury that is an incomplete lesion can be called a partial Brown-
Séquard or incomplete Brown-Séquard syndrome, so long as it has characterized by features of a
motor loss and numbness to touch and vibration on the same side of the spinal injury and loss of
pain and temperature sensation on the opposite side.
Diagnosis
Magnetic resonance imaging (MRI) is the imaging of choice in spinal cord lesions.
Causes
Brown-Séquard syndrome may be caused by a spinal cord tumor, trauma (such as a gunshot
wound or puncture wound to the neck or back), ischemia (obstruction of a blood vessel), or
infectious or inflammatory diseases such as tuberculosis, or multiple sclerosis.
Brown-Séquard syndrome is an incomplete spinal cord lesion characterized by clinical
presentation reflecting hemisection of the spinal cord (cutting the spinal cord in half on one or
the other side). It is diagnosed by finding motor (muscle) paralysis on the same side as the lesion
and deficits in pain and temperature sensation on the opposite side on physical exam. This is
called ipsilateral (on the same side as the spinal cord lesion) hemiplegia and contralateral (on the
opposite side) pain and temperature sensation deficits. The loss of sensation on the opposite side
of the lesion is because these nerve fibers of the spinothalamic tract cross the spinal cord. In its
pure form, it is rarely seen. Incomplete forms are also observed. The most common cause is
penetrating trauma such as a gunshot wound or stab wound to the spinal cord. This may be seen
most often in the cervical (neck) or thoracic spine. Other causes are tumors, bleeding episodes,
tuberculosis, and multiple sclerosis.
The presentation can be progressive and incomplete. It can advance from a typical Brown-
Séquard syndrome to complete paralysis. It is not always permanent, and progression or
resolution depends on the severity of the original spinal cord injury and the underlying pathology
that caused it in the first place.
Pathophysiology
 Brown-Séquard syndrome's symptoms:
* = Side of the lesion
1 = hypotonic paralysis
2 = spastic paralysis and loss of vibration and proprioception (position sense)
3 = loss of pain and temperature sensation
The hemisection of the cord results in a lesion of each of the three main neural systems:
 the principal upper motor neuron pathway of the corticospinal tract
 one or both dorsal columns
 the spinothalamic tract
As a result of the injury to these three main brain pathways the patient will present with three
lesions:
 The corticospinal lesion produces spastic paralysis on the same side of the body (the loss
of moderation by the UMN).
 The lesion to fasciculus gracilis or fasciculus cuneatus results in ipsilateral loss of
vibration and proprioception (position sense).
 The loss of the spinothalamic tract leads to pain and temperature sensation being lost
from the contralateral side beginning one or two segments below the lesion.
Treatment
Treatment is directed at the pathology causing the paralysis. If it is because of trauma such as a
gunshot or knife wound, there may be other life threatening conditions such as bleeding or major
organ damage which should be dealt with on an emergent basis. If the syndrome is caused by a
spinal fracture, this should be identified and treated appropriately. Although steroids may be
used to decrease cord swelling and inflammation, the usual therapy for spinal cord injury is
expectant.
 Reflex
A reflex action, also known as a reflex, is an involuntary and nearly instantaneous movement in
response to a stimulus. In most contexts, in particular those involving humans, reflex actions are
mediated via the reflex arc; this is not always true in other animals, nor does it apply to casual
uses of the term 'reflex'.
Tendon reflexes
The deep tendon reflexes provide information on the integrity of the central and peripheral
nervous system. Generally, decreased reflexes indicate a peripheral problem, and lively or
exaggerated reflexes a central one.
• Biceps reflex (C5, C6)
• Brachioradialis reflex (C5, C6, C7)
• Extensor digitorum reflex (C6, C7)
• Triceps reflex (C6, C7, C8)
• Patellar reflex or knee-jerk reflex (L2, L3, L4)
• Ankle jerk reflex (Achilles reflex) (S1, S2)
• Plantar reflex or Babinski reflex (L5, S1, S2)
Reflexes involving cranial nerves
Name Sensory Motor
Pupillary light reflex II III
Accommodation reflex II III
Jaw jerk reflex V V
Corneal reflex, also known as the blink reflex V VII
Caloric reflex test/Vestibulo-ocular reflex VIII III, IV, VI +
Gag reflex IX X

Tendon reflex
Tendon reflex (or T-reflex) is a feedback mechanism that controls increasing muscle tension by
causing muscle relaxation before tension force becomes so great it may damage the muscle. In a
neurologic exam, deep tendon reflexes are scored from 0-4.
Function
The sensory receptor that detects change in tension is the golgi tendon which lie within tendon. It
causes the muscle to relax via a polysynaptic reflex in order to decrease tension in the tendons.
Another motor neuron sends efferent impulse to its antagonistic muscle, causing it to contract.
Contrast to stretch reflex
The stretch reflex operates as a feedback mechanism to control muscle length by causing muscle
contraction. In contrast, the tendon reflex operates as a feedback mechanism to control muscle
tension by causing muscle relaxation before muscle force becomes so great that tendons might
be torn. Although the tendon reflex is less sensitive than the stretch reflex, it can override the
stretch reflex when tension is great, making you drop a very heavy weight, for example. Like the
stretch reflex, the tendon reflex is ipsilateral. The sensory receptors for this reflex are called
tendon Golgi receptors, which lie within a tendon near its junction with a muscle. In contrast to
muscle spindles, which are sensitive to changes in muscle length, tendon organs detect and
respond to changes in muscle tension that are caused by passive stretch or muscular contraction.
Steps
A tendon reflex operates as follows:
1. As the tension applied to a tendon increases, the Golgi tendon organ (sensory receptor) is
stimulated (depolarized to threshold).
2. Nerve impulses (action potentials) arise and propagate into the spinal cord along a
sensory neuron.
3. Within the spinal cord (integrating center), the sensory neuron activates an inhibitory
interneuron that makes a synapse with a motor neuron.
4. The inhibitory neurotransmitter inhibits (hyperpolarizes) the motor neuron, which then
generates fewer nerve impulses.
5. The muscle relaxes and relieves excess tension.
Pathology
The clasp-knife response is a stretch reflex with a rapid decrease in resistance when attempting
to flex a joint. However, it is actually thought to be caused by the tendon reflex of the
antagonistic muscle of that joint, which gets extended. It is one of the characteristic responses of
a upper motor neurone lesion.

Plantar reflex
In medicine and neurology, the Babinski response to the plantar reflex is a reflex, named after
Joseph Babinski (1857-1932), a Polish neurologist, that can identify disease of the spinal cord
and brain and also exists as a primitive reflex in infants. When non-pathological, it is called the
plantar reflex, while the term Babinski's sign (or Koch's sign) refers to its pathological form.
Methods

Babinski's Sign
The lateral side of the sole of the foot is rubbed with a blunt instrument or device so as not to
cause pain, discomfort or injury to the skin; the instrument is run from the heel along a curve to
the toes (metatarsal pads).
There are three responses possible:
• Flexor: the toes curve inward and the foot everts; this is the response seen in healthy
adults (aka a "negative" Babinski)
• Indifferent: there is no response.
• Extensor: the hallux dorsiflexes and the other toes fan out – the "positive Babinski's sign"
indicating damage to the central nervous system.
As the lesion responsible for the sign expands, so does the area from which the afferent Babinski
response may be elicited. The Babinski response is also normal while asleep and after a long
period of walking. The Babinski’s sign can indicate upper motor neuron damage to the spinal
cord in the thoracic or lumbar region, or brain disease – constituting damage to the corticospinal
tract. Occasionally, a pathological plantar reflex is the first (and only) indication of a serious
disease process and a clearly abnormal plantar reflex often prompts detailed neurological
investigations, including CT scanning of the brain or MRI of the spine, as well as lumbar
puncture for the study of cerebrospinal fluid.
Cerebellum
A human brain, with the cerebellum colored in
purple

Drawing of the human brain, showing cerebellum

and pons
The cerebellum (Latin for little brain) is a region of the brain that plays an important role
in motor control. It is also involved in somecognitive functions such as attention and language,
and probably in some emotional functions such as regulating fear and pleasureresponses.[1] Its
movement-related functions are the most clearly understood, however. The cerebellum does not
initiate movement, but it contributes to coordination, precision, and accurate timing. It receives
input from sensory systems and from other parts of the brain andspinal cord, and integrates these
inputs to fine tune motor activity.[2] Because of this fine-tuning function, damage to the
cerebellum does not cause paralysis, but instead produces disorders in fine
movement, equilibrium, posture, and motor learning.[2]
In terms of anatomy, the cerebellum has the appearance of a separate structure attached to the
bottom of the brain, tucked underneath the cerebral hemispheres. The surface of the cerebellum
is covered with finely spaced parallel grooves, in striking contrast to the broad irregular
convolutions of the cerebral cortex. These parallel grooves conceal the fact that the cerebellum is
actually a continuous thin layer of neural tissue (the cerebellar cortex), tightly folded in the style
of an accordion. Within this thin layer are several types of neurons with a highly regular
arrangement, the most important being Purkinje cells and granule cells. This complex neural
network gives rise to a massive signal-processing capability, but almost the entirety of its output
is directed to a set of small deep cerebellar nuclei lying in the interior of the cerebellum.
In addition to its direct role in motor control, the cerebellum also is necessary for several types
of motor learning, the most notable one being learning to adjust to changes in sensorimotor
relationships. Several theoretical models have been developed to explain sensorimotor
calibration in terms of synaptic plasticity within the cerebellum. Most of them derive from early
models formulated by David Marr andJames Albus, which were motivated by the observation
that each cerebellar Purkinje cell receives two dramatically different types of input: On one hand,
thousands of inputs from parallel fibers, each individually very weak; on the other hand, input
from one single climbing fiber, which is, however, so strong that a single climbing fiber action
potential will reliably cause a target Purkinje cell to fire a burst of action potentials. The basic
concept of the Marr-Albus theory is that the climbing fiber serves as a "teaching signal", which
induces a long-lasting change in the strength of synchronously activated parallel fiber inputs.
Observations of long-term depression in parallel fiber inputs have provided support for theories
of this type, but their validity remains controversial.
Structure
At the level of large-scale anatomy, the cerebellum consists of a tightly folded and crumpled
layer of cortex, with white matter underneath, several deep nuclei embedded in the white matter,
and a fluid-filled ventricle at the base. At the microscopic level, each part of the cerebellar cortex
consists of the same small set of neuronal elements, laid out with a highly stereotyped geometry.
At an intermediate level, the cerebellum and its auxiliary structures can be decomposed into
several hundred or thousand independently functioning modules called "microzones" or
"microcompartments".
Anatomy

Anterior view of the human cerebellum, with numbers indicating salient landmarks
The cerebellum is located at the bottom of the brain, with the large mass of the cerebral
cortex above it and the portion of the brainstem called the pons in front of it.[3] It is separated
from the overlying cerebrum by a layer of leathery dura mater; all of its connections with other
parts of the brain travel through the pons. Anatomists classify the cerebellum as part of
the metencephalon, which also includes the pons; the metencephalon is the upper part of
the rhombencephalon or "hindbrain". Like the cerebral cortex, the cerebellum is divided into two
hemispheres; it also contains a narrow midline zone called the vermis. A set of large folds is, by
convention, used to divide the overall structure into 10 smaller "lobules". Because of its large
number of tiny granule cells, the cerebellum contains more neurons than the rest of the brain put
together, but it takes up only 10% of total brain volume.[4]

Vertical cross-section of the human cerebellum, showing folding pattern of the cortex, and
interior structures
The unusual surface appearance of the cerebellum conceals the fact that most of its volume is
made up of a very tightly folded layer of gray matter, the cerebellar cortex. It has been estimated
that, if the human cerebellar cortex were completely unfolded, it would give rise to a layer of
neural tissue about 1 meter long and averaging 5 centimeters wide — a total surface area of
about 500 square cm, packed within a volume of dimensions 6 cm × 5 cm ×
10 cm.[4] Underneath the gray matter of the cortex lies white matter, made up largely
of myelinated nerve fibers running to and from the cortex. Embedded within the white matter —
which is sometimes called the arbor vitae (Tree of Life) because of its branched, tree-like
appearance in cross-section — are four deep cerebellar nuclei, composed of gray matter.[3]

Subdivisions

Based on surface appearance, three lobes can be distinguished in the cerebellum, called
the flocculonodular lobe, anterior lobe (above the primary fissure), and posterior lobe (below the
primary fissure). These lobes divide the cerebellum from rostral to caudal (in humans, top to
bottom). In terms of function, however, there is a more important distinction along the medial-to-
lateral dimension. Leaving out the flocculonodular part, which has distinct connections and
functions, the cerebellum can be parsed functionally into a medial sector called the
spinocerebellum and a larger lateral sector called the cerebrocerebellum.[3] A narrow strip of
protruding tissue along the midline is called the vermis (Latin for "worm").[3]

Cerebellum and surrounding regions;

sagittal view of one hemisphere. Schematic representation of the major anatomical
A: Midbrain. B: Pons. C: Medulla. subdivisions of the cerebellum. Superior view of an
D: Spinal cord. E:Fourth ventricle. "unrolled" cerebellum, placing the vermis in one
F: Arbor vitae. G: Tonsil. H: Anterior lobe. plane.
I: Posterior lobe.
The smallest region, the flocculonodular lobe, is often called the vestibulocerebellum. It is the
oldest part in evolutionary terms (archicerebellum) and participates mainly in balance and spatial
orientation; its primary connections are with the vestibular nuclei, although it also receives visual
and other sensory input. Damage to it causes disturbances of balance and gait.[3]
The medial zone of the anterior and posterior lobes constitutes the spinocerebellum, also known
as paleocerebellum. This sector of the cerebellum functions mainly to fine-tune body and limb
movements. It receives proprioception input from the dorsal columns of the spinal
cord (including the spinocerebellar tract) and from the trigeminal nerve, as well as from visual
andauditory systems. It sends fibres to deep cerebellar nuclei that, in turn, project to both the
cerebral cortex and the brain stem, thus providing modulation of descending motor systems.[3]
The lateral zone, which in humans is by far the largest part, constitutes the cerebrocerebellum,
also known as neocerebellum. It receives input exclusively from the cerebral cortex (especially
the parietal lobe) via the pontine nuclei (forming cortico-ponto-cerebellar pathways), and sends
output mainly to the ventrolateral thalamus (in turn connected to motor areas of the premotor
cortex and primary motor area of the cerebral cortex) and to the red nucleus.[3] There is
disagreement about the best way to describe the functions of the lateral cerebellum: It is thought
to be involved in planning movement that is about to occur,[5] in evaluating sensory information
for action,[3] and in a number of purely cognitive functions as well.[6]
Two types of neuron play dominant roles in the cerebellar circuit: Purkinje cells and granule
cells. Three types of axons also play dominant roles: mossy fibers and climbing fibers (which
enter the cerebellum from outside), and parallel fibers (which are the axons of granule cells).
There are two main pathways through the cerebellar circuit, originating from mossy
fibers and climbing fibers, both terminating in the deep cerebellar nuclei.
Mossy fibers project directly to the deep nuclei, but also give rise to the pathway: mossy fiber →
granule cells → parallel fibers → Purkinje cells → deep nuclei. Climbing fibers project to
Purkinje cells and also send collaterals directly to the deep nuclei.[4] The mossy fiber and
climbing fiber inputs each carry fiber-specific information; the cerebellum also
receives dopaminergic, serotonergic,noradrenergic, and cholinergic inputs that presumably
perform global modulation.[7]
The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer,
densely packed with granule cells, along with much smaller numbers of interneurons,
mainly Golgi cells. In the middle lies the Purkinje layer, a narrow zone that contains only the cell
bodies of Purkinje cells. At the top lies the molecular layer, which contains the flattened
dendritic trees of Purkinje cells, along with the huge array of parallel fibers penetrating the
Purkinje cell dendritic trees at right angles. This outermost layer of the cerebellar cortex also
contains two types of inhibitory interneurons, stellate cells, and basket cells. Both stellate and
basket cells form GABAergic synapses onto Purkinje cell dendrites.[4]

Deep nuclei

Cross-section of human cerebellum, showing the dentate nucleus, as well as the pons and inferior
olivary nucleus
The deep nuclei of the cerebellum are clusters of gray matter lying within the white matter at the
core of the cerebellum. They are, with the minor exception of the nearby vestibular nuclei, the
sole sources of output from the cerebellum. These nuclei receive collateral projections from
mossy fibers and climbing fibers, as well as inhibitory input from the Purkinje cells of the
cerebellar cortex. The three nuclei (dentate, interpositus, and fastigial) each communicate with
different parts of the brain and cerebellar cortex. The fastigial and interpositus nuclei belong to
the spinocerebellum. The dentate nucleus, which in mammals is much larger than the others, is
formed as a thin, convoluted layer of gray matter, and communicates exclusively with the lateral
parts of the cerebellar cortex. The flocculonodular lobe is the only part of the cerebellar cortex
that does not project to the deep nuclei — its output goes to the vestibular nuclei instead.[4]
The majority of neurons in the deep nuclei have large cell bodies and spherical dendritic trees
with a radius of about 400 μm, and useglutamate as their neurotransmitter. These cells project to
a variety of targets outside the cerebellum. Intermixed with them is a lesser number of small
cells, which use GABA as neurotransmitter and project exclusively to the inferior olivary
nucleus, the source of climbing fibers. Thus, the nucleo-olivary projection provides an inhibitory
feedback to match the excitatory projection of climbing fibers to the nuclei. There is evidence
that each small cluster of nuclear cells projects to the same cluster of olivary cells that send
climbing fibers to it; there is strong and matching topography in both directions.[4]
When a Purkinje cell axon enters one of the deep nuclei, it branches to make contact with both
large and small nuclear cells, but the total number of cells contacted is only about 35 (in cats).
On the converse, a single deep nuclear cell receives input from approximately 860 Purkinje cells
(again in cats).[4]
Function
The strongest clues to the function of the cerebellum have come from examining the
consequences of damage to it. Animals and humans with cerebellar dysfunction show, above all,
problems with motor control. They continue to be able to generate motor activity, but it loses
precision, producing erratic, uncoordinated, or incorrectly timed movements. A standard test of
cerebellar function is to reach with the tip of the finger for a target at arm's length: A healthy
person will move the fingertip in a rapid straight trajectory, whereas a person with cerebellar
damage will reach slowly and erratically, with many mid-course corrections. Deficits in non-
motor functions are more difficult to detect. Thus, the general conclusion reached decades ago is
that the basic function of the cerebellum is not to initiate movements, or to decide which
movements to execute, but rather to calibrate the detailed form of a movement.[3]
Prior to the 1990s, the function of the cerebellum was almost universally believed to be purely
motor-related, but newer findings have brought that view strongly into question. Functional
imaging studies have shown cerebellar activation in relation to language, attention, and mental
imagery; correlation studies have shown interactions between the cerebellum and non-motoric
areas of the cerebral cortex; and a variety of non-motor symptoms have been recognized in
people with damage that appears to be confined to the cerebellum.[13][14]
Kenji Doya has argued that the function of the cerebellum is best understood not in terms of
what behaviors it is involved in but rather in terms of what neural computations it performs; the
cerebellum consists of a large number of more or less independent modules, all with the same
geometrically regular internal structure, and therefore all, it is presumed, performing the same
computation. If the input and output connections of a module are with motor areas (as many are),
then the module will be involved in motor behavior; but, if the connections are with areas
involved in non-motor cognition, the module will show other types of behavioral correlates. The
cerebellum, Doya proposes, is best understood as a device for supervised learning, in contrast to
the basal ganglia, which perform reinforcement learning, and the cerebral cortex, which
performs unsupervised learning.[14]
Principles
The comparative simplicity and regularity of the cerebellar anatomy led to an early hope that it
might imply a similar simplicity of computational function, as expressed in one of the first books
on cerebellar electrophysiology, The Cerebellum as a Neuronal Machine by John C.
Eccles, Masao Ito, and Janos Szentágothai.[15] Although a full understanding of cerebellar
function has remained elusive, at least four principles have been identified as important: (1)
feedforward processing, (2) divergence and convergence, (3) modularity, and (4) plasticity.
1. Feedforward processing: The cerebellum differs from most other parts of the brain (especially
the cerebral cortex) in that the signal processing is almost entirely feedforward - that is, signals
move unidirectionally through the system from input to output, with very little recurrent internal
transmission. The small amount of recurrence that does exist consists of mutual inhibition; there
are no mutually excitatory circuits. This feedforward mode of operation means that the
cerebellum, in contrast to the cerebral cortex, cannot generate self-sustaining patterns of neural
activity. Signals enter the circuit, are processed by each stage in sequential order, and then leave.
As Eccles, Ito, and Szentágothai wrote, "This elimination in the design of all possibility of
reverberatory chains of neuronal excitation is undoubtedly a great advantage in the performance
of the cerebellum as a computer, because what the rest of the nervous system requires from the
cerebellum is presumably not some output expressing the operation of complex reverberatory
circuits in the cerebellum but rather a quick and clear response to the input of any particular set
of information."[16]
2. Divergence and convergence: In the human cerebellum, information from 200 million mossy
fiber inputs is expanded to 40 billion granule cells, whose parallel fiber outputs then converge
onto 15 million Purkinje cells.[4] Because of the way that they are lined up longitudinally, the
1000 or so Purkinje cells belonging to a microzone may receive input from as many as 100
million parallel fibers, and focus their own output down to a group of less than 50 deep
nuclear cells.[10] Thus, the cerebellar network receives a modest number of inputs, processes
them very extensively through its rigorously structured internal network, and sends out the
results via a very limited number of output cells.
3. Modularity: The cerebellar system is functionally divided into more or less independent
modules, which probably number in the hundreds to thousands. All modules have a similar
internal structure, but different inputs and outputs. A module (a multizonal microcompartment in
the terminology of Apps and Garwicz) consists of a small cluster of neurons in the inferior
olivary nucleus, a set of long narrow strips of Purkinje cells in the cerebellar cortex
(microzones), and a small cluster of neurons in one of the deep cerebellar nuclei. Different
modules share input from mossy fibers and parallel fibers, but in other respects they appear to
function independently — the output of one module does not appear to significantly influence
the activity of other modules.[10]
4. Plasticity: The synapses between parallel fibers and Purkinje cells, and the synapses between
mossy fibers and deep nuclear cells, are both susceptible to modification of their strength. In a
single cerebellar module, input from as many as a billion parallel fibers converges onto a group
of less than 50 deep nuclear cells, and the influence of each parallel fiber on those nuclear cells is
adjustable. This arrangement gives tremendous flexibility for fine-tuning the relationship
between cerebellar inputs and outputs.[17]
Learning
There is considerable evidence that the cerebellum plays an essential role in some types of motor
learning. The tasks where the cerebellum most clearly comes into play are those in which it is
necessary to make fine adjustments to the way an action is performed. There has, however, been
much dispute about whether learning takes place within the cerebellum itself, or whether it
merely serves to provide signals that promote learning in other brain structures.[17] Most
theories that assign learning to the circuitry of the cerebellum are derived from early ideas
of David Marr and James Albus, who postulated that climbing fibers provide a teaching signal
that induces synaptic modification in parallel fiber—Purkinje cell synapses.[18] Marr assumed
that climbing fiber input would cause synchronously activated parallel fiber inputs to be
strengthened. Most later cerebellar-learning models, however, have followed Albus in assuming
that climbing fiber activity would be an error signal, and would cause synchronously activated
parallel fiber inputs to be weakened. Some of these later models, such as theAdaptive
Filter model of Fujita[19] made attempts to understand cerebellar function in terms of optimal
control theory.
Pathology

Altered walking gait of a woman with cerebellar disease

The most salient symptoms of cerebellar dysfunction are motor-related — the specific symptoms
depend on which part of the cerebellum is involved and how it is disrupted. Damage to the
flocculonodular lobe (the vestibular part) may show up as a loss of equilibrium and, in particular,
an altered walking gait, with a wide stance that indicates difficulty in balancing. Damage to the
midline portion may disrupt whole-body movements, whereas damage localized more laterally is
more likely to disrupt fine movements of the hands or limbs. Damage to the upper part of the
cerebellum tends to cause gait impairments and other problems with leg coordination; damage to
the lower part is more likely to cause uncoordinated or poorly aimed movements of the arms and
hands, as well as difficulties in speed.[3] This complex of motor symptoms is called "ataxia". To
identify cerebellar problems, the neurological examination includes assessment of gait (a broad-
based gait being indicative of ataxia), finger-pointing tests and assessment of posture.[2] If
cerebellar dysfunction is indicated, a magnetic resonance imagingscan can be used to obtain a
detailed picture of any structural alterations that may exist.[28]

The lower trace shows an attempt by a patient with cerebellar disease to reproduce the upper
trace.
The list of medical problems that can produce cerebellar damage is long: it includes stroke;
hemorrhage; tumors; alcoholism; physical trauma such as gunshot wounds; and chronic
degenerative conditions such as olivopontocerebellar atrophy.[3] Some forms of migraine
headache may also produce temporary dysfunction of the cerebellum, of variable severity.[29]
Aging
The human cerebellum changes with age. These changes may differ from those of other parts of
the brain, for example the gene expressionpattern in the human cerebellum shows less age-
related alteration than in the cerebral cortex.[30] Some studies have reported reductions in
numbers of cells or volume of tissue, but the amount of data relating to this question is not very
large.

Apraxia
Apraxia is a neurological disorder characterized by loss of the ability to execute or carry out
learned purposeful movements, despite having the desire and the physical ability to perform the
movements. It is a disorder of motor planning which may be acquired or developmental, but
may not be caused by incoordination, sensory loss, or failure to comprehend simple commands
(which can be tested by asking the person to recognize the correct movement from a series).
Apraxia should not be confused with aphasia, an inability to produce and/or comprehend
language, abulia, the lack of desire to carry out an action, or allochiria, in which patients
perceive stimuli to one side of the body as occurring on the other.
The root word of apraxia is praxis, Greek for an act, work, or deed. It is preceded by a privative
a, meaning without.
Types
There are several types of apraxia including:
 ideomotor (inability to carry out a motor command, for example, "act as if you are
brushing your teeth" or "salute") - the form most frequently encountered by physicians,
o limb apraxia when movements of the arms and legs are involved,
o nonverbal-oral or buccofacial (inability to carry out facial movements on
command, e.g., lick lips, whistle, cough, or wink),
 ideational (inability to create a plan for or idea of a specific movement, for example,
"pick up this pen and write down your name"),
 limb-kinetic (inability to make fine, precise movements with a limb),
  verbal (difficulty planning the movements necessary for speech), also known as Apraxia
of Speech (see below)
 constructional (inability to draw or construct simple configurations), such as intersecting
pentagons,
 oculomotor (difficulty moving the eye, especially with saccade movements)
Each type may be tested at decreasing levels of complexity; if the person tested fails to execute
the commands, you can make the movement yourself and ask that the person mimic it, or you
can even give them a real object (like a tooth brush) and ask them to use it.
Apraxia may be accompanied by a language disorder called aphasia.
Apraxia of speech
Symptoms of Acquired Apraxia of Speech (AOS) and Childhood Apraxia of Speech (CAS)
include inconsistent articulatory errors, groping oral movements to locate the correct articulatory
position, and increasing errors with increasing word and phrase length. AOS often co-occurs
with Oral Apraxia (during both speech and non-speech movements) and Limb Apraxia.
Childhood Apraxia of Speech (CAS) presents in children who have no evidence of difficulty
with strength or range of motion of the articulators, but are unable to execute speech movements
because of motor planning and coordination problems. This is not to be confused with
phonological impairments in children with normal coordination of the articulators during speech.
Acquired apraxia of speech involves the loss of previously acquired speech levels. It occurs in
both children and adults who have (prior to the onset of apraxia) acquired some level of speaking
ability. Unlike Childhood Apraxia of Speech, AOS is typically the result of a stroke, tumor, or
other known neurological illness or injury.
Causes
Ideomotor apraxia is almost always caused by lesions in the language-dominant (usually left)
hemisphere of the brain, and as such these patients often have concomitant aphasia, especially of
the Broca or conduction type. Left-side ideomotor apraxia may be caused by a lesion of the
anterior corpus callosum.
Ideational apraxia is commonly associated with confusion states and dementia.
Treatment
Recommended treatment for individuals with apraxia includes physical therapy, occupational
therapy and/or speech therapy. Though research is still in its infancy, there have been anecdotal
reports of successful treatment in younger children using a combination of fish oils and vitamins
E and K.
Prognosis
The prognosis for individuals with apraxia varies. With therapy, some patients improve
significantly, while others may show very little improvement. Some individuals with apraxia
may benefit from the use of a communication aid.
Cranial nerves
Nerve: Cranial nerves

Inferior view of the brain and brain stem showing cranial

nerves.
Cranial nerves are nerves that emerge directly from the brain stem, in contrast to spinal nerves
which emerge from segments of the spinal cord.
List of cranial nerves
Sensory,
# Name Motor Origin Nuclei Function
or Both
Transmits the sense of
Anterior
Purely smell; Located in
I Olfactory nerve olfactory
Sensory olfactory foramina of
nucleus
ethmoid
Transmits visual
Purely Ganglion cells
II Optic nerve information to the brain;
Sensory of retina
Located in optic canal
Innervates levator
palpebrae superioris,
Oculomotor superior rectus, medial
nucleus, rectus, inferior rectus,
Mainly
III Oculomotor nerve Midbrain Edinger- and inferior oblique,
Motor
Westphal which collectively
nucleus perform most eye
movements; Located in
superior orbital fissure
Innervates the superior
oblique muscle, which
depresses, rotates
Mainly Trochlear
IV Trochlear nerve Midbrain laterally (around the
Motor nucleus
optic axis), and intorts
the eyeball; Located in
superior orbital fissure
 Principal
Receives sensation from
sensory
the face and innervates
trigeminal
the muscles of
nucleus, Spinal
Both mastication; Located in
trigeminal
Sensory superior orbital fissure
V Trigeminal nerve Pons nucleus,
and (ophthalmic nerve - V1),
Mesencephalic
Motor foramen rotundum
trigeminal
(maxillary nerve - V2),
nucleus,
and foramen ovale
Trigeminal
(mandibular nerve - V3)
motor nucleus
Innervates the lateral
Mainly Posterior margin Abducens rectus, which abducts the
VI Abducens nerve
Motor of Pons nucleus eye; Located in superior
orbital fissure
Provides motor
innervation to the
muscles of facial
expression, posterior
belly of the digastric
muscle, and stapedius
muscle, receives the
Both Pons Facial nucleus, special sense of taste
Sensory (cerebellopontine Solitary nucleus, from the anterior 2/3 of
VII Facial nerve
and angle) above Superior the tongue, and provides
Motor olive salivary nucleus secretomotor innervation
to the salivary glands
(except parotid) and the
lacrimal gland; Located
and runs through internal
acoustic canal to facial
canal and exits at
stylomastoid foramen
Senses sound, rotation
and gravity (essential for
balance & movement).
Vestibulocochlear
More specifically. the
nerve (or auditory- Lateral to CN VII Vestibular
Mostly vestibular branch carries
VIII vestibular nerve or (cerebellopontine nuclei, Cochlear
sensory impulses for equilibrium
statoacoustic angle) nuclei
and the cochlear branch
nerve)
carries impulses for
hearing.; Located in
internal acoustic canal
Receives taste from the
posterior 1/3 of the
Nucleus
Both tongue, provides
ambiguus,
Glossopharyngeal Sensory secretomotor innervation
IX Medulla Inferior salivary
nerve and to the parotid gland, and
nucleus, Solitary
Motor provides motor
nucleus
innervation to the
stylopharyngeus
 (essential for tactile,
pain, and thermal
sensation). Some
sensation is also relayed
to the brain from the
palatine tonsils.
Sensation is relayed to
opposite thalamus and
some hypothalamic
nuclei. Located in
jugular foramen
Supplies branchiomotor
innervation to most
laryngeal and all
pharyngeal muscles
(except the
stylopharyngeus, which
is innervated by the
glossopharyngeal);
provides
parasympathetic fibers to
Nucleus nearly all thoracic and
Both
ambiguus, abdominal viscera down
Sensory Posterolateral
X Vagus nerve Dorsal motor to the splenic flexure;
and sulcus of Medulla
vagal nucleus, and receives the special
Motor
Solitary nucleus sense of taste from the
epiglottis. A major
function: controls
muscles for voice and
resonance and the soft
palate. Symptoms of
damage: dysphagia
(swallowing problems),
velopharyngeal
insufficiency. Located in
jugular foramen
Controls
sternocleidomastoid and
Accessory nerve trapezius muscles,
Nucleus
(or cranial overlaps with functions
Mainly Cranial and ambiguus,
XI accessory nerve or of the vagus. Examples
Motor Spinal Roots Spinal accessory
spinal accessory of symptoms of damage:
nucleus
nerve) inability to shrug, weak
head movement; Located
in jugular foramen
Provides motor
innervation to the
Mainly Hypoglossal muscles of the tongue
XII Hypoglossal nerve Medulla
Motor nucleus (except for the
palatoglossus, which is
innervated by the vagus)
and other glossal
muscles. Important for
swallowing (bolus
formation) and speech
articulation. Located in
hypoglossal canal
Optic nerve

The left optic nerve and the optic tracts.

The optic nerve, also called cranial nerve II, transmits visual information from the retina to the
brain.
Anatomy The optic nerve is the second of twelve paired cranial nerves but is considered to be
part of the central nervous system as it is derived from an outpouching of the diencephalon
during embryonic development. Consequently, the fibers are covered with myelin produced by
oligodendrocytes rather than the Schwann cells of the peripheral nervous system and are encased
within the meninges. Therefore the distinction of nerve is technically a misnomer, as the optic
system lies within the central nervous system and nerves exist, by definition, within the
peripheral nervous system. Therefore peripheral neuropathies like Guillain-Barré syndrome do
not affect the optic nerve.
The optic nerve is ensheathed in all three meningeal layers (dura, arachnoid, and pia mater)
rather than the epineurium, perineurium, and endoneurium found in peripheral nerves. Fiber
tracks of the mammalian central nervous system (as opposed to the peripheral nervous system)
are incapable of regeneration and hence optic nerve damage produces irreversible blindness. The
fibers from the retina run along the optic nerve to nine primary visual nuclei in the brain, whence
a major relay inputs into the primary visual cortex.
The optic nerve is composed of retinal ganglion cell axons and Portort cells. It leaves the orbit
(eye) via the optic canal, running postero-medially towards the optic chiasm where there is a
partial decussation (crossing) of fibers from the nasal visual fields of both eyes. Most of the
axons of the optic nerve terminate in the lateral geniculate nucleus from where information is
relayed to the visual cortex, while other axons terminate in the pretectal nucleus and are involved
in reflexive eye movements and other axons terminate in the suprachiasmatic nucleus and are
involed in regulating the sleep-wake cycle. Its diameter increases from about 1.6 mm within the
eye, to 3.5 mm in the orbit to 4.5 mm within the cranial space. The optic nerve component
lengths are 1 mm in the globe, 24 mm in the orbit, 9 mm in the optic canal and 16 mm in the
cranial space before joining the optic chiasm. There, partial decussation occurs and about 53% of
the fibers cross to form the optic tracts. Most of these fibres terminate in the lateral geniculate
body.
From the lateral geniculate body, fibers of the optic radiation pass to the visual cortex in the
occipital lobe of the brain. More specifically, fibers carrying information from the contralateral
superior visual field traverse Meyer's loop to terminate in the lingual gyrus below the calcarine
fissure in the occipital lobe, and fibers carrying information from the contralateral inferior visual
field terminate more superiorly.
Physiology
The eye's blind spot is a result of the absence of retina where the optic nerve leaves the eye. This
is because there are no photoreceptors in this area. Each optic nerve contains around 1.2 million
nerve fibers, which are axons of the retinal ganglion cells of one retina. In the fovea, which has
high acuity, these ganglion cells connect to as few as 5 photoreceptors; in other areas of retina,
they connect to many thousand photoreceptors.
Shortfalls in our knowledge
We do not yet have any comprehensive knowledge of how the visual signals are processed, or
how they cope with the apparently limited "channel-capacity" — though there are some plausible
theories.
Role in disease
Damage to the optic nerve typically causes permanent and potentially severe loss of vision, as
well as an abnormal pupillary reflex, which is diagnostically important. The type of visual field
loss will depend on which portions of the optic nerve were damaged. Generally speaking:
 Damage before the optic chiasm causes loss of vision in the visual field of the same side
only.
 Damage in the chiasm causes loss of vision laterally in both visual fields (bitemporal
hemianopia). It may occur in large pituitary adenoma.
 Damage after the chiasm causes loss of vision on one side but affecting both visual
fields: the visual field affected is located on the opposite side of the lesion.
Injury to the optic nerve can be the result of congenital or inheritable problems like Leber's
Hereditary Optic Neuropathy, glaucoma, trauma, toxicity, inflammation, ischemia, infection
(very rarely), or compression from tumors or aneurysms. By far, the three most common injuries
to the optic nerve are from glaucoma, optic neuritis (especially in those younger than 50 years of
age) and anterior ischemic optic neuropathy (usually in those older than 50).

Homonymous hemianopsia
Homonymous hemianopsia

Paris as seen with left homonymous hemianopsia

Homonymous hemianopsia, or homonymous hemianopia, is a medical term for a type of partial
blindness resulting in a loss of vision in the same visual field of both eyes.
Causes
It is usually caused by injury to the brain itself such as from stroke or trauma, or as a byproduct
of certain surgical procedures and does not indicate a malfunctioning of the eyes themselves. It
may also be caused by tumour localised at the occipital lobe in the brain.
Vascular and neoplastic (malignant or benign tumours) lesions of the optic tract, visual cortex or
uncal herniation can cause a contralateral homonymous hemianopsia. For example, a person who
has a lesion of the right optic tract will no longer see objects on his left side. Similarly, a person
who has a stroke to the right occipital lobe will have the same visual field defect, but there will
be macular sparing. Thus injury to the right side of the brain will affect the left visual fields of
each eye.
A stroke on the right side of the brain, in addition to producing a homonymous hemianopsia,
may also lead to the syndrome of hemispatial neglect.
However, the symptom of homonymous hemianopsia isn't necessarily of a lethal cause. For
instance, it can constitute the aura phase of migraine.
Effects
Mobility can be difficult for people with homonymous hemianopia. “Patients frequently
complain of bumping into obstacles on the side of the field loss, thereby bruising their arms and
legs.”
People with homonymous hemianopia often experience discomfort in crowds. “A patient with
this condition may be unaware of what he or she cannot see and frequently bumps into walls,
trips over objects or walks into people on the side where the visual field is missing.”

Binasal hemianopsia
Binasal hemianopsia

Paris as seen with binasal hemianopsia

Paris as seen with full visual fields

Binasal hemianopsia (or Binasal hemianopia) is the medical description of a type of partial
blindness where vision is missing in the inner half of both the right and left visual field. It is
associated with certain lesions of the eye and of the central nervous system, such as congenital
hydrocephalus.
Causes
In binasal hemianopsia, vision is missing in the inner (nasal or medial) half of both the right
and left visual fields. Information from the nasal visual field falls on the temporal (lateral) retina.
Those lateral retinal nerve fibers do not cross in the optic chiasm. Calcification of the internal
carotid arteries can impinge the uncrossed, lateral retinal fibers leading to loss of vision in the
nasal field.

Bitemporal hemianopsia
Bitemporal hemianopsia

Paris as seen with bitemporal hemianopia

Paris as seen with full visual fields
Bitemporal hemianopsia (or Bitemporal hemianopia) is the medical description of a type of
partial blindness where vision is missing in the outer half of both the right and left visual field. It
is usually associated with lesions of the optic chiasm, the area where the optic nerves from the
right and left eyes cross near the pituitary gland.
Causes
In bitemporal hemianopsia vision is missing in the outer (temporal or lateral) half of both the
right and left visual fields. Information from the temporal visual field falls on the nasal (medial)
retina. The nasal retina is responsible for carrying the information along the optic nerve, and
crosses to the other side at the optic chiasm. When there is compression at optic chiasm the
visual impulse from both nasal retina are affected, leading to inability to view the temporal, or
peripheral, vision. This phenomenon is known as bitemporal hemianopsia. Knowing the
neurocircuitry of visual signal flow through the optic tract is very important in understanding
bitemporal hemianopsia.
Bitemporal hemianopsia most commonly occurs as a result of tumors located at the mid-optic
chiasm. Since the adjacent structure is the pituitary gland, some common tumors causing
compression are Pituitary adenomas, and Craniopharyngiomas. Also another relatively common
neoplastic etiology is Meningiomas.
Oculomotor nerve
Nerve: Oculomotor nerve

Nerves of the orbit. Seen from above.

Latin nervus oculomotorius
The oculomotor nerve is the third of twelve paired cranial nerves. It controls most of the eye's
movement, constriction of the pupil, and maintains an open eyelid. (Note: cranial nerves IV and
VI also participate in control of eye movement.)
Path
Nuclei
The oculomotor nerve arises from the anterior aspect of mesencephalon (midbrain). There are
two nuclei for the oculomotor nerve:
• The oculomotor nucleus originates at the level of the superior colliculus. The muscles it
controls are the striated muscle in levator palpebrae superioris and all extraocular muscles except
for the superior oblique muscle and the lateral rectus muscle.
• The Edinger-Westphal nucleus supplies parasympathetic fibres to the eye via the ciliary
ganglion, and thus controls the sphincter pupillae muscle (affecting pupil constriction) and the
ciliary muscle (affecting accommodation).
Sympathetic postganglionic fibres also join the nerve from the plexus on the internal carotid
artery in the wall of the cavernous sinus and are distributed through the nerve, e.g. to the smooth
muscle of levator palpebrae superioris.

Emergence from brain

On emerging from the brain, the nerve is invested with a sheath of pia mater, and enclosed in a
prolongation from the arachnoid.
It passes between the superior cerebellar (below) and posterior cerebral arteries (above), and then
pierces the dura mater anterior and lateral to the posterior clinoid process, passing between the
free and attached borders of the tentorium cerebelli.
It runs along the lateral wall of the cavernous sinus, above the other orbital nerves, receiving in
its course one or two filaments from the cavernous plexus of the sympathetic, and a
communicating branch from the ophthalmic division of the trigeminal.

Superior and inferior rami

It then divides into two branches, which enter the orbit through the superior orbital fissure,
between the two heads of the lateral rectus. Here the nerve is placed below the trochlear nerve
and the frontal and lacrimal branches of the ophthalmic nerve, while the nasociliary nerve is
placed between its two rami:
 superior branch of oculomotor nerve
 inferior branch of oculomotor nerve
Testing the oculomotor nerve
Eye muscles
Cranial nerves III, IV and VI are usually tested together. The examiner typically instructs the
patient to hold his head still and follow only with the eyes a finger or penlight that circumscribes
a large "H" in front of the patient. By observing the eye movement and eyelids, the examiner is
able to obtain more information about the extraocular muscles, the levator palpebrae superioris
muscle, and cranial nerves III, IV, and VI.
Since the oculomotor nerve controls most of the eye muscles, it may be easier to detect damage
to it. Damage to this nerve, termed oculomotor nerve palsy is also known by the down n' out
symptoms, because of the position of the affected eye.

Pupillary reflex
The oculomotor nerve also controls the constriction of the pupils and thickening of the lens of
the eye. This can be tested in two main ways. By moving a finger towards a person's face to
induce accommodation, as well as them going cross-eyed, their pupils should constrict.
Shining a light into their eyes should also make their pupils constrict. Both pupils should
constrict at the same time, independent of what eye the light is actually shone on.
Pathology
Paralysis of the oculomotor nerve, i.e. palsy, is a rare condition. It can arise due to:
 direct trauma,
 demyelinating diseases (e.g. multiple sclerosis),
 increased intracranial pressure (leading to uncal herniation)
o due to a space-occupying lesion (e.g. brain cancer) or a
o spontaneous subarachnoid haemorrhage (e.g. berry aneurysm), and
 microvascular disease, e.g. diabetes.
In people with diabetes and older than 50 years of age, an oculomotor nerve palsy, classically,
occurs with sparing (or preservation) of the pupillary reflex. This is thought to arise due the
anatomical arrangement of the nerve fibers in the oculomotor nerve; fibers controlling the
pupillary function are superficial and spared from ischemic injuries typical of diabetes.
Conversely, a subarachnoid haemorrhage, which leads to compression of the oculomotor nerve,
usually affects the superficial fibers and manifests as a palsy with loss of the pupillary reflex.
Oculomotor nerve palsy
Oculomotor nerve palsy

Eye nerves diagram

Oculomotor nerve palsy is an eye condition resulting from damage to the third cranial nerve or
a branch thereof. As the name suggests, the oculomotor nerve supplies the majority of the
muscles controlling eye movements. Thus, damage to this nerve will result in the affected
individual being unable to move their eye normally. In addition, the nerve also supplies the upper
eyelid muscle (the Levator palpebrae superioris) and the muscles responsible for pupil
constriction (termed miosis) and dilation (termed mydriasis). The limitations of eye movements
resulting from the condition are generally so severe that the affected individual is unable to
maintain normal alignment of their eyes when looking straight ahead, leading to strabismus and,
as a consequence, double vision (diplopia).
Eye Position
A complete Oculomotor nerve palsy will result in a characteristic down n' out position in the
affected eye. The eye will be displaced downward, because the superior oblique (innervated by
the fourth cranial or trochlear nerve), is unantagonized by the paralyzed superior rectus and
inferior oblique and displaced outward, because the lateral rectus (innervated by the sixth or
abducens cranial nerve) is unantagonized by the paralyzed medial rectus. The affected individual
will also have a ptosis, or drooping of the eyelid, and pupil dilation.
It should be borne in mind, however, that the branched structure of the oculomotor nerve means
that damage sustained at different points along its pathway, or damage caused in different ways
(compression versus loss of blood supply, for example), will result in different muscle groups or,
indeed, different individual muscles being affected, thus producing different presentation
patterns.
Cause
Oculomotor palsy can arise as a result of a number of different conditions.
Congenital Oculomotor Palsy
The origins of the vast majority of congenital oculomotor palsies are unknown, or idiopathic to
use the medical term. There is some evidence of a familial tendency to the condition, particularly
to a partial palsy involving the superior division of the nerve with an autosomal recessive
inheritance. The condition can also result from aplasia or hypoplasia of one or more of the
muscles supplied by the oculomotor nerve. It can also occur as a consequence of severe birth
trauma.
Acquired oculomotor palsy
 1. Vascular disorders such as diabetes, heart disease, atherosclerosis and aneurysm,
particularly of the posterior communicating artery
 2. Space occupying lesions or tumours, both malignant and non-malignant
 3. Inflammation and Infection
 4. Trauma
 5. Demyelinating disease (Multiple sclerosis)
 6. Autoimmune disorders such as Myasthenia gravis
 7. Post operatively as a complication of neurosurgery
  8. Cavernous sinus thrombosis
Ischemic insult selectively affects somatic fibers over parasympathetic fibers, while traumatic
insult affects both types more equally. Therefore, while almost all forms cause ptosis and
impaired movement of the eye, pupillary abnormalities are more commonly associated with
trauma than with ischemia.

Trochlear nerve
Nerve: Trochlear nerve

The trochlear nerve (the fourth cranial nerve, also called the fourth nerve, IV, or Layton's
nerve in the UK) is a motor nerve (a “somatic efferent” nerve) that innervates a single muscle:
the superior oblique muscle of the eye.

The trochlear nerve is unique among the cranial nerves in several respects. It is the smallest
nerve in terms of the number of axons it contains. It has the greatest intracranial length. Along
with the optic nerve (cranial nerve II), it is the only cranial nerve that decussates (crosses to the
other side) before innervating its target. Finally, it is the only cranial nerve that exits from the
dorsal aspect of the brainstem.
Homologous trochlear nerves are found in all jawed vertebrates. The unique features of the
trochlear nerve, including its dorsal exit from the brainstem and its contralateral innervation, are
seen in the primitive brains of sharks.[2]
Peripheral anatomy
The Cavernous Sinus
The trochlear nerve emerges from the dorsal aspect of the brainstem at the level of the caudal
mesencephalon, just below the inferior colliculus. It circles anteriorly around the brainstem and
runs forward toward the eye in the subarachnoid space. It passes between the posterior cerebral
artery and the superior cerebellar artery, and then pierces the dura just under free margin of the
tentorium cerebelli, close to the crossing of the attached margin of the tentorium and within
millimeters of the posterior clinoid process.[3] It enters the cavernous sinus, where it is joined by
the other two extraocular nerves (III and VI), the internal carotid artery, and portions of the
trigeminal nerve (V). Finally, it enters the orbit through the superior orbital fissure and
innervates the superior oblique muscle.
The superior oblique muscle ends in a tendon that passes through a fibrous loop, the trochlea,
located anteriorly on the medial aspect of the orbit. Trochlea means “pulley” in Latin; the fourth
nerve is named after this structure.
Actions of the superior oblique muscle
In order to understand the actions of the superior oblique muscle, it is useful to imagine the
eyeball as a sphere that is constrained – like the trackball of a computer mouse – in such a way
that only certain rotational movements are possible. Allowable movements for the superior
oblique are (1) rotation in a vertical plane – looking down and up (depression and elevation of
the eyeball) and (2) rotation in the plane of the face (intorsion and extorsion of the eyeball).
The body of the superior oblique muscle is located behind the eyeball, but the tendon (which is
redirected by the trochlea) approaches the eyeball from the front. The tendon attaches to the top
(superior aspect) of the eyeball at an angle of 51 degrees with respect to the primary position of
the eye (looking straight forward). The force of the tendon’s pull therefore has two components:
a forward component that tends to pull the eyeball downward (depression), and a medial
component that tends to rotate the top of the eyeball toward the nose (intorsion).
The relative strength of these two forces depends on which way the eye is looking. When the eye
is adducted (looking toward the nose), the force of depression increases. When the eye is
abducted (looking away from the nose), the force of intorsion increases, while the force of
depression decreases. When the eye is in the primary position (looking straight ahead),
contraction of the superior oblique produces depression and intorsion in roughly equal amounts.
To summarize, the actions of the superior oblique muscle are (1) depression of the eyeball,
especially when the eye is adducted; and (2) intorsion of the eyeball, especially when the eye is
abducted. The clinical consequences of weakness in the superior oblique (caused, for example,
by fourth nerve palsies) are discussed below.
This summary of the superior oblique muscle describes its most important functions. However, it
is an oversimplification of the actual situation. For example, the tendon of the superior oblique
inserts behind the equator of the eyeball in the frontal plane, so contraction of the muscle also
tends to abduct the eyeball (turn it outward). In fact, each of the six extraocular muscles exerts
rotational forces in all three planes (elevation-depression, adduction-abduction, intorsion-
extorsion) to varying degrees, depending on which way the eye is looking. The relative forces
change every time the eyeball moves – every time the direction of gaze changes. The central
control of this process, which involves the continuous, precise adjustment of forces on twelve
different tendons in order to point both eyes in exactly the same direction, is truly remarkable.
The recent discovery of soft tissue pulleys in the orbit – similar to the trochlea, but anatomically
more subtle and previously missed – has completely changed (and greatly simplified) our
understanding of the actions of the extraocular muscles[4]. Perhaps the most important finding is
that a 2-dimensional representation of the visual field is sufficient for most purposes.
Central anatomy

Transverse Section of the Brainstem at the level of the Inferior Colliculus

The nucleus of the trochlear nerve is located in the caudal mesencephalon beneath the cerebral
aqueduct. It is immediately below the nucleus of the oculomotor nerve (III) in the rostral
mesencephalon.
The trochlear nucleus is unique in that its axons run dorsally and cross the midline before
emerging from the brainstem. Thus a lesion of the trochlear nucleus affects the contralateral eye.
Lesions of all other cranial nuclei affect the ipsilateral side.
Clinical syndromes
Vertical diplopia
Injury to the trochlear nerve cause weakness of downward eye movement with consequent
vertical diplopia (double vision). The affected eye drifts upward relative to the normal eye, due
to the unopposed actions of the remaining extraocular muscles. The patient sees two visual fields
(one from each eye), separated vertically. To compensate for this, patients learn to tilt the head
forward (tuck the chin in) in order to bring the fields back together – to fuse the two images into
a single visual field. This accounts for the “dejected” appearance of patients with “pathetic
nerve” palsies.
As would be expected, the diplopia gets worse when the affected eye looks toward the nose – the
contribution of the superior oblique muscle to downward gaze is greater in this position.
Common activities requiring this type of convergent gaze are reading the newspaper and walking
down stairs. Diplopia associated with these activities may be the initial symptom of a fourth
nerve palsy.
Alfred Bielschowsky's head tilt test is a test for palsy of the superior oblique muscle caused by
damage to cranial nerve IV (trochlear nerve).
Torsional diplopia
Trochlear nerve palsy also affects torsion (rotation of the eyeball in the plane of the face).
Torsion is a normal response to tilting the head sideways. The eyes automatically rotate in an
equal and opposite direction, so that the orientation of the environment remains unchanged –
vertical things remain vertical.
Weakness of intorsion results in torsional diplopia, in which two different visual fields, tilted
with respect to each other, are seen at the same time. To compensate for this, patients with
trochlear nerve palsies tilt their heads to the opposite side, in order to fuse the two images into a
single visual field.
The characteristic appearance of patients with fourth nerve palsies (head tilted to one side, chin
tucked in) suggests the diagnosis, but other causes must be ruled out. For example, tortico
llis can produce a similar appearance.
Causes
The clinical syndromes can originate from both peripheral and central lesions.

Peripheral lesions
A peripheral lesion is a damage to the bundle of nerves, in contrast to a central lesion, which is a
damage to the trochlear nucleus. Acute symptoms are probably a result of a trauma or disease,
while chronic symptoms probably are congenital.
Acute palsy
The most common cause of acute fourth nerve palsy is head trauma.[5] Even relatively minor
trauma can transiently stretch the fourth nerve (by transiently displacing the brainstem relative to
the posterior clinoid process). Patients with minor damage to the fourth nerve will complain of
“blurry” vision. Patients with more extensive damage will notice frank diplopia and rotational
(torsional) disturbances of the visual fields. The usual clinical course is complete recovery within
weeks to months.
Isolated injury to the fourth nerve can be caused by any process that stretches or compresses the
nerve. A generalized increase in intracranial pressure – hydrocephalus, pseudotumor cerebri,
hemorrhage, edema – will affect the fourth nerve, but the abducens nerve (VI) is usually affected
first (producing horizontal diplopia, not vertical diplopia). Infections (meningitis, herpes
zoster), demyelination (multiple sclerosis), diabetic neuropathy and cavernous sinus disease can
affect the fourth nerve, as can orbital tumors and Tolosa-Hunt syndrome. In general, these
diseases affect other cranial nerves as well. Isolated damage to the fourth nerve is uncommon in
these settings.
Chronic palsy
The most common cause of chronic fourth nerve palsy is a congenital defect, in which the
development of the fourth nerve (or its nucleus) is abnormal or incomplete. Congenital defects
may be noticed in childhood, but minor defects may not become evident until adult life, when
compensatory mechanisms begin to fail. Congenital fourth nerve palsies are amenable to surgical
treatment.

Central lesions

Central damage is a damage to the trochlear nucleus. It affects the contralateral eye. The nuclei
of all other cranial nerves affect ipsilateral structures.
The trochlear nucleus and its axons within the brainstem can be damaged by infarctions,
hemorrhage, arteriovenous malformations, tumors and demyelination. Collateral damage to other
structures will usually dominate the clinical picture.
The fourth nerve is one of the final common pathways for cortical systems that control eye
movement in general. Cortical control of eye movement (saccades, smooth pursuit,
accommodation) involves conjugate gaze, not unilateral eye movement.
Abducens nerve
Nerve: Abducens nerve

The path of the Abducens nerve

The abducens nerve or abducent nerve (the sixth cranial nerve, also called the sixth nerve,
VI, or the do-nothing nerve) is a “somatic efferent” nerve that controls the movement of a
single muscle, the lateral rectus muscle of the eye.
"Abducens" and "Abducent"
The Latin name for the sixth cranial nerve is nervus abducens. The Terminologia Anatomica
officially recognizes two different English translations: abducent nerve and abducens nerve.
Either term is correct.
“Abducens” is more common in recent literature, while “abducent” predominates in the older
literature. The United States National Library of Medicine uses “abducens nerve” in its Medical
Subject Heading (MeSH) vocabulary to index the vast MEDLINE and PubMed biomedical
databases. The 39th edition of Gray’s Anatomy (2005) also prefers “abducens nerve.”[2]
Peripheral anatomy

The Clivus
The abducens nerve leaves the brainstem at the junction of the pons and the medulla, medial to
the facial nerve. In order to reach the eye, it runs upward (superiorly) and then bends forward
(anteriorly).
The nerve enters the subarachnoid space when it emerges from the brainstem. It runs upward
between the pons and the clivus, and then pierces the dura mater to run between the dura and the
skull. At the tip of the petrous temporal bone it makes a sharp turn forward to enter the
cavernous sinus. In the cavernous sinus it runs alongside the internal carotid artery. It then enters
the orbit through the superior orbital fissure and innervates the lateral rectus muscle of the eye.
The long course of the abducens nerve between the brainstem and the eye makes it vulnerable to
injury at many levels. For example, fractures of the petrous temporal bone can selectively
damage the nerve, as can aneurysms of the intracavernous carotid artery. Mass lesions that push
the brainstem downward can damage the nerve by stretching it between the point where it
emerges from the pons and the point where it hooks over the petrous temporal bone.
Central anatomy

Axial section of the Brainstem (Pons) at the level of the Facial Colliculus
The abducens nucleus is located in the pons, on the floor of the fourth ventricle, at the level of
the facial colliculus. Axons from the facial nerve loop around the abducens nucleus, creating a
slight bulge (the facial colliculus) that is visible on the dorsal surface of the floor of the fourth
ventricle. The abducens nucleus is close to the midline, like the other motor nuclei that control
eye movements (the oculomotor and trochlear nuclei).
Motor axons leaving the abducens nucleus run ventrally and caudally through the pons. They
pass lateral to the corticospinal tract (which runs longitudinally through the pons at this level)
before exiting the brainstem at the pontomedullary junction.
The central anatomy of the sixth nerve predicts (correctly) that infarcts affecting the dorsal pons
at the level of the abducens nucleus can also affect the facial nerve, producing an ipsilateral
facial palsy together with a lateral rectus palsy. The anatomy also predicts (correctly) that
infarcts involving the ventral pons can affect the sixth nerve and the corticospinal tract
simultaneously, producing a lateral rectus palsy associated with a contralateral hemiparesis.
These rare syndromes are of interest primarily as useful summaries of the anatomy of the
brainstem.
Clinical syndromes
Peripheral lesions
Complete interruption of the peripheral sixth nerve causes diplopia (double vision), due to the
unopposed action of the medial rectus muscle. The affected eye is pulled medially. In order to
see without double vision, patients will rotate their heads so that both eyes are looking sideways.
On formal testing, the affected eye cannot abduct past the midline – it cannot look sideways,
toward the temple. Partial damage to the sixth nerve causes weak or incomplete abduction of the
affected eye. The diplopia is worse on attempted lateral gaze, as would be expected (since the
lateral gaze muscle is impaired).
Peripheral sixth nerve damage can be caused by tumors, aneurysms, or fractures – anything that
directly compresses or stretches the nerve. Other processes that can damage the sixth nerve
include strokes (infarctions), demyelination, infections (e.g. meningitis), cavernous sinus
diseases and various neuropathies. Perhaps the most common overall cause of sixth nerve
impairment is diabetic neuropathy.
Rare causes of isolated sixth nerve damage include Wernicke-Korsakoff syndrome and Tolosa-
Hunt syndrome. Wernicke-Korsakoff syndrome is caused by thiamine deficiency, classically due
to alcoholism. The characteristic ocular abnormalities are nystagmus and lateral rectus weakness.
Tolosa-Hunt syndrome is an idiopathic granulomatous disease that causes painful oculomotor
(especially sixth nerve) palsies.
Indirect damage to the sixth nerve can be caused by any process (brain tumor, hydrocephalus,
pseudotumor cerebri, hemorrhage, edema) that exerts downward pressure on the brainstem,
causing the nerve to stretch along the clivus. This type of traction injury can affect either side
first. A right-sided brain tumor can produce either a right-sided or a left-sided sixth nerve palsy
as an initial sign. Thus a right-sided sixth nerve palsy does not necessarily imply a right-sided
cause. Sixth nerve palsies are infamous as “false localizing signs.” Isolated sixth nerve palsies in
children are assumed to be due to brain tumors until proven otherwise.
Nuclear lesions
Damage to the abducens nucleus does not produce an isolated sixth nerve palsy, but rather a
horizontal gaze palsy that affects both eyes simultaneously. The abducens nucleus contains two
types of cells: motor neurons that control the lateral rectus muscle on the same side, and
interneurons that cross the midline and connect to the contralateral oculomotor nucleus (which
controls the medial rectus muscle of the opposite eye). In normal vision, lateral movement of one
eye (lateral rectus muscle) is precisely coupled to medial movement of the other eye (medial
rectus muscle), so that both eyes remain fixed on the same object.
The control of conjugate gaze is mediated in the brainstem by the medial longitudinal fasciculus
(MLF), a nerve tract that connects the three extraocular motor nuclei (abducens, trochlear and
oculomotor) into a single functional unit. Lesions of the abducens nucleus and the MLF produce
observable sixth nerve problems, most notably internuclear ophthalmoplegia (INO).
Supranuclear lesions
The sixth nerve is one of the final common pathways for numerous cortical systems that control
eye movement in general. Cortical control of eye movement (saccades, smooth pursuit,
accommodation) involves conjugate gaze, not unilateral eye movement.
Tuberculosis
15-40% of people with tuberculosis have some resulting cranial nerve deficit. The sixth nerve is
the most commonly affected cranial nerve in immunocompetent people with tuberculosis.
 Medial longitudinal fasciculus
The medial longitudinal fasciculus (MLF) is a pair of crossed fiber tracts (group of axons), one

Brain: Medial longitudinal

fasciculus

Coronal section through mid-brain.

1. Corpora quadrigemina.
2. Cerebral aqueduct.
3. Central gray stratum.
4. Interpeduncular space.
Transverse section of mid-brain at level of 5. Sulcus lateralis.
inferior colliculi. (Medial longitudinal 6. Substantia nigra.
fasciculus labeled at center right.) 7. Red nucleus of tegmentum.
8. Oculomotor nerve, with 8’, its nucleus of origin. a. Lemniscus (in blue)
with a’ the medial lemniscus and a" the lateral lemniscus. b. Medial
longitudinal fasciculus. c. Raphé. d. Temporopontine fibers. e. Portion of
medial lemniscus, which runs to the lentiform nucleus and insula. f.
Cerebrospinal fibers. g. Frontopontine fibers.
on each side of the brainstem. These bundles of axons are situated near the midline of the
brainstem and are composed of both ascending and descending fibers that arise from a number of
sources and terminate in different areas.
Function
The MLF carries information about the direction that the eyes should move.
It yokes the cranial nerve nuclei III (Oculomotor nerve), IV (Trochlear nerve) and VI (Abducens
nerve) together, and integrates movements directed by the gaze centers (frontal eye field) and
information about head movement (from cranial nerve VIII, Vestibulocochlear nerve). It is an
integral component of saccadic eye movements as well as vestibulo-ocular and optokinetic
reflexes.
It also carries the descending tectospinal tract and medial vestibulospinal tracts into the cervical
spinal cord, and innervates some muscles of the neck and upper limbs.
Inputs
The descending MLF mainly arises from the medial Vestibular nucleus (VN) and is thought to
be involved in the maintenance of gaze. This is achieved by inputs to the VN from
1. the Vestibulocochlear (8th cranial) nerve about head movements,
2. gain adjustments from the flocculus of the cerebellum,
 3. head and neck propioceptors and foot and ankle muscle spindle, via the fastigial nucleus.
Descending fibers can also arise from the superior colliculus in the rostral midbrain for visual
reflexes, the accessory occulomotor nuclei in the rostral midbrain for visual tracking, and the
pontine reticular formation, which facilitates extensor muscle tone. Ascending tracts arise from
the Vestibular nucleus (VN) and terminate in the III, IV and VI nuclei, which are important for
visual tracking.
Pathology
Lesions of the MLF produce internuclear ophthalmoplegia. Lesions to the MLF are very
common manifestations of the disease Multiple sclerosis[1],where it presents as nystagmus and
occasionally diplopia[2]. These lesions cause damage to the ipsilateral (same side) eye.
History
In 1846 neurologist Benedict Stilling first referred to what is now known as the MLF as the
acusticus, followed by Theodor Meynert in 1872 calling it posterior. But in 1891, Heinrich
Schutz chose the name dorsal to describe the longitudinal bundle, "for brevity's sake". This name
stuck despite other authors attempting further renaming (Ramon y Cajal's periependymal in
1904, Theodor Ziehen's nubecula dorsalis in 1913). But finally, it was Wilhelm His, Sr. who
changed the name to medial for the sake of the Basle nomenclature to end the confusion.
Trigeminal nerve
Nerve: Trigeminal nerve

Trigeminal nerve, shown in yellow.

The trigeminal nerve (the fifth cranial nerve, also called the fifth nerve, or simply V) is
responsible for sensation in the face. Sensory information from the face and body is processed by
parallel pathways in the central nervous system.
The fifth nerve is primarily a sensory nerve, but it also has certain motor functions (biting,
chewing, and swallowing). These are discussed separately.
Function
The sensory function of the trigeminal nerve is to provide the tactile, proprioceptive, and
nociceptive afference of the face and mouth. The posterior scalp and the neck are innervated by
C2-C3, not by the trigeminal nerve.
The motor function activates the muscles of mastication, the tensor tympani, tensor veli palatini,
mylohyoid, and anterior belly of the digastric.
Peripheral anatomy

Dermatome Distribution of the Trigeminal Nerve

The trigeminal nerve is the largest of the cranial nerves. Its name ("trigeminal" = triplets with a
common origin) derives from the fact that it has three major branches: the ophthalmic nerve
(V1), the maxillary nerve (V2), and the mandibular nerve (V3). The ophthalmic and maxillary
nerves are purely sensory. The mandibular nerve has both sensory and motor functions.
The three branches converge on the trigeminal ganglion (also called the semilunar ganglion or
gasserian ganglion), that is located within Meckel's cave, and contains the cell bodies of
incoming sensory nerve fibers. The trigeminal ganglion is analogous to the dorsal root ganglia of
the spinal cord, which contain the cell bodies of incoming sensory fibers from the rest of the
body.
From the trigeminal ganglion, a single large sensory root enters the brainstem at the level of the
pons. Immediately adjacent to the sensory root, a smaller motor root emerges from the pons at
the same level.
Motor fibers pass through the trigeminal ganglion on their way to peripheral muscles, but their
cell bodies are located in the nucleus of the fifth nerve, deep within the pons. Motor fibers of
the eye are distributed (together with sensory fibers) in branches of the mandibular nerve.
The areas of cutaneous distribution (dermatomes) of the three branches of the trigeminal nerve
have sharp borders with relatively little overlap (unlike dermatomes in the rest of the body,
which show considerable overlap). Injection of local anesthetics such as lidocaine results in the
complete loss of sensation from well-defined areas of the face and mouth. For example, the teeth
on one side of the jaw can be numbed by injecting the mandibular nerve.
Sensory branches of the trigeminal nerve

Dermatome Distribution of the Trigeminal Nerve

The ophthalmic, maxillary and mandibular branches leave the skull through three separate
foramina: the superior orbital fissure, the foramen rotundum and the foramen ovale. The
mnemonic standing room only can be used to remember that V1 passes through the superior
orbital fissure, V2 through the foramen rotundum, and V3 through the foramen ovale.
 The ophthalmic nerve carries sensory information from the scalp and forehead, the upper
eyelid, the conjunctiva and cornea of the eye, the nose (including the tip of the nose,
except alae nasi), the nasal mucosa, the frontal sinuses, and parts of the meninges (the
dura and blood vessels).
 The maxillary nerve carries sensory information from the lower eyelid and cheek, the
nares and upper lip, the upper teeth and gums, the nasal mucosa, the palate and roof of
the pharynx, the maxillary, ethmoid and sphenoid sinuses, and parts of the meninges.
 The mandibular nerve carries sensory information from the lower lip, the lower teeth
and gums, the chin and jaw (except the angle of the jaw, which is supplied by C2-C3),
parts of the external ear, and parts of the meninges.

o The mandibular nerve carries touch/position and pain/temperature sensation
from the mouth. It does not carry taste sensation, but one of its branches, the
lingual nerve carries multiple types of nerve fibers that do not originate in the
mandibular nerve.
Motor branches of the trigeminal nerve
Motor branches of the trigeminal nerve are distributed in the mandibular nerve. These fibers
originate in the motor nucleus of the fifth nerve, which is located near the main trigeminal
nucleus in the pons. Motor nerves are functionally quite different from sensory nerves, and their
association in the peripheral branches of the mandibular nerve is more a matter of convenience
than of necessity.
In classical anatomy, the trigeminal nerve is said to have general somatic afferent (sensory)
components, as well as special visceral efferent (motor) components. The motor branches of the
trigeminal nerve control the movement of eight muscles, including the four muscles of
mastication.
 Muscles of mastication
 masseter
 temporalis
 medial pterygoid
 lateral pterygoid
 Other
 tensor veli palatini
 mylohyoid
 anterior belly of digastric
 tensor tympani
With the exception of tensor tympani, all of these muscles are involved in biting, chewing and
swallowing. All have bilateral cortical representation. A central lesion (e.g., a stroke), no matter
how large, is unlikely to produce any observable deficit. However, injury to the peripheral nerve
can cause paralysis of muscles on one side of the jaw. The jaw deviates to the paralyzed side
when it opens.
Central anatomy
The fifth nerve is primarily a sensory nerve. The anatomy of sensation in the face and mouth is
the subject of the remainder of this article. Background information on sensation is reviewed,
followed by a summary of central sensory pathways. The central anatomy of the fifth nerve is
then discussed in detail.
Sensation
There are two basic types of sensation: touch/position and pain/temperature. They are
distinguished, roughly speaking, by the fact that touch/position input comes to attention
immediately, whereas pain/temperature input reaches the level of consciousness only after a
perceptible delay. Think of stepping on a pin. There is immediate awareness of stepping on
something, but it takes a moment before it starts to hurt.
In general, touch/position information is carried by myelinated (fast-conducting) nerve fibers,
whereas pain/temperature information is carried by unmyelinated (slow-conducting) nerve
fibers. The primary sensory receptors for touch/position (Meissner’s corpuscles, Merkel's
receptors, Pacinian corpuscles, Ruffini’s corpuscles, hair receptors, muscle spindle organs, Golgi
tendon organs) are structurally more complex than the primitive receptors for pain/temperature,
which are bare nerve endings.
The term "sensation", as used in this article, refers to the conscious perception of touch/position
and pain/temperature information. It does not refer to the so-called "special senses" (smell, sight,
taste, hearing and balance), which are processed by different cranial nerves and sent to the
cerebral cortex through different pathways. The perception of magnetic fields, electrical fields,
low-frequency vibrations and infrared radiation by certain nonhuman vertebrates is processed by
the equivalent of the fifth cranial nerve in these animals.
The term "touch", as used in this article, refers to the perception of detailed, localized tactile
information, such as two-point discrimination (the difference between touching one point and
two closely-spaced points) or the difference between grades of sandpaper (coarse, medium and
fine). People that lack touch/position perception can still "feel" the surface of their bodies, and
can therefore perceive "touch" in a crude, yes-or-no way, but they lack the rich perceptual detail
that we normally experience.
The term "position", as used in this article, refers to conscious proprioception. Proprioceptors
(muscle spindle organs and Golgi tendon organs) provide information about joint position and
muscle movement. Much of this information is processed at an unconscious level (mainly by the
cerebellum and the vestibular nuclei). However, some of this information is available at a
conscious level.
The two types of sensation in humans, touch/position and pain/temperature, are processed by
different pathways in the central nervous system. The distinction is hard-wired, and it is
maintained all the way to the cerebral cortex. Within the cerebral cortex, sensations are further
hard-wired to (associated with) other cortical areas.
Sensory pathways
Sensory pathways from the periphery to the cortex are summarized below. There are separate
pathways for touch/position sensation and pain/temperature sensation. All sensory information is
sent to specific nuclei in the thalamus. Thalamic nuclei, in turn, send information to specific
areas in the cerebral cortex.
Each pathway consists of three bundles of nerve fibers, connected together in series:

It is noteworthy that the secondary neurons in each pathway decussate (cross to the other side of
the spinal cord or brainstem). The reason for this is unknown.
Sensory pathways are often depicted as chains of individual neurons connected in series. This is
an oversimplification. Sensory information is processed and modified at each level in the chain
by interneurons and by input from other areas of the nervous system. For example, cells in the
main trigeminal nucleus (“Main V” in the diagram) receive input (not shown) from the reticular
formation and from the cerebral cortex. This information contributes to the final output of the
cells in Main V to the thalamus.
Touch/position information from the body is carried to the thalamus by the medial lemniscus;
touch/position information from the face is carried to the thalamus by the trigeminal lemniscus.
Pain/temperature information from the body is carried to the thalamus by the spinothalamic tract;
pain/temperature information from the face is carried to the thalamus by the trigeminothalamic
tract (also called the quintothalamic tract).
Pathways for touch/position sensation from the face and body merge together in the brainstem. A
single touch/position sensory map of the entire body is projected onto the thalamus. Likewise,
pathways for pain/temperature sensation from the face and body merge together in the brainstem.
A single pain/temperature sensory map of the entire body is projected onto the thalamus.
From the thalamus, touch/position and pain/temperature information is projected onto various
areas of the cerebral cortex. Exactly where, when, and how this information becomes conscious
is entirely beyond our understanding at the present time. The explanation of consciousness is one
of the great unsolved mysteries in science. The details of the pathways connecting the lower
body to the cerebral cortex are beyond the scope of this article. The details of the pathways
connecting the face and mouth to the cerebral cortex are discussed below.
Trigeminal nucleus
Brainstem Nuclei: Red = Motor; Blue = Sensory; Dark Blue = Trigeminal Nucleus
It is not widely appreciated that all sensory information from the face (all touch/position
information and all pain/temperature information) is sent to the trigeminal nucleus. In classical
anatomy, most sensory information from the face is carried by the fifth nerve, but sensation from
certain parts of the mouth, certain parts of the ear and certain parts of the meninges is carried by
“general somatic afferent” fibers in cranial nerves VII (the facial nerve), IX (the
glossopharyngeal nerve) and X (the vagus nerve).
Without exception, however, all sensory fibers from these nerves terminate in the trigeminal
nucleus. On entering the brainstem, sensory fibers from V, VII, IX, and X are sorted out and sent
to the trigeminal nucleus, which thus contains a complete sensory map of the face and mouth.
The spinal counterparts of the trigeminal nucleus (cells in the dorsal horn and dorsal column
nuclei of the spinal cord) contain a complete sensory map of the rest of the body.
The trigeminal nucleus extends throughout the entire brainstem, from the midbrain to the
medulla, and continues into the cervical cord, where it merges with the dorsal horn cells of the
spinal cord. The nucleus is divided anatomically into three parts, visible in microscopic sections
of the brainstem. From caudal to rostral (i.e., going up from the medulla to the midbrain) they are
the spinal trigeminal nucleus, the main trigeminal nucleus, and the mesencephalic
trigeminal nucleus.
The three parts of the trigeminal nucleus receive different types of sensory information. The
spinal trigeminal nucleus receives pain/temperature fibers. The main trigeminal nucleus receives
touch/position fibers. The mesencephalic nucleus receives proprioceptor and mechanoreceptor
fibers from the jaws and teeth.
Spinal trigeminal nucleus
The spinal trigeminal nucleus represents pain/temperature sensation from the face.
Pain/temperature fibers from peripheral nociceptors are carried in cranial nerves V, VII, IX, and
X. On entering the brainstem, sensory fibers are grouped together and sent to the spinal
trigeminal nucleus. This bundle of incoming fibers can be identified in cross sections of the pons
and medulla as the spinal tract of the trigeminal nucleus, which parallels the spinal trigeminal
nucleus itself. The spinal tract of V is analogous to, and continuous with, Lissauer’s tract in the
spinal cord.
The spinal trigeminal nucleus contains a pain/temperature sensory map of the face and mouth.
From the spinal trigeminal nucleus, secondary fibers cross the midline and ascend in the
trigeminothalamic tract to the contralateral thalamus. The trigeminothalamic tract runs parallel
to the spinothalamic tract, which carries pain/temperature information from the rest of the
body. Pain/temperature fibers are sent to multiple thalamic nuclei. As discussed below, the
central processing of pain/temperature information is markedly different from the central
processing of touch/position information.
Somatotopic representation

Onion Skin Distribution of the Trigeminal Nerve

Exactly how pain/temperature fibers from the face are distributed to the spinal trigeminal nucleus
has been a subject of considerable controversy. The present understanding is that all
pain/temperature information from all areas of the human body is represented (in the spinal cord
and brainstem) in an ascending, caudal-to-rostral fashion. Information from the lower extremities
is represented in the lumbar cord. Information from the upper extremities is represented in the
thoracic cord. Information from the neck and the back of the head is represented in the cervical
cord. Information from the face and mouth is represented in the spinal trigeminal nucleus. [
Within the spinal trigeminal nucleus, information is represented in an onion skin fashion. The
lowest levels of the nucleus (in the upper cervical cord and lower medulla) represent peripheral
areas of the face (the scalp, ears and chin). Higher levels (in the upper medulla) represent more
central areas (nose, cheeks, lips). The highest levels (in the pons) represent the mouth, teeth, and
pharyngeal cavity.
The onion skin distribution is entirely different from the dermatome distribution of the
peripheral branches of the fifth nerve. Lesions that destroy lower areas of the spinal trigeminal
nucleus (but which spare higher areas) preserve pain/temperature sensation in the nose (V1),
upper lip (V2) and mouth (V3) while removing pain/temperature sensation from the forehead
(V1), cheeks (V2) and chin (V3). Analgesia in this distribution is “nonphysiologic” in the
traditional sense, because it crosses over several dermatomes. Nevertheless, analgesia in exactly
this distribution is found in humans after surgical sectioning of the spinal tract of the trigeminal
nucleus.
The spinal trigeminal nucleus sends pain/temperature information to the thalamus. It also sends
information to the mesencephalon and the reticular formation of the brainstem. The latter
pathways are analogous to the spinomesencephalic and spinoreticular tracts of spinal cord,
which send pain/temperature information from the rest of the body to the same areas. The
mesencephalon modulates painful input before it reaches the level of consciousness. The
reticular formation is responsible for the automatic (unconscious) orientation of the body to
painful stimuli.
Main trigeminal nucleus
The main trigeminal nucleus represents touch/position sensation from the face. It is located in
the pons, close to the entry site of the fifth nerve. Fibers carrying carry touch/position
information from the face and mouth (via cranial nerves V, VII, IX, and X) are sent to the main
trigeminal nucleus when they enter the brainstem.
The main trigeminal nucleus contains a touch/position sensory map of the face and mouth, just
as the spinal trigeminal nucleus contains a complete pain/temperature map. The main nucleus is
analogous to the dorsal column nuclei (the gracile and cuneate nuclei) of the spinal cord, which
contain a touch/position map of the rest of the body.
From the main trigeminal nucleus, secondary fibers cross the midline and ascend in the
trigeminal lemniscus to the contralateral thalamus. The trigeminal lemniscus runs parallel to the
medial leminscus, which carries touch/position information from the rest of the body to the
thalamus.
Some sensory information from the teeth and jaws is sent from the main trigeminal nucleus to
the ipsilateral thalamus, via the small dorsal trigeminal tract. Thus touch/position information
from the teeth and jaws is represented bilaterally in the thalamus (and hence in the cortex). The
reason for this special processing is discussed below.
Mesencephalic trigeminal nucleus
The mesencephalic trigeminal nucleus is not really a “nucleus.” Rather, it is a sensory ganglion
(like the trigeminal ganglion) that happens to be imbedded in the brainstem. The mesencephalic
“nucleus” is the sole exception to the general rule that sensory information passes through
peripheral sensory ganglia before entering the central nervous system.
Only certain types of sensory fibers have cell bodies in the mesencephalic nucleus: proprioceptor
fibers from the jaw and mechanoreceptor fibers from the teeth. Some of these incoming fibers go
to the motor nucleus of V, thus entirely bypassing the pathways for conscious perception. The
jaw jerk reflex is an example. Tapping the jaw elicits a reflex closure of the jaw, in exactly the
same way that tapping the knee elicits a reflex kick of the lower leg. Other incoming fibers from
the teeth and jaws go to the main nucleus of V. As noted above, this information is projected
bilaterally to the thalamus. It is available for conscious perception.
Activities like biting, chewing and swallowing require symmetrical, simultaneous coordination
of both sides of the body. They are essentially automatic activities, to which we pay little
conscious attention. They involve a sensory component (feedback about touch/position) that is
processed at a largely unconscious level.
The unusual anatomy of “mesencephalic V” has been found in all vertebrates, with the exception
of lampreys and hagfishes. Lampreys and hagfishes are the only vertebrates without jaws. It is
evident, therefore, that information about biting, chewing and swallowing is singled out for
special processing in the vertebrate brainstem, specifically in the mesencephalic nucleus.
Lampreys and hagfishes have cells in their brainstems that can be identified as the evoutionary
precursors of the mesencephalic nucleus. These “internal ganglion” cells were discovered in the
latter part of the 19th century by a young medical student named Sigmund Freud.[2]
Pathways to the thalamus and the cortex
We have defined sensation as the conscious perception of touch/proprioception and
pain/temperature information. With the sole exception of smell, all sensory input (touch/position,
pain/temperature, sight, taste, hearing, and balance) is sent to the thalamus before being sent to
the cortex.
The thalamus is anatomically subdivided into a number of separate nuclei. The thalamic nuclei
involved in sensation, and their cortical projections, are discussed below.
Touch/Position sensation
The Sensory Homunculus (Updated)
Touch/position information from the body is sent to the ventral posterolateral nucleus (VPL) of
the thalamus. Touch/position information from the face is sent to the ventral posteromedial
nucleus (VPM) of the thalamus. From the VPL and VPM, information is projected to the
primary sensory cortex (SI) in the postcentral gyrus of the parietal lobe.
The representation of sensory information in SI is organized somatotopically. Adjacent areas in
the body are represented by adjacent areas in the cortex. When body parts are drawn in
proportion to the density of their innervation, however, the result is a strangely distorted “little
man,” the sensory homunculus.
Many textbooks reproduce the classic Penfield-Rasmussen diagram, which is now outdated. For
example, the toes and genitals are shown in the classic diagram on the mesial surface of the
cortex, when in fact they are represented on the convexity.[3] What is more important, the classic
diagram implies a single primary sensory map of the body, when in fact there are multiple
primary maps. At least four separate, anatomically-distinct sensory homunculi have been
identified in SI. They represent different blends of input from surface receptors, deep receptors,
rapidly adapting receptors, and slowly-adapting peripheral receptors. For example, smooth
objects will activate certain cells, whereas edged objects will activate other cells.
Information from all four maps in the primary sensory cortex (SI) is sent to the secondary
sensory cortex (SII) in the parietal lobe. SII contains two more sensory homunculi.
In general, information from one side of the body is represented on the opposite side in SI, but
on both sides in SII. Functional MRI imaging of a defined stimulus (e.g., stroking the skin with a
toothbrush) “lights up” a single focus in SI and two foci in SII.
Pain/Temperature sensation
Pain/temperature information is sent to the VPL (body) and VPM (face) of the thalamus (the
same nuclei that receive touch/position information). From the thalamus, pain/temperature and
touch/position information is projected onto SI.
In marked contrast to touch/position information, however, pain/temperature information is also
sent to other thalamic nuclei, and is projected onto additional areas of the cerebral cortex. Some
pain/temperature fibers are sent to the medial dorsal thalamic nucleus (MD), which projects to
the anterior cingulate cortex. Other fibers are sent to the ventromedial prefrontal cortex (VM)
nucleus of the thalamus, which projects to the insular cortex. Finally, some fibers are sent to the
intralaminar (IL) nuclei of the thalamus via the reticular formation. The IL project diffusely to
all parts of the cerebral cortex.
The insula and cingulate cortex are areas of the brain that represent our perception of
touch/position and pain/temperature in the context of other simultaneous perceptions (sight,
smell, taste, hearing and balance), and in the context of our memories and present emotional
state. It is noteworthy that peripheral pain/temperature information is channeled directly into the
brain at these deep levels, without prior processing. This contrasts markedly with the way that
touch/position information is handled.
Diffuse thalamic projections from the IL and other thalamic nuclei are responsible for one’s
overall level of consciousness. The thalamus and reticular formation “activate” the entire brain.
It is noteworthy that peripheral pain/temperature information feeds directly into this system as
well.
Summary
The complex processing of pain/temperature information in the thalamus and cerebral cortex (as
opposed to the relatively simple, straightforward processing of touch/position information)
reflects a phylogenetically older, more primitive sensory system. The rich, detailed information
we receive from peripheral touch/position receptors is superimposed on a background of
awareness, memory and emotions that is set, in part, by peripheral pain/temperature receptors.
The thresholds for touch/position perception are relatively easy to measure, and are similar in all
humans. The thresholds for pain/temperature perception are difficult to define and even more
difficult to measure. “Touch” is an objective sensation. “Pain” is a highly individualized,
personal sensation that varies markedly among different people. It is conditioned by their
memories and by their emotions. The fundamental anatomical differences between the pathways
for touch/position perception and pain/temperature sensation help to explain why pain, especially
chronic pain, is so difficult to manage.
Wallenberg syndrome
Wallenberg syndrome (also called the lateral medullary syndrome) is a classic clinical
demonstration of the anatomy of the fifth nerve. It provides a useful summary of essential points
about the processing of sensory information by the trigeminal nerve.
A stroke usually affects only one side of the body. If a stroke causes loss of sensation, the deficit
will be lateralized to the right side or the left side of the body. The only exceptions to this rule
are certain spinal cord lesions and the medullary syndromes, of which Wallenberg syndrome is
the most famous example. In Wallenberg syndrome, a stroke causes loss of pain/temperature
sensation from one side of the face and the other side of the body.
The explanation involves the anatomy of the brainstem. In the medulla, the ascending
spinothalamic tract (which carries pain/temperature information from the opposite side of the
body) is adjacent to the descending spinal tract of the fifth nerve (which carries pain/temperature
information from the same side of the face). A stroke that cuts off the blood supply to this area
(e.g., a clot in the posterior inferior cerebellar artery) destroys both tracts simultaneously. The
result is loss of pain/temperature sensation (but not touch/position sensation) in a unique
“checkerboard” pattern (ipsilateral face, contralateral body) that is entirely diagnostic.

Trigeminal neuralgia
Trigeminal neuralgia (TN), tic douloureux (also known as prosopalgia) is a neuropathic
disorder of one or both of the trigeminal nerves. Its nickname is "the suicide disease"[2] because
it causes one of the most severe pains that a human being can experience, and is not easily
controlled or cured. It causes episodes of intense pain in any or all of the following: the ear, eye,
lips, nose, scalp, forehead, teeth or jaw on one and along side of the face.[3] It is estimated that 1
in 15,000 people suffer from trigeminal neuralgia, although the actual figure may be significantly
higher due to frequent misdiagnosis. TN usually develops after the age of 50, more commonly in
females, although there have been cases with patients being as young as three years of age [4].
TN brings about stabbing, mind-numbing, electric shock-like pain from just a finger's glance of
the cheek or spontaneously without any stimulation by the patient. Cold wind, high pitched
sounds, loud noise such as concerts or crowds, chewing, talking, can aggravate the condition,
and for the worst cases, even smiling, a scarf, the wind or hair on the side of the face is too much
to bear.
Pathophysiology, causes, and differential diagnosis
The symptoms of trigeminal neuralgia are often falsely attributed to a pathology of dental origin.
"Rarely do patients come to the surgeon without having removed many, and not infrequently all,
teeth on the affected side or both sides." [5] Extractions do not help. The pain is originating in the
trigeminal nerve itself - often in its roots - and not in an individual nerve of a tooth but real tooth
pain may be referred to the same areas of the face as that of trigeminal neuralgia. Because of this
difficulty, many patients go untreated unless a correct diagnosis is made.
The trigeminal nerve is the fifth cranial nerve, a mixed cranial nerve responsible for sensory data
such as tactition (pressure), thermoception (temperature), and nociception (pain) originating
from the face above the jawline; it is also responsible for the motor function of the muscles of
mastication, the muscles involved in chewing but not facial expression.
Several theories exist to explain the possible causes of this pain syndrome. It was once believed
that the nerve was compressed in the opening from the inside to the outside of the skull; but
newer leading research indicates that it is an enlarged blood vessel - possibly the superior
cerebellar artery - compressing or throbbing against the microvasculature of the trigeminal nerve
near its connection with the pons. Such a compression can injure the nerve's protective myelin
sheath and cause erratic and hyperactive functioning of the nerve. This can lead to pain attacks at
the slightest stimulation of any area served by the nerve as well as hinder the nerve's ability to
shut off the pain signals after the stimulation ends. This type of injury may rarely be caused by
an aneurysm (an outpouching of a blood vessel); by a tumor; by an arachnoid cyst in the
cerebellopontine angle[6]; or by a traumatic event such as a car accident or even a tongue
piercing.[7]
A large amount of multiple sclerosis patients have TN, but not everyone with TN has MS. Only
two to four percent of patients with TN, usually younger, have evidence of multiple sclerosis,
which may damage either the trigeminal nerve or other related parts of the brain. It has been
theorized that this is due to damage to the spinal trigeminal complex.[8] Trigeminal pain has a
similar presentation in patients with and without MS.[9]
When there is no structural cause, the syndrome is called idiopathic. Postherpetic Neuralgia,
which occurs after shingles, may cause similar symptoms if the trigeminal nerve is damaged.
Symptoms
The disorder is characterised by episodes of intense facial pain that usually last from a few
seconds to several minutes or hours. The episodes of intense pain may occur paroxysmally. To
describe the pain sensation, patients may describe a trigger area on the face, so sensitive that
touching or even air currents can trigger an episode. It affects lifestyle as it can be triggered by
common activities such as eating, talking, shaving and toothbrushing. The attacks are said by
those affected to feel like stabbing electric shocks, burning, pressing, crushing, exploding or
shooting pain that becomes intractable.
Individual attacks usually affect one side of the face at a time, lasting from several seconds to a
few minutes and repeat up to hundreds of times throughout the day. The pain also tends to occur
in cycles with remissions lasting months or even years. 10-12% of cases are bilateral, or
occurring on both sides. This normally indicates problems with both trigeminal nerves since one
serves strictly the left side of the face and the other serves the right side. Pain attacks typically
worsen in frequency or severity over time. Many patients develop the pain in one branch, then
over years the pain will travel through the other nerve branches.
Outwardly visible signs of TN can sometimes be seen in males who may deliberately miss an
area of their face when shaving, in order to avoid triggering an episode. Successive recurrences
are incapacitating and the dread of provoking an attack may make sufferers unable to engage in
normal daily activities.
There is also a variant of trigeminal neuralgia called atypical trigeminal neuralgia. In some cases
of atypical trigeminal neuralgia the sufferer experiences a severe, relentless underlying pain
similar to a migraine in addition to the stabbing shock-like pains. This variant is often called
"trigeminal neuralgia, type 2"[10], based on a recent classification of facial pain[11]. In other cases,
the pain is stabbing and intense but may feel like burning or prickling, rather than a shock.
Sometimes the pain is a combination of shock-like sensations, migraine-like pain and burning or
prickling pain. It can also feel as if a boring piercing pain is unrelenting. Some recent studies
suggest that ATN may be an early development of Trigeminal Neuralgia.
Common hurdles to receiving treatment
As with many conditions without clear physical or laboratory diagnosis, TN is unfortunately
sometimes misdiagnosed. A TN sufferer will sometimes seek the help of numerous clinicians
before a firm diagnosis is made.
There is evidence that points towards the need to quickly treat and diagnose trigeminal neuralgia
(TN). It is thought that the longer a patient suffers from TN, the harder it may be to reverse the
neural pathways associated with the pain.
Dentists who suspect TN should proceed in the most conservative manner possible and should
ensure that all tooth structures are "truly" compromised before performing extractions or other
procedures.
Medications
 Anticonvulsants are a common treatment strategy for trigeminal neuralgia.
Carbamazepine is the first line drug; second line drugs include baclofen, lamotrigine,
oxcarbazepine, phenytoin, gabapentin, and sodium valproate. Uncontrolled trials have
suggested that clonazepam and lidocaine may be effective.[12]
 Low doses of some antidepressants such as amytriptiline are thought to be effective in
treating neuropathic pain, but a tremendous amount of controversy exists on this topic,
and their use is often limited to treating the depression that is associated with chronic
pain, rather than the actual sensation of pain from the trigeminal nerve.
 Botox can be injected into the nerve by a physician, and has been found helpful using the
"migraine" pattern adapted to the patient's special needs.
 Patients may also find relief by having their neurologist implant a neuro-stimulator.
Many patients cannot tolerate medications for years, and an alternative treatment is to take a
drug such as gabapentin and apply it externally. This preparation is prepared extemporaneously
by pharmacists. Also helpful is taking a "drug holiday" when remissions occur and rotating
medications if one becomes ineffective.
 Opiates such as morphine and oxycodone can be prescribed, and there is evidence of their
effectiveness on neuropathic pain, especially if combined with gabapentin.[13][14]
 A case report found sumatriptan effective in the management of drug-resistant
Trigeminal Neuralgia [15]
Surgery
Surgery may be recommended, either to relieve the pressure on the nerve or to selectively
damage it in such a way as to disrupt pain signals from getting through to the brain. In trained
hands, surgery has been reported to have an initial success rate approaching 90 percent.
However, some patients require follow-up procedures if a recurrence of the pain begins.
Of the five surgical options, the microvascular decompression is the only one aimed at fixing the
presumed cause of the pain. In this procedure, the surgeon enters the skull through a 25-
millimetre (1 in) hole behind the ear. The nerve is then explored for an offending blood vessel,
and when one is found, the vessel and nerve are separated or "decompressed" with a small pad,
usually made from an inert surgical material such as Gore-Tex[16][17]. When successful, MVD
procedures can give permanent pain relief with little to no facial numbness.
Three other procedures use needles or catheters that enter through the face into the opening
where the nerve first splits into its three divisions. Excellent success rates using a cost effective
percutaneous surgical procedure known as balloon compression have been reported[18]. This
technique has been helpful in treating the elderly for whom surgery may not be an option due to
coexisting health conditions. Balloon compression is also the best choice for patients who have
ophthalmic nerve pain or have experienced recurrent pain after microvascular decompression.
Similar success rates have been reported with glycerol injections and radiofrequency
rhizotomies. Glycerol injections involve injecting an alcohol-like substance into the cavern that
bathes the nerve near its junction. This liquid is corrosive to the nerve fibers and can mildly
injure the nerve enough to hinder the errant pain signals. In a radiofrequency rhizotomy, the
surgeon uses an electrode to heat the selected division or divisions of the nerve. Done well, this
procedure can target the exact regions of the errant pain triggers and disable them with minimal
numbness.
Stereotactic radiation therapy
The nerve can also be damaged to prevent pain signal transmission using Gamma Knife or a
linear accelerator-based radiation therapy (e.g. Trilogy, Novalis, CyberKnife). No incisions are
involved in this procedure. It uses very precisely targeted radiation to bombard the nerve root,
this time targeting the selective damage at the same point where vessel compressions are often
found. This option is used especially for those people who are medically unfit for a long general
anaesthetic, or who are taking medications for prevention of blood clotting (e.g., warfarin,
heparin, aspirin). A prospective Phase I trial performed at Marseille, France, showed that 83% of
patients were pain-free at 12 months, with 58% pain-free and off all medications. Side effects
were mild, with 6% experiencing mild tingling and 4% experiencing mild numbness.[19]
There has only been one prospective clinical trial for surgical therapy for trigeminal neuralgia. In
a prospective cohort trial, microvacular decompression was found to be significantly superior to
stereotactic radiosurgery in achieving and maintaining a pain-free status in patients with
trigeminal neuralgia and provided similar early and superior longer-term patient satisfaction rates
compared with those treated with stereotactic radiosurgery [20]
Social consequences of trigeminal neuralgia
Most suffers of TN do not present with any outwardly noticeable symptoms, though some will
exhibit brief facial spasms during an attack. Some physicians will seek a psychological root
cause rather than a physiological abnormality. This is especially true of those suffering from
atypical TN, who may not have any compression of the TN and in whom the sole criterion of the
diagnosis may be the complaint of severe pain (constant electric-like shocks, constant crushing
or pressure sensations, or a constant severe ache) and in this case trigeminal neuralgia still exists
but is not visible to physicians because it was caused by the nerve being damaged during a dental
procedure such as root canals, extractions, gum surgeries or it may be a condition secondary to
multiple sclerosis.
Many TN sufferers are confined to their homes or are unable to work because of the frequency of
their attacks. It is important for friends and family to educate themselves on the intense severity
of TN pain and to be understanding of limitations that TN places upon the sufferer. However, at
the same time, the TN patient must be extremely proactive in furthering his or her rehabilitative
efforts. Enrolling in a chronic pain support group, or seeking one-on-one counseling, can help to
teach a TN patient how to adapt to the newfound affliction. As with any chronic pain syndrome,
TN not being the exception, clinical depression has the potential to set in, especially in younger
patients who often are undertreated for chronic pain. Friends and family, as well as clinicians,
must be alert to the signs of a rapid change in behavior and should take appropriate measures
when necessary. It must be constantly reinforced to the sufferer of TN that treatment options do
exist.
Other
In one case of trigeminal neuralgia associated with tongue-piercing, the condition resolved after
the jewelry was removed. Some patients have reported a correlation between dental work and the
onset of their trigeminal nerve pain.
Recently, some researchers have investigated the link between neuropathatic pain, such as TN,
and coeliac disease.
Facial nerve
Nerve: Facial nerve

Cranial nerve VII The nerves of the scalp, face, and side of neck.
The facial nerve is the seventh (VII) of twelve paired cranial nerves. It emerges from the
brainstem between the pons and the medulla, and controls the muscles of facial expression, and
taste to the anterior two-thirds of the tongue. It also supplies preganglionic parasympathetic
fibers to several head and neck ganglia.
Course
The motor and part of the facial nerve arises from the facial nerve nucleus in the pons while the
sensory part of the facial nerve arises from the nervus intermedius.
The motor part and sensory part of the facial nerve enters the petrous temporal bone into the
internal auditory meatus (intimately close to the inner ear) then runs a tortuous course (including
two tight turns) through the facial canal, emerges from the stylomastoid foramen and passes
through the parotid gland, where it divides into five major branches. Though it passes through
the parotid gland, it does not innervate the gland. This action is the responsibility of cranial nerve
IX, the glossopharyngeal nerve.
The facial nerve forms the geniculate ganglion prior to entering the facial canal.
Branches

Inside the internal acoustic meatus

 Greater petrosal nerve - provides parasympathetic innervation to lacrimal gland, sphenoid

sinus, frontal sinus, maxillary sinus, ethmoid sinus, nasal cavity, as well as special
sensory taste fibers to the palate via the Vidian nerve.
 Nerve to stapedius - provides motor innervation for stapedius muscle in middle ear
 Chorda tympani - provides parasympathetic innervation to submandibular gland and
sublingual gland and special sensory taste fibers for the anterior 2/3 of the tongue.

Outside skull (distal to stylomastoid foramen)

  Posterior auricular nerve - controls movements of some of the scalp muscles around the
ear
 Branch to Posterior belly of Digastric and Stylohyoid muscle
 Five major facial branches (in parotid gland) - from top to bottom:
o Temporal (frontal) branch of the facial nerve
o Zygomatic branch of the facial nerve
o Buccal branch of the facial nerve
o Marginal mandibular branch of the facial nerve
o Cervical branch of the facial nerve
A traditional mnemonic device for the five major branches of the facial nerve is, "The Zebra Bit
My Cat." Other mnemonics for the divisions of the facial nerve include, "Today Zoe Broke My
Car", "To Zanzibar By Motor Car", "Tell Ziggy Bob Marley Called", "The Zoo Bought Monkey
Clothes", "To Zanarkand by Machina Chocobo", "To Zooland by Mani Chandrasekhar", and
"Ten Zebra Broke My Car".
Embryology
The facial nerve is developmentally derived from the hyoid arch (second pharyngeal branchial
arch).
Function
Efferent
Its main function is motor control of most of the muscles of facial expression. It also innervates
the posterior belly of the digastric muscle, the stylohyoid muscle, and the stapedius muscle of the
middle ear. All of these muscles are striated muscles of branchiomeric origin developing from
the 2nd pharyngeal arch.
The facial also supplies parasympathetic fibers to the submandibular gland and sublingual glands
via chorda tympani. Parasympathetic innervation serves to increase the flow of saliva from these
glands. It also supplies parasympathetic innervation to the nasal mucosa and the lacrimal gland
via the pterygopalatine ganglion.
The facial nerve also functions as the efferent limb of the corneal reflex and the blink reflex.
Afferent
In addition, it receives taste sensations from the anterior two-thirds of the tongue and sends them
to the gustatory portion of the solitary nucleus. The facial nerve also supplies a small amount of
afferent innervation to the oropharynx below the palatine tonsil. There is also a small amount of
cutaneous sensation carried by the nervus intermedius from the skin in and around the auricle
(earlobe).
Location of Cell Bodies
The cell bodies for the facial nerve are grouped in anatomical areas called nuclei or ganglia. The
cell bodies for the afferent nerves are found in the geniculate ganglion for both taste and general
afferent sensation. The cell bodies for muscular efferent nerves are found in the facial motor
nucleus whereas the cell bodies for the parasympathetic efferent nerves are found in the superior
salivatory nucleus.
Pathology
People may suffer from acute facial nerve paralysis, which is usually manifested by facial
paralysis. Bell's palsy is one type of idiopathic acute facial nerve paralysis, which is more
accurately described as a multiple cranial nerve ganglionitis that involves the facial nerve, and
most likely results from viral infection and also sometimes as a result of Lyme disease.
Iatrogenic Bell's Palsy may also be as a result of an incorrectly placed dental local-anesthetic
(Inferior alveolar nerve block). Although giving the appearance of a hemi-plegic stroke, effects
dissipate with the drug.
Testing the facial nerve
Voluntary facial movements, such as wrinkling the brow, showing teeth, frowning, closing the
eyes tightly (lagophthalmos) , pursing the lips and puffing out the cheeks, all test the facial
nerve. There should be no noticeable asymmetry.
In an UMN lesion, called central seven, only the lower part of the face on the contralateral side
will be affected, due to the bilateral control to the upper facial muscles (frontalis and orbicularis
oculi).
Lower motor neuron lesions can result in a CNVII palsy (Bell's palsy is the term used to describe
the idiopathic form of facial nerve palsy), manifested as both upper and lower facial weakness on
the same side of the lesion.
Taste can be tested on the anterior 2/3 of the tongue. This can be tested with a swab dipped in a
flavoured solution, or with electronic stimulation (similar to putting your tongue on a battery).
Corneal Reflex. The afferent arc is mediated by the General Sensory afferents of the Trigeminal
Nerve. The efferent arc occurs via the Facial Nerve. The reflex involves consensual blinking of
both eyes in response to stimulation of one eye. This is due to the Facial Nerve's innervation of
the muscles of facial expression, namely Orbicularis Oculi, responsible for blinking. Thus, the
corneal reflex effectively tests the proper functioning of both Cranial Nerves V and VII.

Facial nerve paralysis

Facial nerve paralysis

Facial nerve
Facial nerve paralysis is a common problem that involves the paralysis of any structures
innervated by the facial nerve. The pathway of the facial nerve is long and relatively convoluted,
and so there are a number of causes that may result in facial nerve paralysis. The most common
is Bell's palsy, an idiopathic disease that may only be diagnosed by exclusion.
A thorough medical history and physical examination are the first steps in making a diagnosis.

Moche Culture Representation of Facial Paralysis. 300 A.D.

During the physical examination, a distinction must first be made between paralysis and paresis
(incomplete paralysis). Not surprisingly, paralysis is far more serious and requires immediate
treatment. It must also be determined whether the forehead is involved in the motor defect or not.
This is usually accomplished by assessing how well a patient can raise her eyebrows. The
question is an important one because it helps determine if the lesion is in the upper motor neuron
component of the facial nerve, or in its lower motor neuron component.
Laboratory investigations include an audiogram, nerve conduction studies (ENoG), computed
tomography (CT) or magnetic resonance imaging (MRI).
Causes
Supranuclear and nuclear lesions
Central facial palsy can be caused by a lacunar infarct affecting fibers in the internal capsule
going to the nucleus.
The facial nucleus itself can be affected by infarcts of the pontine arteries.
Infranuclear lesions

Bell's palsy

Bell's palsy is the most common cause of acute facial nerve paralysis (>80%). Previously
considered idiopathic, it has been recently linked to herpes simplex infection. Another more
severe form of facial palsy, called Ramsay-Hunt syndrome, is linked to herpes zoster infection of
the facial nerve. Other, less common, etiologies are Lyme disease) polio, TB.
Bell's palsy is an exclusion diagnosis. Some factors that tend to rule out Bell's palsy include:
1. Recurrent paralysis
2. Slowly progressive paralysis (The onset of Bell's palsy is very sudden)
3. Twitching
4. Associated symptoms (either cochlear or neurologic)
Bell's palsy is believed in the most recent studies to be due to herpes virus. Other proposed
etiologies include vascular problems in the inner ear. Treatment includes steroids and antivirals.

Trauma

Physical trauma, especially fractures of the temporal bone, may also cause acute facial nerve
paralysis. Understandably, the likelihood of facial paralysis after trauma depends on the location
of the trauma. Most commonly, facial paralysis follows temporal bone fractures, though the
likelihood depends on the type of fracture.
Transverse fractures in the horizontal plane present the highest likelihood of facial paralysis (40-
50%). Patients may also present with hemotympanum (blood behind the tympanic membrane),
sensory deafness, and vertigo – the latter two symptoms due to damage to vestibulocochlear
nerve (cranial nerve VIII) and the inner ear. Longitudinal fracture in the vertical plane present a
lower likelihood of paralysis (20%). Patients may present with hematorrhea (blood coming out
of the external auditory meatus), tympanic membrane tear, fracture of external auditory canal,
and conductive hearing loss.
Traumatic injuries can be assessed by computed tomography (CT) and nerve conduction studies
(ENoG). In patients with mild injury, management is the same as with Bell's palsy – protect the
eyes and wait. In patients with severe injury, progress is followed with nerve conduction studies.
If nerve conduction studies show a large (>90%) change in nerve conduction, the nerve should
be decompressed. The facial paralysis can follow immediately the trauma due to direct damage
to the facial nerve, in such cases a surgical treatment may be attempted. In other cases the facial
paralysis can occur a long time after the trauma due to oedema and inflammation. In those cases
steroids can be a good help.
Herpes zoster oticus

Main article: Ramsay Hunt syndrome type II

Herpes zoster oticus is essentially a herpes zoster infection that affects cranial nerves VII (facial
nerve) and VIII (vestibulocochlear nerve). Patients present with facial paralysis, ear pain,
vesicles, sensorineural hearing loss, and vertigo. Management includes Antiviral drugs and oral
steroids.

Acute and chronic otitis media

Otitis media is an infection in the middle ear, which can spread to the facial nerve and inflame it,
causing compression of the nerve in its canal. Antibiotics are used to control the otitis media, and
other options include a wide myringotomy (an incision in the tympanic membrane) or
decompression if the patient does not improve
Chronic otitis media usually presents in an ear with chronic discharge (otorrhea), or hearing loss,
with or without ear pain (otalgia). Once suspected, there should be immediate surgical
exploration to determine if a cholesteatoma has formed and must be removed. Inflamation from
medial ear can be spread to the canalis facialis of temporal bone,through this canal travel facial
nerve together with steatoacustisus nerve,in case of inflamation,nerve is exposed to edema and
so the high preassure,this condition lead to periferic type palsy,which is the most common
cause.inflamation of this chanel can be caused by cold condition too,for example when we drive
with open window of car etc,all the changes which happen in this chanel are known as Genc
Paqarizi's causes of palsy

Neurosarcoidosis

Facial nerve paralysis, sometimes bilateral, is a common manifestation of neurosarcoidosis

(sarcoidosis of the nervous system), itself a rare condition.

Moebius syndrome

Moebius syndrome is a bilateral facial paralysis resulting from the underdevelopment of the VII
cranial nerve (facial nerve), which is present at birth. The VI cranial nerve, which controls lateral
eye movement, is also affected, so people with Moebius syndrome cannot form facial expression
or move their eyes from side to side. Moebius syndrome is extremely rare, and its cause or
causes are not known.
Multiple Tumors
A tumor compressing the facial nerve anywhere along its complex pathway can result in facial
paralysis. Common culprits are facial neuromas, congenital cholesteatomas, hemangiomas,
acoustic neuromas, parotid gland neoplasms, or metastases of other tumours.
Patients with facial nerve paralysis resulting from tumours usually present with a progressive,
twitching paralysis, other neurological signs, or a recurrent Bell's palsy-type presentation. The
latter should always be suspicious, as Bell's palsy should not recur. A chronically discharging ear
must be treated as a cholesteatoma until proven otherwise; hence, there must be immediate
surgical exploration.
Computed tomography (CT) or magnetic resonance (MR) imaging should be used to identify the
location of the tumour, and it should be managed accordingly.
Often times, since facial neoplasms have such an intimate relationship with the facial nerve,
removing tumors in the facial region becomes perplexing as the physician is unsure how to
manage the tumor without causing even more palsy. Typically, benign tumors should be
removed in a fashion that preserves the facial nerve, while malignant tumors should always be
resected along with large areas of tissue around them, including the facial nerve. While this will
inevitably lead to heightened paralysis, safe removal of a malignant neoplasm is worth the often
treatable palsy that follows. In the best case scenario, paralysis can be corrected with techniques
including hypoglossal-facial nerve anastomosis, end-to-end nerve repair, cross facial nerve
grafting, or muscle transfer/transposition techniques, such as the gracilis free muscle transfer.

Glossopharyngeal nerve
Nerve: Glossopharyngeal nerve

Course and distribution of the glossopharyngeal, vagus, and

Plan of upper portions of glossopharyngeal, vagus, and
accessory nerves. (Label for glossopharyngeal is at upper
accessory nerves.
right.)
The glossopharyngeal nerve is the ninth (IX) of twelve pairs of cranial nerves (24 nerves total).
It exits the brainstem out from the sides of the upper medulla, just rostral (closer to the nose) to
the vagus nerve.
Functions
There are a number of functions of the glossopharyngeal nerve:
 It receives general sensory fibers (ventral trigeminothalamic tract) from the tonsils, the
pharynx, the middle ear and the posterior 1/3 of the tongue.
 It receives special sensory fibers (taste) from the posterior one-third of the tongue.
 It receives visceral sensory fibers from the carotid bodies.
 It supplies parasympathetic fibers to the parotid gland via the otic ganglion.
 It supplies motor fibers to stylopharyngeus muscle, the only motor component of this
cranial nerve.
 It contributes to the pharyngeal plexus.
Brainstem connections
The glossopharyngeal nerve is mostly sensory. The glossopharyngeal nerve also aids in tasting,
swallowing and salivary secretions. Its superior and inferior (petrous) ganglia contain the cell
bodies of pain fibers. It also projects into many different structures in the brainstem:
  Solitary nucleus: Taste from the posterior one-third of the tongue and information from
carotid baroreceptors and carotid body chemoreceptors
 Spinal nucleus of the trigeminal nerve: Somatic sensory fibers from the middle ear.
 Lateral Nucleus of Ala Cinerea: Visceral pain.
 Nucleus ambiguus: The lower motor neurons for the stylopharyngeus muscle.
 Inferior salivatory nucleus: Parasympathetic input to the parotid and mucous glands.
Path
From the medulla oblongata, the glossopharyngeal nerve passes laterally across or below the
flocculus, and leaves the skull through the central part of the jugular foramen. From the superior
and inferior ganglia in jugular foramen it has its own sheath of dura mater. The inferior ganglion
on the inferior surface of petrous part of temporal is related with a triangular deppression into
which the aqueduct of cochlea opens. Inferiorly the glossopharyngeal nerve is lateral and
anterior to the vagus nerve and accessory nerve.
In its passage through the jugular foramen it passes between the internal jugular vein and internal
carotid artery. It descends in front of the latter vessel, and beneath the styloid process and the
muscles connected with it, to the lower border of the stylopharyngeus. It then curves forward,
forming an arch on the side of the neck and lying upon the stylopharyngeus and middle
pharyngeal constrictor muscle. From there it passes under cover of the hyoglossus muscle, and is
finally distributed to the palatine tonsil, the mucous membrane of the fauces and base of the
tongue, and the mucous glands of the mouth.
Branches
 Tympanic
 Stylopharyngeal
 Tonsillar
 Nerve to carotid sinus
 Branches to the posterior third of tongue
 Lingual branches
 A communicating branch to the Vagus nerve
Note: The glossopharyneal nerve contributes in the formation of the pharyngeal plexus along
with the vagus nerve.
Testing the glossopharyngeal nerve
The integrity of the glossopharyngeal nerve may be evaluated by testing the patient's general
sensation and that of taste on the posterior third of the tongue.

Vagus nerve
Nerve: Vagus nerve
Plan of upper portions of glossopharyngeal, vagus, and
accessory nerves.

The vagus nerve (pronounced /ˈveɪɡəs/, US dict: vā′·gəs), also called pneumogastric nerve,
cranial nerve X, the Wanderer or sometimes the Rambler, is the tenth of twelve (excluding
CN0) paired cranial nerves. Upon leaving the medulla between the olivary nucleus and the
inferior cerebellar penduncle, it extends through the jugular foramen, then passing into the
carotid sheath between the internal carotid artery and the internal jugular vein down below the
head, to the neck, chest and abdomen, where it contributes to the innervation of the viscera.
Besides output to the various organs in the body the vagus nerve conveys sensory information
about the state of the body's organs to the central nervous system. 80-90% of the nerve fibers in
the vagus nerve are afferent (sensory) nerves communicating the state of the viscera to the brain.
The medieval Latin word vagus means literally "Wandering" (the words vagrant, vagabond, and
vague come from the same root). Sometimes the branches are spoken of in the plural and are
thus called vagi (pronounced /ˈveɪdʒаɪ/, US dict: vā′·jī). The vagus is also called the
pneumogastric nerve since it innervates both the lungs and the stomach.
Branches
 Auricular nerve
 Pharyngeal nerve
 Superior laryngeal nerve
 Superior cervical cardiac branches of vagus nerve
 Inferior cervical cardiac branch
 Recurrent laryngeal nerve
 Thoracic cardiac branches
 Branches to the pulmonary plexus
 Branches to the esophageal plexus
 Anterior vagal trunk
 Posterior vagal trunk
Innervation
Both right and left vagus nerves descend from the brain in the carotid sheath, lateral to the
carotid artery.
The right vagus nerve gives rise to the right recurrent laryngeal nerve which hooks around the
right subclavian artery and ascends into the neck between the trachea and esophagus. The right
vagus then crosses anteriorly to the right subclavian artery and runs posterior to the superior vena
cava and descends posterior to the right main bronchus and contributes to cardiac, pulmonary
and esophageal plexuses. It forms the posterior vagal trunk at the lower part of the esophagus
and enters the diaphragm through the esophageal hiatus.
The left vagus nerve enters the thorax between left common carotid artery and left subclavian
artery and descends on the aortic arch. It gives rise to the left recurrent laryngeal nerve which
hooks around the aortic arch to the left of the ligamentum arteriosum and ascends between the
trachea and esophagus. The left vagus further gives off thoracic cardiac branches, breaks up into
pulmonary plexus, continues into the esophageal plexus and enters the abdomen as the anterior
vagal trunk in the esophageal hiatus of the diaphragm.
The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal
(adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus
also controls a few skeletal muscles, namely:
 Cricothyroid muscle
 Levator veli palatini muscle
 Salpingopharyngeus muscle
 Palatoglossus muscle
 Palatopharyngeus muscle
 Superior, middle and inferior pharyngeal constrictors
 Muscles of the larynx (speech).
This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal
peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the
recurrent laryngeal nerve) and keeping the larynx open for breathing (via action of the posterior
cricoarytenoid muscle, the only abductor of the vocal folds). It also has some afferent fibers that
innervate the inner (canal) portion of the outer ear, via the Auricular branch (also known as
Alderman's nerve) and part of the meninges. This explains why a person may cough when
tickled on their ear (such as when trying to remove ear wax with a cotton swab).
The vagus nerve and the heart

Fibres of the vagus nerve (right/bottom of image) innervate the sinoatrial node tissue (central
and left of image). H&E stain.
Parasympathetic innervation of the heart is mediated by the vagus nerve. Specifically, the vagus
nerve acts to lower the heart rate. The right vagus innervates the sinoatrial node. Parasympathetic
hyperstimulation predisposes those affected to bradyarrhythmias. The left vagus when
hyperstimulated predisposes the heart to atrioventricular (AV) blocks.
At this location Otto Loewi first proved that nerves secrete substances called neurotransmitters
which have effects on receptors in target tissues. Loewi described the substance released by the
vagus nerve as vagusstoff, which was later found to be acetylcholine.
The vagus nerve has three nuclei in the CNS associated with cardiovascular control, the dorsal
motor nucleus, the nucleus ambiguus and the solitary nucleus. The parasympathetic output to the
heart comes mainly from neurons in the nucleus ambiguus and to a lesser extent from the dorsal
motor nucleus.[2] The solitary nucleus receives sensory input about the state of the cardiovascular
system, being an integrational hub for the baroreflex.
Drugs that inhibit the muscarinic cholinergic receptor (anticholinergics) such as atropine and
scopolamine are called vagolytic because they inhibit the action of the vagus nerve on the heart,
gastrointestinal tract and other organs. Anticholinergic drugs increase heart rate and are used to
treat bradycardia (slow heart rate) and asystole, which is when the heart has no electrical activity.
Medical treatment involving the vagus nerve
Vagus nerve stimulation (VNS) therapy using a pacemaker-like device implanted in the chest is
a treatment used since 1997 to control seizures in epilepsy patients and has recently been
approved for treating drug-resistant cases of clinical depression.[3] A convenient, non-invasive
VNS device that stimulates an afferent branch of the vagus nerve is also being developed and
will soon undergo trials.
VNS may also be achieved by one of the vagal maneuvers: holding the breath for a few seconds,
dipping the face in cold water, coughing, or tensing the stomach muscles as if to bear down to
have a bowel movement (valsalva maneuver).[4] Patients with supraventricular tachycardia,[4]
atrial fibrillation, and other illnesses may be trained to perform vagal maneuvers (or find one or
more on their own).
Vagus nerve blocking (VBLOC) therapy, similar to VNS but only used during the day, has
caused 31 obese participants in a six month open label trial involving three medical centers in
Australia, Mexico and Norway to lose an average of nearly 15 percent of their excess weight. A
one year 300 participant double blind phase II trial has begun.[5]
Vagotomy (cutting of the vagus nerve) is a now-obsolete therapy that was performed for peptic
ulcer disease. Vagotomy is currently being researched as a less invasive alternative weight loss
procedure to gastric bypass surgery.[6] The procedure curbs the feeling of hunger and is
sometimes performed in conjunction with putting bands on patients' stomachs, resulting in
average weight loss of 43% at six months with diet and exercise.[7]
Physical and emotional effects
Activation of the vagus nerve typically leads to a reduction in heart rate, blood pressure, or both.
This occurs commonly in the setting of gastrointestinal illness such as viral gastroenteritis or
acute cholecystitis, or in response to other stimuli, including carotid sinus massage, Valsalva
maneuver, or pain from any cause, particularly having blood drawn. When the circulatory
changes are great enough, vasovagal syncope results. Relative dehydration tends to amplify these
responses.
Excessive activation of the vagal nerve during emotional stress, which is a parasympathetic
overcompensation of a strong sympathetic nervous system response associated with stress, can
also cause vasovagal syncope because of a sudden drop in blood pressure and heart rate.
Vasovagal syncope affects young children and women more often. It can also lead to temporary
loss of bladder control under moments of extreme fear.
Research has shown that women who have complete transection of the spinal cord can
experience orgasms through the vagus nerve, which can go from the uterus, cervix and probably
the vagina to the brain.[8][9]
Effects of vagus nerve lesions
The patient complains of hoarse voice, difficulty in swallowing (dysphagia) and choking when
drinking fluid. There is also loss of gag reflex. Uvula deviates away from the side of lesion and
there is failure of palate elevation.
Accessory nerve

In anatomy, the accessory nerve is a nerve that controls specific muscles of the neck. As a part of
it was formerly believed to originate in the brain, it is considered a cranial nerve. Based on its
location relative to other such nerves, it is designated the eleventh of twelve cranial nerves, and
is thus abbreviated CN XI. Although anatomists typically refer to the accessory nerve in
singular, there are in reality two accessory nerves, one on each side of the body.
Traditional descriptions of the accessory nerve divide it into two parts: a spinal part and a cranial
part. But because the cranial component rapidly joins the vagus nerve and serves the same
function as other vagal nerve fibers, modern descriptions often consider the cranial component
part of the vagus nerve and not part of the accessory nerve proper. Thus in contemporary
discussions of the accessory nerve, the common practice is to dismiss the cranial part altogether,
referring to the accessory nerve specifically as the spinal accessory nerve.
The spinal accessory nerve provides motor innervation from the central nervous system to two
muscles of the neck: the sternocleidomastoid muscle and the trapezius muscle. The
sternocleidomastoid muscle tilts and rotates the head, while the trapezius muscle has several
actions on the scapula, including shoulder elevation and adduction of the scapula.
Range of motion and strength testing of the neck and shoulders can be measured during a
neurological examination to assess function of the spinal accessory nerve. Limited range of
motion or poor muscle strength are suggestive of damage to the spinal accessory nerve, which
can result from a variety of causes. Injury to the spinal accessory nerve is most commonly
caused by medical procedures that involve the head and neck.
Course
Upon exiting the skull via the jugular foramen, the spinal accessory nerve pierces the
sternocleidomastoid muscle before terminating on the trapezius muscle.
Like other cranial nerves, the spinal accessory nerve begins in the central nervous system and
exits the cranium through a specialized hole (or foramen). However, unlike all other cranial
nerves, the spinal accessory nerve begins outside the skull rather than inside. In particular, in the
majority of individuals, the fibers of the spinal accessory nerve originate solely in neurons
situated in the upper spinal cord. These fibers coalesce to form spinal rootlets, roots, and finally
the spinal accessory nerve itself, which enters the skull through the foramen magnum, the large
opening at the base of the skull. The nerve courses along the inner wall of the skull towards the
jugular foramen, through which it exits the skull with the glossopharyngeal (CN IX) and vagus
nerves (CN X). Owing to its peculiar course, the spinal accessory nerve is notable for being the
only cranial nerve to both enter and exit the skull.
Traditionally, the accessory nerve is described as having a small cranial component that
descends from the medulla oblongata and briefly connects with the spinal accessory component
before branching off of the nerve to join the vagus nerve. A recent study of twelve subjects
suggests that in the majority of individuals, this cranial component does not make any distinct
connection to the spinal component; the roots of these distinct components were separated by a
fibrous sheath in all but one subject. Once the cranial component has detached from the spinal
component, the spinal accessory nerve continues alone and heads posteriorly (backwards) and
inferiorly (downwards) upon exiting the skull. It pierces the sternocleidomastoid muscle while
sending it motor branches, then continues inferiorly until it reaches the trapezius muscle to
provide motor innervation to its upper portion.
Origin
Main article: Spinal accessory nucleus
The fibers that form the spinal accessory nerve are formed by lower motor neurons located in the
upper segments of the spinal cord. This cluster of neurons, called the spinal accessory nucleus, is
located in the lateral horn of the spinal cord. This is in contrast to most other motor neurons,
whose cell bodies are found in the spinal cord's anterior horn. The lateral horn of high cervical
segments appears to be continuous with the nucleus ambiguus of the medulla oblongata, from
which the cranial component of the accessory nerve is derived.
Classification
Among investigators there is disagreement regarding the terminology used to describe the type
of information carried by the accessory nerve. As the trapezius and sternocleidomastoid muscles
are derived from the branchial arches, some investigators believe the spinal accessory nerve that
innervates them must carry branchiomeric (special visceral efferent, SVE) information.[5] This
is in line with the observation that the spinal accessory nucleus appears to be continuous with the
nucleus ambiguus of the medulla. Others, notably Haines, consider the spinal accessory nerve to
carry general somatic efferent (GSE) information.[6] Still others believe it is reasonable to
conclude that the spinal accessory nerve contains both SVE and GSE components.[7]
Function
The nerve functions to control the sternocleidomastoid and trapezius muscles.
Injury
Injury to the spinal accessory nerve can cause an accessory nerve disorder or spinal accessory
nerve palsy, which results in diminished or absent function of the sternocleidomastoid muscle
and upper portion of the trapezius muscle.
The distal part of the spinal accessory nerve is most susceptible to injury. Throughout much of
its course, the nerve is protected from injury by the muscles it innervates. It is in the interval
between protection from these muscles, which corresponds to the distal part of the nerve, that the
spinal accessory nerve is most vulnerable to injury.
Assessment of function
As physical examination cannot directly assess the functioning of nerves, assessment of spinal
accessory nerve function is usually done indirectly. This is often accomplished through gross
observation, range of motion testing, and strength testing, with specific attention to the trapezius
and sternocleidomastoid muscles which are innervated by the spinal accessory nerve.
The trapezius muscle is tested by asking the patient to shrug their shoulders with and without
resistance. A one-sided weakness is indicative of an injury to the spinal accessory nerve on the
same side (termed ipsilateral) of the body being assessed. The sternocleidomastoid muscle is
tested by asking the patient to turn their head to the left or right against resistance. Weakness in
head-turning suggests injury to the contralateral spinal accessory nerve: a weak leftward turn is
indicative of a weak right sternocleidomastoid muscle (and thus right spinal accessory nerve
injury), while a weak rightward turn is indicative of a weak left sternocleidomastoid muscle (and
thus left spinal accessory nerve).
Gross observation may identify other findings associated with spinal accessory nerve injury.
Patients with spinal accessory nerve palsy may exhibit signs of lower motor neuron disease such
as diminished muscle mass (atrophy) and fasciculations of the sternocleidomastoid and trapezius
muscles.
Hypoglossal nerve
Nerve: Hypoglossal nerve

Hypoglossal nerve, cervical plexus, and their branches.

The hypoglossal nerve is the twelfth cranial nerve (XII), leading to the tongue. The nerve arises
from the hypoglossal nucleus and emerges from the medulla oblongata in the preolivary sulcus
separating the olive and the pyramid. It then passes through the hypoglossal canal. On emerging
from the hypoglossal canal, it gives off a small meningeal branch and picks up a branch from the
anterior ramus of C1. It spirals behind the vagus nerve and passes between the internal carotid
artery and internal jugular vein lying on the carotid sheath. After passing deep to the posterior
belly of the digastric muscle, it passes to the submandibular region to enter the tongue.
It supplies motor fibres to all of the muscles of the tongue, except the palatoglossus muscle
which is innervated by the vagus nerve (cranial nerve X) or, according to some classifications,
by fibers from the glossopharyngeal nerve (cranial nerve IX) that "hitchhike" within the vagus.
Testing the hypoglossal nerve
To test the function of the nerve, a person is asked to poke out their tongue. If there is a loss of
function on one side (unilateral paralysis) the tongue will point towards the affected side.
The strength of the tongue can be tested by getting the person to poke the inside of their cheek,
and feeling how strongly they can push a finger pushed against their cheek - a more elegant way
of testing than directly touching the tongue.
The tongue can also be looked at for signs of lower motor neuron disease, such as fasciculation
and atrophy.
Paralysis/paresis of one side of the tongue results in ipsilateral curvature of the tongue (apex
toward the impaired side of the mouth) i.e., the tongue will move towards the affected side.
CROSSING ALTERNATING SYNDROMES
Lateral medullary syndrome
Lateral medullary syndrome
Classification and external resources

Medulla oblongata, shown by a transverse section

passing through the middle of the olive. (Lateral
medullary syndrome can affect structures in upper
left: #9, #10, #11, #12, #13, and #14.)
Lateral medullary syndrome (also called Wallenberg syndrome and posterior inferior cerebellar
artery syndrome) is a disease in which the patient has a constellation of neurologic symptoms
due to injury to the lateral part of the medulla in the brain, resulting in tissue ischemia and
necrosis.
Signs and symptoms
This syndrome is characterized by sensory deficits affecting the trunk (torso) and extremities on
the opposite side of the infarction and sensory deficits affecting the face and cranial nerves on
the same side with the infarct. Specifically, there is a loss of pain and temperature sensation on
the contralateral (opposite) side of the body and ipsilateral (same) side of the face. This crossed
finding is diagnostic for the syndrome.
Clinical symptoms include difficulty swallowing, or dysphagia,[1] slurred speech, ataxia, facial
pain, vertigo, nystagmus, Horner syndrome,diplopia, and possibly palatal myoclonus.
Affected persons have difficulty in swallowing (dysphagia) resulting from involvement of
the nucleus ambiguus, as well as slurred speech (dysarthria)and disordered vocal quality
( dysphonia ) . Damage to the spinal trigeminal nucleus causes absence of pain on the ipsilateral
side of the face, as well as an absent corneal reflex.
The spinothalamic tract is damaged, resulting in loss of pain and temperature sensation to the
opposite side of the body. The damage to the cerebellum or the inferior cerebellar pedunclecan
cause ataxia. Damage to the hypothalamospinal fibers disrupts sympathetic nervous system relay
and gives symptoms analogous to Horner syndrome.
Nystagmus and vertigo, which may result in falling, caused from involvement of the region
of Deiters' nucleus and other vestibular nuclei. Onset is usually acute with severe vertigo.
Palatal myoclonus may be observed due to disruption of the central tegmental tract.
Cause
The three major arteries of the cerebellum: the SCA, AICA, and
PICA. (Posterior inferior cerebellar artery is PICA.)

Human brainstem blood supply description. PICA is #12.

It is the clinical manifestation resulting from occlusion of the posterior inferior cerebellar
artery (PICA) or one of its branches or of the vertebral artery, in which the lateral part of
the medulla oblongata infarcts, resulting in a typical pattern. The most commonly affected artery
is the vertebral artery, followed by the PICA, superior middle and inferior medullary arteries.

Medial medullary syndrome

Medial medullary syndrome
Classification and external resources

Medulla oblongata, shown by a transverse section

passing through the middle of the olive. (Medial
medullary syndrome can affect structures in lower
left: especially #5, #6, #8.)
Medial medullary syndrome, also known as inferior alternating syndrome, hypoglossal
alternating hemiplegia, lower alternating hemiplegia,[1] or Dejerine syndrome,[2] is a type
of alternating hemiplegia characterized by a set of clinical features resulting from occlusion of
the vertebral artery or of a branch of the vertebral or lower basilar artery. This results in the
infarction of medial part of themedulla oblongata.
Pathophysiology
The infarction leads to death of the ipsilateral medullary pyramid, the ipsilateral medial
leminiscus, and hypoglossal nerve fibers that pass through the medulla. The spinothalamic
tract is spared because it is located more laterally in the brainstem and is not supplied by the
anterior spinal artery, but rather by the vertebral and posterior inferior cerebellar arteries.
The trigeminal nucleus is also spared, since most of it is higher up in the pons, and the spinal part
of it found in the medulla is lateral to the infarct.
Presentation
The condition usually consists of:
Number
Description Source of damage on
diagram
a deviation of the tongue to the ipsilateral side of the
infarct on attempted protrusion, caused by muscle hypoglossal nerve fibers #8
weakness on the ipsilateral side
medullary pyramid and hence
limb weakness (or hemiplegia, depending on
to the corticospinal fibers of #5
severity), on the contralateralside of the infarct
the pyramidal tract
a loss of discriminative touch,
conscious proprioception, and vibration sense on medial leminiscus #6
the contralateral side of the infarct

Sensation to the face is preserved, due to the sparing of the trigeminal nucleus.
The syndrome is said to be "alternating" because the lesion causes symptoms both contralaterally
and ipsilaterally. Sensation of pain and temperature is preserved, because the spinothalamic
tract is located more laterally in the brainstem and is also not supplied by the anterior spinal
artery (instead supplied by the posterior inferior cerebellar arteries and the vertebral arteries).

Weber's syndrome
Weber's syndrome
Classification and external resources

Midbrain cross section showing lesion

Weber's syndrome (superior alternating hemiplegia) is a form of stroke characterized by the
presence of an oculomotor nerve palsy and contralateral hemiparesis or hemiplegia.
Cause and presentation
This lesion is usually unilateral and affects several structures in the midbrain including:
Structure damaged Effect
contralateral parkinsonism because its dopaminergic projections to
substantia nigra
the basal ganglia innervate the contralateral hemisphere motor field
corticospinal fibers contralateral hemiparesis and typical upper motor neuron findings
difficulty with contralateral lower facial muscles and hypoglossal
corticobulbar tract
nerve functions
oculomotor ipsilateral oculomotor nerve palsy with a drooping eyelid and fixed wide
nervefibers pupil pointed down and out. This leads todiplopia
It is caused by midbrain infarction as a result of occlusion of the paramedian branches of
the posterior cerebral artery or of basilar bifurcation perforating arteries.[1]

Millard-Gubler syndrome
Millard-Gubler syndrome

Pons
Millard-Gubler syndrome is a lesion of the pons.[1]
Presentation
It is a syndrome of unilateral softening of the brain tissue arising from obstruction of the blood
vessels of the pons, involving the sixth and seventh cranial nerves and fibers of the corticospinal
tract, and is associated with paralysis of the abducens (including diplopia, internal strabismus,
and loss of power to rotate the affected eye outward) and facial nerves and contralateral
hemiplegia of the extremities. It is also known as "crossed hemiplegia".
Diagnosis
This syndrome is easier to diagnose today thanks to the technical advances in brain imaging (CT,
MRI).
Autonomic nervous system

The autonomic nervous system

Blue = parasympathetic
Red = sympathetic

The autonomic nervous system (ANS or visceral nervous system) is the part of theperipheral nervous
system that acts as a control system functioning largely below the level of consciousness, and
controls visceral functions. The ANS affects heart rate, digestion,respiration rate, salivation, perspiration,
diameter of the pupils, micturition (urination), andsexual arousal. Whereas most of its actions are involuntary,
some, such as breathing, work in tandem with the conscious mind.
It is classically divided into two subsystems: the parasympathetic nervous system andsympathetic nervous
system. Relatively recently, a third subsystem of neurons that have been named 'non-adrenergic and non-
cholinergic' neurons (because they use nitric oxide as a neurotransmitter) have been described and found to be
integral in autonomic function, particularly in the gut and the lungs.
With regard to function, the ANS is usually divided into sensory (afferent) and motor (efferent) subsystems.
Within these systems, however, there are inhibitory and excitatory synapsesbetween neurons.
The enteric nervous system is sometimes considered part of the autonomic nervous system, and sometimes
considered an independent system.
Anatomy
ANS innervation is divided into sympathetic nervous system and parasympathetic nervous system divisions.
The sympathetic division has thoracolumbar “outflow”, meaning that the neurons begin at the thoracic and
lumbar (T1-L2) portions of the spinal cord. The parasympathetic division has craniosacral “outflow”, meaning
that the neurons begin at the cranial nerves (CN 3, CN7, CN 9, CN10) and sacral (S2-S4) spinal cord.
The ANS is unique in that it requires a sequential two-neuron efferent pathway; the preganglionic neuron must
first synapse onto a postganglionic neuron before innervating the target organ. The preganglionic, or first,
neuron will begin at the “outflow” and will synapse at the postganglionic, or second, neuron’s cell body. The
post ganglionic neuron will then synapse at the target organ.
Sympathetic division
The sympathetic division (thoracolumbar outflow) consists of cell bodies in the lateral horn of spinal
cord (intermediolateral cell columns) of the spinal cord from T1 to L2. These cell bodies are GVE neurons
(general visceral efferent), and are the preganglionic neurons. There are several locations upon which
preganglionic neurons can synapse for their postganglionic neurons:
 Paravertebral ganglia of the sympathetic chain (these run on either side of the vertebral bodies)
 Prevertebral ganglia (celiac ganglia, superior mesenteric ganglia, inferior mesenteric ganglia)
 Chromaffin cells of adrenal medulla (this is the one exception to the two-neuron pathway rule: synapse
is direct onto cell bodies)
These ganglia provide the postganglionic neurons from which innervation of target organs follows. Examples of
splanchnic (visceral) nerves are:
 Cervical cardiac nerves & thoracic visceral nerves which synapse in the sympathetic chain
 Thoracic splanchnic nerves (greater, lesser, least) which synapse in the prevertebral ganglion
 Lumbar splanchnic nerves which synapse in the prevertebral ganglion
 Sacral splanchnic nerves which synapse in the inferior hypogastric plexus
These all contain afferent (sensory) nerves as well, also known as GVA neurons (general visceral afferent).
Parasympathetic division
The parasympathetic division (craniosacral outflow) consists of cell bodies from one of two
locations: brainstem (Cranial Nerves 3, 7, 9, 10) or sacral spinal cord (S2, S3, S4). These are the preganglionic
neurons, which synapse with postganglionic neurons in these locations:
 Parasympathetic ganglia of the head (Ciliary (CN3), Submandibular (CN7), Pterygopalatine (CN7),
Otic (CN9))
 In or near wall of organ innervated (hfVagus (CN10), Sacral nerves (S2, S3, S4))
These ganglia provide the postganglionic neurons from which innervations of target organs follows. Examples
are:
 The preganglionic parasympathetic splanchnic (visceral) nerves
 Vagus nerve, which wanders through the thorax and abdominal regions innervating, among other
organs, the heart, lungs, liver and stomach
Sensory neurons
The sensory arm is made of “primary visceral sensory neurons” found in the peripheral nervous system (PNS),
in “cranial sensory ganglia”: the geniculate, petrosal and nodose ganglia, appended respectively to cranial
nerves VII, IX and X. These sensory neurons monitor the levels of carbon dioxide, oxygen and sugar in the
blood, arterial pressure and the chemical composition of the stomach and gut content. (They also convey the
sense of taste, a conscious perception). Blood oxygen and carbon dioxide are in fact directly sensed by the
carotid body, a small collection of chemosensors at the bifurcation of the carotid artery, innervated by the
petrosal (IXth) ganglion. Primary sensory neurons project (synapse) onto “second order” or relay visceral
sensory neurons located in the medulla oblongata, forming the nucleus of the solitary tract (nTS), that
integrates all visceral information. The nTS also receives input from a nearby chemosensory center, the area
postrema, that detects toxins in the blood and the cerebrospinal fluid and is essential for chemically induced
vomiting or conditional taste aversion (the memory that ensures that an animal which has been poisoned by a
food never touches it again). All these visceral sensory informations constantly and unconsciously modulate
the activity of the motor neurons of the ANS
Motor neurons
Motor neurons of the ANS are also located in ganglia of the PNS, called “autonomic ganglia”. They belong to
three categories with different effects on their target organs (see below “Function”): sympathetic,
parasympathetic and enteric.
Sympathetic ganglia are located in two sympathetic chains close to the spinal cord: the prevertebral and pre-
aortic chains. Parasympathetic ganglia, in contrast, are located in close proximity to the target organ:
the submandibular ganglion close to salivary glands, paracardiac ganglia close to the heart etc... Enteric
ganglia, which as their name implies innervate the digestive tube, are located inside its walls and collectively
contain as many neurons as the entire spinal cord, including local sensory neurons, motor neurons and
interneurons. It is the only truly autonomous part of the ANS and the digestive tube can function surprisingly
well even in isolation. For that reason the enteric nervous system has been called “the second brain”.
The activity of autonomic ganglionic neurons is modulated by “preganglionic neurons” (also called improperly
but classically "visceral motoneurons") located in the central nervous system. Preganglionic sympathetic
neurons are in the spinal cord, at thoraco-lumbar levels. Preganglionic parasympathetic neurons are in the
medulla oblongata (forming visceral motor nuclei: the dorsal motor nucleus of the vagus nerve (dmnX),
the nucleus ambiguus, and salivatory nuclei) and in the sacral spinal cord. Enteric neurons are also modulated
by input from the CNS, from preganglionic neurons located, like parasympathetic ones, in the medulla
oblongata (in the dmnX).
The feedback from the sensory to the motor arm of visceral reflex pathways is provided by direct or indirect
connections between the nucleus of the solitary tract and visceral motoneurons.
Function
Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is
better termed complementary in nature rather than antagonistic. For an analogy, one may think of the
sympathetic division as the accelerator and the parasympathetic division as the brake. The sympathetic
division typically functions in actions requiring quick responses. The parasympathetic division functions with
actions that do not require immediate reaction. Consider sympathetic as "fight or flight" and parasympathetic as
"rest and digest".
However, many instances of sympathetic and parasympathetic activity cannot be ascribed to "fight" or "rest"
situations. For example, standing up from a reclining or sitting position would entail an unsustainable drop in
blood pressure if not for a compensatory increase in the arterial sympathetic tonus. Another example is the
constant, second to second modulation of heart rate by sympathetic and parasympathetic influences, as a
function of the respiratory cycles. More generally, these two systems should be seen as permanently
modulating vital functions, in usually antagonistic fashion, to achieve homeostasis. Some typical actions of the
sympathetic and parasympathetic systems are listed below.
Sympathetic nervous system
Promotes a "fight or flight" response, corresponds with arousal and energy generation, and inhibits digestion.
 Diverts blood flow away from the gastro-intestinal (GI) tract and skin via vasoconstriction.
 Blood flow to skeletal muscles and the lungs is enhanced (by as much as 1200% in the case of
skeletal muscles).
 Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange.
 Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism
for the enhanced blood flow to skeletal muscles.
 Dilates pupils and relaxes the ciliary muscle to the lens, allowing more light to enter the eye and far
vision.
 Provides vasodilation for the coronary vessels of the heart.
 Constricts all the intestinal sphincters and the urinary sphincter.
 Inhibits peristalsis.
 Stimulates orgasm.
 Diabetes peristalsis
Parasympathetic nervous system
Promotes a "rest and digest" response, promotes calming of the nerves return to regular function, and
enhances digestion.
 Dilates blood vessels leading to the GI tract, increasing blood flow. This is important following the
consumption of food, due to the greater metabolic demands placed on the body by the gut.
 The parasympathetic nervous system can also constrict the bronchiolar diameter when the need for
oxygen has diminished.
 Dedicated cardiac branches of the Vagus and thoracic Spinal Accessory nerves
impart Parasympathetic control of the Heart orMyocardium.
 During accommodation, the parasympathetic nervous system causes constriction of the pupil and
contraction of the ciliary muscle to the lens, allowing for closer vision.
 The parasympathetic nervous system stimulates salivary gland secretion, and accelerates peristalsis,
so, in keeping with the rest and digest functions, appropriate PNS activity mediates digestion of food and
indirectly, the absorption of nutrients.
 Is also involved in erection of genitals, via the pelvic splanchnic nerves 2–4.
 Stimulates sexual arousal.
Neurotransmitters and pharmacology
At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with
other cotransmitters such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and
the adrenal medulla:
 Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the
postganglionic neurotransmitter of parasympathetic neurons. Nerves that release acetylcholine are said to
be cholinergic. In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter,
to stimulate muscarinic receptors.
 At the adrenal cortex, there is no postsynaptic neuron. Instead the presynaptic neuron releases
acetylcholine to act on nicotinic receptors.
 Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream which will
act on adrenoceptors, producing a widespread increase in sympathetic activity.
The following table reviews the actions of these neurotransmitters as a function of their receptors.
Nervous system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
α1: contracts M3: relaxes
Pupil dilator muscle
(causes mydriasis) (causes miosis)
β2: relaxes M3: contracts
Ciliary muscle
(causes long-range focus) (causes short-range focus)
Digestive system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
β: stimulates
M3: stimulates watery
salivary glands: secretions viscous, amylase secretions
secretions
α1: stimulates potassium cation
lacrimal glands (tears) β: stimulates protein secretion ---
kidney (renin) β1: secretes ---
parietal cells --- M1: Gastric acid secretion
liver α1, β2: glycogenolysis, gluconeogenesis ---
adipose cells β1, β3: stimulates lipolysis ---
GI tract (smooth muscle)
α1, α2, β2: decreases M3, (M1) : increases
motility
sphincters of GI tract α1 , α2 , β2: contracts M3: relaxes
glands of GI tract no effect M3: secretes
Endocrine system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
α2: decreases secretion from beta cells, M3 increases stimulation from alpha
pancreas(islets)
increases secretion fromalpha cells cells andbeta cells
adrenal N (nicotinic ACh receptor):
---
medulla secretes epinephrine and norepinephrine
Urinary system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
Detrusor urinae muscle of bladder wall β2: relaxes M3: contracts
urethral sphincter (internal) α1: contracts relaxes
sphincter α1: contracts; β2 relaxes M3: relaxes
Reproductive system
Target Sympathetic (adrenergic) Parasympathetic (muscarinic)
α1: contracts (pregnant)
uterus ---
β2: relaxes (non-pregnant)
genitalia α1: contracts (ejaculation) M3: erection
Integumentary system
Target Sympathetic (muscarinic and adrenergic) Parasympathetic (muscarinic)
sweat M: stimulates (major contribution); α1: stimulates
---
gland secretions (minor contribution)
arrector pili α1: stimulates ---
Sympathetic nervous system
Brain: Sympathetic nervous system

The sympathetic nervous system extends from the thoracic to

lumbar vertebrae and has connections with the thoracic,cat, and
pelvic plexuses.
Latin Pars sympathica divisionis autonomici systematis nervosi
The (ortho-) sympathetic nervous system (SNS) is one of the three parts of the autonomic nervous system,
along with the enteric and parasympathetic systems. Its general action is to mobilize the body's resources
under stress; to induce the fight-or-flight response. It is, however, constantly active at a basal level in order to
maintain homeostasis.
Overview
Along side the other two components of the autonomic nervous system, the sympathetic nervous system aids
in the control of most of the body's internal organs. Stress - as in theflight-or-fight response - and so may be
thought to counteract the parasympathetic system, which generally works to promote maintenance of the body
at rest. In truth, the functions of both systems are not so straightforward, but this is a useful rule of thumb.
There are two kinds of neurons involved in the transmission of any signal through the sympathetic system; pre-
and post- ganglionic. The shorter preganglionic neurons originate from the thoracolumbar region of the spinal
cord (levels T1 - L2, specifically) and travel to a ganglion, often one of the paravertebral ganglia, where they
synapse with a postganglionic neuron. From there, the long postganglionic neurons extend across most of the
body.
At the synapses within the ganglia, preganglionic neurons release acetylcholine, aneurotransmitter which
activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus
postganglionic neurons - with two important exceptions - release norepinephrine, which activates adrenergic
receptors on the peripheral target tissues. It is the activation of target tissue receptors which causes the effects
associated with the sympathetic system.
The two exceptions mentioned above are postganglionic neurons innervating sweat glands - which release
acetylcholine for the activation ofmuscarinic receptors - and the adrenal medulla. The adrenal
medulla develops in tandem with the sympathetic nervous system, and acts as a modified sympathetic
ganglion: synapses occur between pre- and post- ganglionic neurons within it, but the post ganglionic neurons
do not leave the medulla; instead they directly release norepinephrine and epinephrine into the blood.
Function
Organ Effect
Eye Dilates pupil
Heart Increases rate and force of contraction
Lungs Dilates bronchioles
Digestive tract Inhibits peristalsis
Kidney Increases renin secretion
Penis Promotes ejaculation
Examples of sympathetic system action on various organs.
The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in
living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some
regulatory function to things as diverse as pupil diameter,gut motility, and urinary output. It is perhaps best
known for mediating the neuronal and hormonal stress response commonly known as thefight-or-flight
response. This response is also known as sympatho-adrenal response of the body, as
the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers)
secrete acetylcholine, which activates the great secretion of adrenaline (epinephrine) and to a lesser extent
noradrenaline (norepinephrine) from it. Therefore, this response that acts primarily on the cardiovascular
system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly
via catecholamines secreted from the adrenal medulla.
Some evolutionary theorists suggest that the sympathetic nervous system operated in early organisms to
maintain survival as the sympathetic nervous system is responsible for priming the body for action. One
example of this priming is in the moments before waking, in which sympathetic outflow spontaneously
increases in preparation for action.
Organization
Sympathetic nerves originate inside the vertebral column, toward the middle of the spinal cord in
the intermediolateral cell column (or lateral horn), beginning at the first thoracic segment of the spinal cord and
are thought to extend to the second or third lumbar segments. Because its cells begin in the thoracic and
lumbar regions of the spinal cord, the SNS is said to have a thoracolumbar outflow. Axons of these nerves
leave the spinal cord through the anterior rootlet/root. They pass near the spinal (sensory) ganglion, where they
enter the anterior rami of the spinal nerves. However, unlike somatic innervation, they quickly separate out
through white rami connectors (so called from the shiny white sheaths of myelin around each axon) which
connect to the either the paravertebral (which lie near the vertebral column) or prevertebral (which lie near the
aortic bifurcation) ganglia extending alongside the spinal column.
In order to reach the target organs and glands, the axons must travel long distances in the body, and, to
accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of
the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic
cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic
cell). The message is then carried to the final destination.
Presynaptic nerves' axons terminate in either the paravertebral ganglia or prevertebral ganglia. This can occur
through one of four methods:
1. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve, and then ascends to a
more superior paravertebral ganglion, where it synapses with the postsynaptic cell.
2. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve and synapses with the
postsynaptic cell at that level.
3. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve, and then descends to
a more inferior paravertebral ganglion, where it synapses with the postsynaptic cell.
4. The nerve enters the paravertebral ganglion at the level of its originating spinal nerve and then descends to
a prevertebral ganglion, where it synapses with the postsynaptic cell.
The postsynaptic cell then goes on to innervate the targeted end effector (ie gland, smooth muscle, etc.).
Because paravertebral and prevertebral ganglia are relatively close to the spinal cord, presynaptic neurons are
generally much shorter than their postsynaptic counterparts, which must extend throughout the body to reach
their destinations.
A notable exception to the routes mentioned above is the sympathetic innervation of the suprarenal (adrenal)
glands. In this case, presynaptic neurons pass through paraverterbral ganglia, on through prevertebral ganglia
and then synapse directly with suprarenal tissue. This tissue consists of cells that have pseudo-neuron like
qualities in that when activated by the presynaptic neuron, they will release their neurotransmitter (epinephrine)
directly into the blood stream.
In the SNS and other components of the peripheral nervous system, these synapses are made at sites called
ganglia. The cell that sends its fiber is called a preganglionic cell, while the cell whose fiber leaves the ganglion
is called a postganglionic cell. As mentioned previously, the preganglionic cells of the SNS are located between
the first thoracic segment and third lumbar segments of the spinal cord. Postganglionic cells have their cell
bodies in the ganglia and send their axons to target organs or glands.
The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle and inferior),
which sends sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric
ganglia (which send sympathetic fibers to the gut).
Information transmission
Messages travel through the SNS in a bidirectional flow. Efferent messages can trigger changes in different
parts of the body simultaneously. For example, the sympathetic nervous system can accelerate heart rate;
widen bronchial passages; decrease motility (movement) of thelarge intestine; constrict blood vessels;
increase peristalsis in the esophagus; cause pupillary dilation, piloerection (goose bumps) and perspiration
(sweating); and raise blood pressure. Afferent messages carry sensations such as heat, cold, or pain.
The first synapse (in the sympathetic chain) is mediated by nicotinic receptors physiologically activated by
acetylcholine, and the target synapse is mediated by adrenergic receptors physiologically activated by either
noradrenaline (norepinephrine) or adrenaline (epinephrine). An exception is with sweat glands which receive
sympathetic innervation but have muscarinic acetylcholine receptors which are normally characteristic of
Parasympathetic nervous system. Another exception is with certain deep muscle blood vessels, which dilate
(rather than constrict) with an increase in sympathetic tone.This is because of the presence of more beta2
receptors(rather than alpha1 which are frequently found on other vessels).
Sympathicotonia
Sympathicotonia is a stimulated condition of the sympathetic nervous system, marked by vascular
spasm, elevated blood pressure, and goose bumps.
Parasympathetic nervous system
Brain: Parasympathetic nervous system

Autonomic nervous system innervation, showing the sympathetic

and parasympathetic (craniosacral) systems, in red and blue,
respectively
Latin Pars parasympathica divisionis autonomici systematis
nervosi
The parasympathetic nervous system (PSNS) is one of the three main divisions of theautonomic nervous
system (ANS). The ANS is responsible for regulation of internal organs and glands, which occurs
unconsciously. The parasympathetic system specifically is responsible for stimulation of activities that occur
when the body is at rest, includingsalivation, lacrimation, urination, digestion and defecation. Its action is
described as being complementary to that of one of the other main branches of the ANS, the sympathetic
nervous system, which is responsible for stimulating activities associated with the fight-or-flight response.
Because of this relationship, the action of the parasympathetic nervous system is often described as "rest and
digest".
Relation to sympathetic nervous system
Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is
better understood as complementary in nature rather than antagonistic. For an analogy, one may think of the
sympathetic division as the accelerator and the parasympathetic division as the brake. The sympathetic
division typically functions in actions requiring quick responses. The parasympathetic division functions with
actions that do not require immediate reaction. A useful acronym to summarize the functions of the
parasympathetic nervous system is SLUDD (salivation, lacrimation, urination, digestion and defecation).
Physical location
The parasympathetic nerves (PSN) are autonomic (aka "visceral") branches of the peripheral nervous
system (PNS). Parasympathetic nerve fibers arise from the central nervous system with the S2, S3, and
S4 spinal nerves and from the third, seventh, ninth, and tenth cranial nerves. Because of its location the
parasympathetic system is commonly referred to as having "craniosacral outflow", which stands in contrast to
the sympathetic nervous system which is said to have "thoracolumbar outflow".
The parasympathetic nerves that arise from the S2, S3, and S4 spinal nerves are commonly referred to as
the pelvic splanchnic nerves or the "nervi erigentes".
Pathways
As is true in the sympathetic nervous system, efferent parasympathetic nerve signals are carried from the
central nervous system to their targets by a system of two neurons. The first neuron in this pathway is referred
to as the preganglionic or presynaptic neuron. Its cell body sits in the central nervous system and its axon
usually extends to a ganglion somewhere else in the body where it synapses with thedendrites of the second
neuron in the chain. This second neuron is referred to as the postganglionic or postsynaptic neuron.
The axons of presynaptic parasympathetic neurons are usually long: they extend from the CNS into a ganglion
that is either very close to or embedded in their target organ. As a result, the postsynaptic parasympathetic
nerve fibers are very short.
In the cranium, preganglionic PSN (CN III, CN VII, and CN IX) usually arise from specific nuclei in the Central
Nervous System (CNS) and synapse at one of four parasympathetic ganglia: ciliary, pterygopalatine, otic,
or submandibular. From these four ganglia the PSN complete their journey to target tissues via CN V
(trigeminal) branches (ophthalmic nerve CN V1, maxillary nerve CN V2, mandibular nerve CN V3).
The vagus nerve (CN X) does not participate in these cranial ganglion as most of its PSN fibers are destined
for a broad array of ganglia on or near thoracic vicera (esophagus, trachea, heart, lungs) and abdominal
viscera (stomach, pancreas, liver, kidneys). It travels all the way down to the midgut/hindgut junction, which
occurs just before the splenic flexure of the transverse colon at a point called "cannon bohm".
The pelvic splanchnic efferent preganglionic nerve cell bodies reside in the lateral gray horn of the spinal
cord at the S2-S4 spinal levels.Their axons continue away from the CNS to synapse at an autonomic ganglion.
The PSN ganglion where these preganglionic neurons synapse will be close to the organ of innervation. This
differs from the sympathetic nervous system, where synapses between pre- and post-ganglionic efferent
nerves generally occur at ganglia that are farther away from the target organ.
Sensation
The afferent fibers of the autonomic nervous system, which transmit sensory information from the internal
organs of the body back to the central nervous system, are not divided into parasympathetic and sympathetic
fibers as the efferent fibers are. Instead, autonomic sensory information is conducted by general visceral
afferent fibers.
General visceral afferent sensations are mostly unconscious visceral motor reflex sensations from hollow
organs and glands that are transmitted to the CNS. While the unconscious reflex arcs normally are
undetectable, in certain instances they may send pain sensations to the CNS masked as referred pain. If
the peritoneal cavity becomes inflamed or if the bowel is suddenly distended your body will interpret the
afferent pain stimulus as somatic in origin. This pain is usually non-localized. The pain is also usually referred
to dermatomes that are at the same spinal nerve level as the visceral afferent synapse.
Cranial Nerve Parasympathetic Paths and Control
The oculomotor nerve is responsible for several parasympathetic functions related to the eye. The oculomotor
PNS fibers originate in theEdinger-Westphal nucleus in the CNS and travel through the superior orbital
fissure to synapse in the ciliary ganglion located just behind the orbit (eye). From the ciliary ganglion the
postganglionic PSN fibers leave via short ciliary nerve fibers, a continuation of the nasociliary nerve (a branch
of ophthalmic division of the trigeminal nerve, CN V1). The short ciliary nerves innervate the orbit to control the
ciliary muscle (responsible for accommodation) and the sphincter pupillae muscle which is responsible for
miosis or constriction of the pupil (in response to light or accommodation).
The parasympathetic aspect of the facial nerve controls secretion of the sublingual and submandibular salivary
glands, the lacrimal gland, and the glands associated with the nasal cavity. The preganglionic fibers originate
within the CNS in the superior salivatory nucleus and leave as the intermediate nerve (which some consider a
separate cranial nerve altogether) to connect with the facial nerve just distal (further out) to it surfacing the
CNS. Just after the facial nerve geniculate ganglion (general sensory ganglion) in the temporal bone, the facial
nerve gives off two separate parasympathetic nerves. The first is the greater petrosal nerve and the second is
the chorda tympani. The greater petrosal nerve travels through the middle ear and eventually combines with
the deep petrosal nerve (sympathetic fibers) to form the nerve of the pterygoid canal. The PSN fibers of the
nerve of the pterygoid canal synapse at the pterygopalatine ganglion, which is closely associated with the
maxillary division of the trigeminal nerve (CN V2). The postganglionic PSN fibers leave the pterygopalatine
ganglion in several directions. One division leaves on the zygomatic division of CN V2 and travels on a
communicating branch to unite with the lacrimal nerve (branch of the ophthalmic nerve of CN V1) before
synapsing at the lacrimal gland. These PSN to the lacrimal gland control tear production.
A separate group of PSN leaving from the pterygopalatine ganglion are the descending palatine nerves (CN
V2 branch) which include the greater and lesser palatine nerves. The greater palatine PSN synapse on the hard
palate and regulate mucus glands located there. The lesser palatine nerve synapses at the soft palate and
controls sparse taste receptors and mucus glands. Yet another set of divisions from the pterygopalatine
ganglion are the posterior, superior, and inferior lateral nasal nerves; and the nasopalatine nerves (all branches
of CN V2, maxillary division of the trigeminal nerve) that bring PSN to glands of the nasal mucosa. The second
PSN branch that leaves the facial nerve is the chorda tympani. This nerve carries secretomotor fibers to
the submandibular and sublingual glands. The chorda tympani travels through the middle ear and attaches to
the lingual nerve (mandibular division of trigeminal, CN V3). After joining the lingual nerve the preganglionic
fibers synapse at the submandibular ganglion and send postganglionic fibers to the sublingual and
submandibular salivary glands.
The glossopharyngeal nerve, CNIX, has parasympathetic fibers that innervate the parotid salivary gland. The
preganglionic fibers depart CNIX as the tympanic nerve and continue to the middle ear where they make up a
tympanic plexus on the cochlear promontory of the mesotympanum. The tympanic plexus of nerves rejoin and
form the lesser petrosal nerve and exit through the foramen ovale to synapse at the otic ganglion. From the otic
ganglion postganglionic parasympathetic fibers travel with the auriculotemporal nerve (mandibular branch of
trigeminal, CN V3) to the parotid salivary gland.
The vagus nerve, named from the Latin word vagus means literally "Wandering", since the nerve controls such
a broad range of target tissues, has PSN that originate in the dorsal nucleus of the vagus nerve and
the nucleus ambiguus in the CNS. The vagus nerve is an unusual cranial PSN in that it doesn't join the
trigeminal nerve in order to get to its target tissues. Another peculiarity is that the vagus has anautonomic
ganglion associated with it at approximately the level of C1 vertebra. The vagus gives no PSN to the cranium.
The vagus nerve is hard to track definitively due to its ubiquitous nature in the thorax and abdomen so the
major contributions will be discussed. Several PSN nerves come off the vagus nerve as it enters the thorax.
One nerve is the recurrent laryngeal nerve, which becomes the inferior laryngeal nerve. From the left vagus
nerve the recurrent laryngeal nerve hooks around the aorta to travel back up to the larynx and
proximal esophaguswhile, from the right vagus nerve, the recurrent laryngeal nerve hooks around the
right subclavian artery to travel back up to the same location as its counterpart. These different paths are a
direct result of embryological development of the circulatory system. Each recurrent laryngeal nerve supplies
the trachea and the esophagus with parasympathetic secretomotor innervation for glands associated with them
(and other fibers that are not PSN).
Another nerve that comes off the vagal nerves approximately at the level of entering the thorax are the cardiac
nerves. These cardiac nerves go on to form cardiac and pulmonary plexuses around the heart and lungs. As
the main vagus nerves continue into the thorax they become intimately linked with the esophagus and
sympathetic nerves from the sympathetic trunks to form the esophageal plexus. This is very efficient as the
major function of the vagus nerve from there on will be control of the gut smooth muscles and glands. As
the esophageal plexus enter the abdomen through the esophageal hiatus anterior and posterior vagal trunks
form. The vagal trunks then join with preaortic sympathetic ganglion around the aorta to disperse with the blood
vessels and sympathetic nerves throughout the abdomen. The extent of the PSN in the abdomen include
the pancreas, kidneys, liver, gall bladder, stomach and gut tube. The vagal contribution of PSN continues down
the gut tube until the end of the midgut. The midgut ends 2/3 of the way across the transverse colon near
the splenic flexure.
Pelvic Splanchnic Control
The pelvic splanchnic nerves, S2-4, work in tandem to innervate the pelvic viscera. Unlike in the cranium,
where one PSN was in charge of one particular tissue or region, for the most part the pelvic splanchnics each
contribute fibers to pelvic viscera by first traveling to one or more plexuses before being dispersed to the target
tissue. These plexuses are composed of mixed autonomic nerve fibers (PSN and SN) and include the vesical,
prostatic, rectal, uterovaginal and inferior hypogastric plexus. The preganglionic neurons in the neurons do not
synapse in named ganglion as in the cranium but rather in the walls of the tissues or organs that they
innervate. The fiber paths are variable and each individual's autonomic nervous system in the pelvis is unique.
The visceral tissues in the pelvis that the PSN control include: urinary bladder, ureters, urinary sphincter, anal
sphincter, uterus, prostate, glands, vagina and penis. Unconsciously, the PSN will cause peristaltic movements
of the ureters helping to move urine from the kidneys into the bladder and move feces down the intestinal tract
and upon necessity, the PSN will assist excreting urine from the bladder or defecation. Stimulation of the PSN
will cause the detrusor muscle (urinary bladder wall) to contract and simultaneously relax the internal sphincter
urethrae muscle to relax allowing void of urine. Also, PSN stimulation to the internal anal sphincter will relax
this muscle and allow defecation. There are other skeletal muscles involved with these processes but the PSN
play a huge role in continence.
Another role that the PSN play in the pelvis is in sexual activity. In males, the cavernous nerves from the
prostatic plexus stimulate smooth muscle in the fibrous trabeculae of the coiled helicene arteries to relax and
allow blood to fill the corpora cavernosum and the corpus spongiosum of the penis, making it rigid to prepare
for sexual activity. Upon emission of ejaculate, the sympathetics participate and cause peristalsis of the ductus
deferens and closure of the internal urethral sphincter to prevent semen from entering the bladder. At the same
time, parasympathetics cause peristalsis of the urethral muscle, and the pudendal nerve causes contraction of
the bulbospongiosus (skeletal muscle is not via PSN), to forcibly emit the semen. During remission the penis
becomes flaccid again. In the female, there is erectile tissue analogous to the male yet less substantial that
plays a large role in sexual stimulation. The PSN cause release of secretions in the female that decrease
friction. Also in the female, the parasympathetics innervate the fallopian tubes which helps peristaltic
contractions and movement of the oocyte to the uterus for implantation. The secretions from the female genital
tract aids in semen migration. The PSN (and SN to a lesser extent) play a huge role in reproduction.
Clinical Significance
The parasympathetic nervous system promotes digestion and the synthesis of glycogen, and allows for normal
function and behavior.
Receptors
The parasympathetic nervous system uses chiefly acetylcholine (ACh) as its neurotransmitter, although
other peptides (such ascholecystokinin) may act on the PSNS as a neurotransmitter. The ACh acts on two
types of receptors, the muscarinic and nicotiniccholinergic receptors. Most transmissions occur in two stages:
When stimulated, the preganglionic nerve releases ACh at the ganglion, which acts on nicotinic receptors
of postganglionic neurons. The postganglionic nerve then releases ACh to stimulate the muscarinic receptors
of the target organ.
Cerebellum
Brain: Cerebellum

A human brain, with the cerebellum colored in purple

Drawing of the human brain, showing cerebellum and pons

Part of Metencephalon
Artery SCA, AICA, PICA
Vein superior, inferior
NeuroLex ID birnlex_1489
The cerebellum (Latin for little brain) is a region of the brain that plays an important role inmotor control. It is
also involved in some cognitive functions such as attention and language, and probably in
some emotional functions such as regulating fear and pleasure responses.Its movement-related functions are
the most clearly understood, however. The cerebellum does not initiate movement, but it contributes
to coordination, precision, and accurate timing. It receives input from sensory systems and from other parts of
the brain and spinal cord, and integrates these inputs to fine tune motor activity. Because of this fine-tuning
function,damage to the cerebellum does not cause paralysis, but instead produces disorders in fine
movement, equilibrium, posture, and motor learning.
In terms of anatomy, the cerebellum has the appearance of a separate structure attached to the bottom of the
brain, tucked underneath the cerebral hemispheres. The surface of the cerebellum is covered with finely
spaced parallel grooves, in striking contrast to the broad irregular convolutions of the cerebral cortex. These
parallel grooves conceal the fact that the cerebellum is actually a continuous thin layer of neural
tissue (the cerebellar cortex), tightly folded in the style of an accordion. Within this thin layer are several types
of neurons with a highly regular arrangement, the most important being Purkinje cells and granule cells. This
complex neural network gives rise to a massive signal-processing capability, but almost the entirety of its
output is directed to a set of small deep cerebellar nuclei lying in the interior of the cerebellum.
In addition to its direct role in motor control, the cerebellum also is necessary for several types of motor
learning, the most notable one being learning to adjust to changes in sensorimotor relationships. Several
theoretical models have been developed to explain sensorimotor calibration in terms of synaptic
plasticity within the cerebellum. Most of them derive from early models formulated by David Marr and James
Albus, which were motivated by the observation that each cerebellar Purkinje cell receives two dramatically
different types of input: On one hand, thousands of inputs from parallel fibers, each individually very weak; on
the other hand, input from one single climbing fiber, which is, however, so strong that a single climbing fiber
action potential will reliably cause a target Purkinje cell to fire a burst of action potentials. The basic concept of
the Marr-Albus theory is that the climbing fiber serves as a "teaching signal", which induces a long-lasting
change in the strength of synchronously activated parallel fiber inputs. Observations of long-term depression in
parallel fiber inputs have provided support for theories of this type, but their validity remains controversial.
Structure
At the level of large-scale anatomy, the cerebellum consists of a tightly folded and crumpled layer of cortex,
with white matter underneath, several deep nuclei embedded in the white matter, and a fluid-filled ventricle at
the base. At the microscopic level, each part of the cerebellar cortex consists of the same small set of neuronal
elements, laid out with a highly stereotyped geometry. At an intermediate level, the cerebellum and its auxiliary
structures can be decomposed into several hundred or thousand independently functioning modules called
"microzones" or "microcompartments".
Anatomy

Anterior view of the human cerebellum, with numbers indicating salient landmarks
The cerebellum is located at the bottom of the brain, with the large mass of the cerebral cortexabove it and the
portion of the brainstem called the pons in front of it. It is separated from the overlying cerebrum by a layer of
leathery dura mater; all of its connections with other parts of the brain travel through the pons. Anatomists
classify the cerebellum as part of the metencephalon, which also includes the pons; the metencephalon is the
upper part of the rhombencephalon or "hindbrain". Like the cerebral cortex, the cerebellum is divided into two
hemispheres; it also contains a narrow midline zone called the vermis. A set of large folds is, by convention,
used to divide the overall structure into 10 smaller "lobules". Because of its large number of tiny granule cells,
the cerebellum contains more neurons than the rest of the brain put together, but it takes up only 10% of total
brain volume.

Vertical cross-section of the human cerebellum, showing folding pattern of the cortex, and interior structures
The unusual surface appearance of the cerebellum conceals the fact that most of its volume is made up of a
very tightly folded layer of gray matter, the cerebellar cortex. It has been estimated that, if the human cerebellar
cortex were completely unfolded, it would give rise to a layer of neural tissue about 1 meter long and averaging
5 centimeters wide — a total surface area of about 500 square cm, packed within a volume of dimensions 6 cm
× 5 cm × 10 cm. Underneath the gray matter of the cortex lies white matter, made up largely
of myelinated nerve fibers running to and from the cortex. Embedded within the white matter — which is
sometimes called the arbor vitae (Tree of Life) because of its branched, tree-like appearance in cross-section
— are four deep cerebellar nuclei, composed of gray matter.
Subdivisions
Based on surface appearance, three lobes can be distinguished in the cerebellum, called theflocculonodular
lobe, anterior lobe (above the primary fissure), and posterior lobe (below the primary fissure). These lobes
divide the cerebellum from rostral to caudal (in humans, top to bottom). In terms of function, however, there is a
more important distinction along the medial-to-lateral dimension. Leaving out the flocculonodular part, which
has distinct connections and functions, the cerebellum can be parsed functionally into a medial sector called
the spinocerebellum and a larger lateral sector called the cerebrocerebellum. A narrow strip of protruding tissue
along the midline is called the vermis (Latin for "worm").
Cerebellum and surrounding regions; sagittal view of
one hemisphere. A: Midbrain. B: Pons. C: Medulla. Schematic representation of the major anatomical subdivisions of
D: Spinal cord. E:Fourth ventricle. F: Arbor vitae. the cerebellum. Superior view of an "unrolled" cerebellum, placing
G: Tonsil. H: Anterior lobe. I: Posterior lobe. the vermis in one plane.

The smallest region, the flocculonodular lobe, is often called the vestibulocerebellum. It is the oldest part in
evolutionary terms (archicerebellum) and participates mainly in balance and spatial orientation; its primary
connections are with the vestibular nuclei, although it also receives visual and other sensory input. Damage to
it causes disturbances of balance and gait.
The medial zone of the anterior and posterior lobes constitutes the spinocerebellum, also known as
paleocerebellum. This sector of the cerebellum functions mainly to fine-tune body and limb movements. It
receives proprioception input from the dorsal columns of the spinal cord(including the spinocerebellar tract) and
from the trigeminal nerve, as well as from visual and auditory systems. It sends fibres to deep cerebellar nuclei
that, in turn, project to both the cerebral cortex and the brain stem, thus providing modulation of descending
motor systems.
The lateral zone, which in humans is by far the largest part, constitutes the cerebrocerebellum, also known as
neocerebellum. It receives input exclusively from the cerebral cortex (especially the parietal lobe) via
the pontine nuclei (forming cortico-ponto-cerebellar pathways), and sends output mainly to the
ventrolateral thalamus (in turn connected to motor areas of the premotor cortex and primary motor area of the
cerebral cortex) and to the red nucleus. There is disagreement about the best way to describe the functions of
the lateral cerebellum: It is thought to be involved in planning movement that is about to occur, in evaluating
sensory information for action, and in a number of purely cognitive functions as well.
Cellular components

Microcircuitry of the cerebellum. (+): excitatory; (-): inhibitory; MF: Mossy fiber; DCN: Deep cerebellar nuclei; IO: Inferior
olive; CF: Climbing fiber; GC: Granule cell; PF:Parallel fiber; PC: Purkinje cell; GgC: Golgi cell; SC:Stellate cell; BC: Basket
cell
Transverse section of a cerebellar folium, showing principle cell types and connections
Two types of neuron play dominant roles in the cerebellar circuit: Purkinje cells andgranule cells. Three types
of axons also play dominant roles: mossy fibers and climbing fibers (which enter the cerebellum from outside),
and parallel fibers (which are the axons of granule cells). There are two main pathways through the cerebellar
circuit, originating from mossy fibers and climbing fibers, both terminating in the deep cerebellar nuclei.
Mossy fibers project directly to the deep nuclei, but also give rise to the pathway: mossy fiber → granule cells
→ parallel fibers → Purkinje cells → deep nuclei. Climbing fibers project to Purkinje cells and also send
collaterals directly to the deep nuclei. The mossy fiber and climbing fiber inputs each carry fiber-specific
information; the cerebellum also receives dopaminergic, serotonergic, noradrenergic, and cholinergic inputs
that presumably perform global modulation.
The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer, densely packed
with granule cells, along with much smaller numbers of interneurons, mainly Golgi cells. In the middle lies the
Purkinje layer, a narrow zone that contains only the cell bodies of Purkinje cells. At the top lies the molecular
layer, which contains the flattened dendritic trees of Purkinje cells, along with the huge array of parallel fibers
penetrating the Purkinje cell dendritic trees at right angles. This outermost layer of the cerebellar cortex also
contains two types of inhibitory interneurons, stellate cells, and basket cells. Both stellate and basket cells
form GABAergic synapses onto Purkinje cell dendrites.
Purkinje cells
Purkinje cells are among the most distinctive neurons in the brain, and also among the earliest types to be
recognized — they were first described by the Czech anatomist Jan Evangelista Purkyně in 1837. They are
distinguished by the shape of the dendritic tree: The dendrites branch very profusely, but are severely flattened
in a plane perpendicular to the cerebellar folds. Thus, the dendrites of a Purkinje cell form a dense planar net,
through which parallel fibers pass at right angles. The dendrites are covered with dendritic spines, each of
which receives synaptic input from a parallel fiber. Purkinje cells receive more synaptic inputs than any other
type of cell in the brain — estimates of the number of spines on a single human Purkinje cell run as high as
200,000. The large, spherical cell bodies of Purkinje cells are packed into a narrow layer (one cell thick) of the
cerebellar cortex, called thePurkinje layer. After emitting collaterals that innervate nearby parts of the cortex,
their axons travel into the deep cerebellar nuclei, where they make on the order of 1,000 contacts each with
several types of nuclear cells, all within a small domain. Purkinje cells use GABA as their neurotransmitter, and
therefore exert inhibitory effects on their targets.

Drawing of a Purkinje cell from cat cerebellum

Purkinje cells form the heart of the cerebellar circuit, and their large size and distinctive activity patterns have
made it relatively easy to study their response patterns in behaving animals using extracellular recording
techniques. Purkinje cells normally emit action potentials at a high rate even in the absence of synaptic input.
In awake, behaving animals, mean rates averaging around 40 Hz are typical. The spike trains show a mixture
of what are called simple and complex spikes. A simple spike is a single action potential followed by a
refractory period of about 10 msec; a complex spike is a stereotyped sequence of action potentials with very
short inter-spike intervals and declining amplitudes. Physiological studies have shown that complex spikes
(which occur at baseline rates around 1 Hz and never at rates much higher than 10 Hz) are reliably associated
with climbing fiber activation, while simple spikes are produced by a combination of baseline activity and
parallel fiber input. Complex spikes are often followed by a pause of several hundred msec during which simple
spike activity is suppressed.
Granule cells
Cerebellar granule cells, in contrast to Purkinje cells, are among the smallest neurons in the brain. They are
also easily the most numerous neurons in the brain: In humans, estimates of their total number average around
50 billion, which means that about 3/4 of the brain's neurons are cerebellar granule cells. Their cell bodies are
packed into a thick layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites,
each of which ends in an enlargement called a dendritic claw. These enlargements are sites of excitatory input
from mossy fibers and inhibitory input from Golgi cells.

Granule cells, parallel fibers, and Purkinje cells with flattened dendritic trees
The thin, unmyelinated axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where
they split in two, with each branch traveling horizontally to form a parallel fiber; the splitting of the vertical
branch into two horizontal branches gives rise to a distinctive "T" shape. A parallel fiber runs for an average of
3 mm in each direction from the split, for a total length of about 6 mm (about 1/10 of the total width of the
cortical layer). As they run along, the parallel fibers pass through the dendritic trees of Purkinje cells, contacting
one of every 3–5 that they pass, making a total of 80–100 synaptic connections with Purkinje cell dendritic
spines. Granule cells use glutamate as their neurotransmitter, and therefore exert excitatory effects on their
targets.
Granule cells receive all of their input from mossy fibers, but outnumber them 200 to 1 (in humans). Thus, the
information in the granule cell population activity state is the same as the information in the mossy fibers, but
recoded in a much more expansive way. Because granule cells are so small and so densely packed, it has
been very difficult to record their spike activity in behaving animals, so there is little data to use as a basis of
theorizing. The most popular concept of their function was proposed by David Marr, who suggested that they
could encode combinations of mossy fiber inputs. The idea is that with each granule cell receiving input from
only 4–5 mossy fibers, a granule cell would not respond if only a single one of its inputs were active, but would
respond if more than one were active. This combinatorial coding scheme would potentially allow the cerebellum
to make much finer distinctions between input patterns than the mossy fibers alone would permit.
Mossy fibers
Mossy fibers enter the granular layer from their points of origin, many arising from the pontine nuclei, others
from the spinal cord, vestibular nuclei, etc. In the human cerebellum, the total number of mossy fibers has been
estimated at about 200 million. These fibers form excitatory synapses with the granule cells and the cells of the
deep cerebellar nuclei. Within the granular layer, a mossy fiber generates a series of enlargements
called rosettes. The contacts between mossy fibers and granule cell dendrites take place within structures
calledglomeruli. Each glomerulus has a mossy fiber rosette at its center, and up to 20 granule cell dendritic
claws contacting it. Terminals fromGolgi cells infiltrate the structure and make inhibitory synapses onto the
granule cell dendrites. The entire assemblage is surrounded by a sheath of glial cells. Each mossy fiber sends
collateral branches to several cerebellar folia, generating a total of 20–30 rosettes; thus a single mossy fiber
makes contact with an estimated 400–600 granule cells.
Climbing fibers
Purkinje cells also receive input from the inferior olivary nucleus (IO) on the contralateral side of the brainstem,
via climbing fibers. Although the IO lies in the medulla oblongata, and receives input from the spinal cord,
brainstem, and cerebral cortex, its output goes entirely to the cerebellum. A climbing fiber gives off collaterals
to the deep cerebellar nuclei before entering the cerebellar cortex, where it splits into about 10 terminal
branches, each of which innervates a single Purkinje cell. In striking contrast to the 100,000-plus inputs from
parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the
dendrites of the Purkinje cell, winding around them and making a total of up to 300 synapses as it goes. The
net input is so strong that a single action potential from a climbing fiber is capable of producing an extended
complex spike in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a
pause during which activity is suppressed. The climbing fiber synapses cover the cell body and proximal
dendrites; this zone is devoid of parallel fiber inputs.
Climbing fibers fire at low rates, but a single climbing fiber action potential induces a burst of several action
potentials in a target Purkinje cell (a complex spike). The contrast between parallel fiber and climbing fiber
inputs to Purkinje cells (over 100,000 of one type versus exactly one of the other type) is perhaps the most
provocative feature of cerebellar anatomy, and has motivated much of the theorizing. In fact, the function of
climbing fibers is the most controversial topic concerning the cerebellum. There are two schools of thought, one
following Marr and Albus in holding that climbing fiber input serves primarily as a teaching signal, the other
holding that its function is to shape cerebellar output directly. Both views have been defended in great length in
numerous publications. In the words of one review, "In trying to synthesize the various hypotheses on the
function of the climbing fibers, one has the sense of looking at a drawing by Escher. Each point of view seems
to account for a certain collection of findings, but when one attempts to put the different views together, a
coherent picture of what the climbing fibers are doing does not appear. For the majority of researchers, the
climbing fibers signal errors in motor performance, either in the usual manner of discharge frequency
modulation or as a single announcement of an 'unexpected event'. For other investigators, the message lies in
the degree of ensemble synchrony and rhythmicity among a population of climbing fibers."
Deep nuclei

Cross-section of human cerebellum, showing the dentate nucleus, as well as the pons and inferior olivary nucleus
The deep nuclei of the cerebellum are clusters of gray matter lying within the white matter at the core of the
cerebellum. They are, with the minor exception of the nearby vestibular nuclei, the sole sources of output from
the cerebellum. These nuclei receive collateral projections from mossy fibers and climbing fibers, as well as
inhibitory input from the Purkinje cells of the cerebellar cortex. The three nuclei (dentate, interpositus, and
fastigial) each communicate with different parts of the brain and cerebellar cortex. The fastigial and interpositus
nuclei belong to the spinocerebellum. The dentate nucleus, which in mammals is much larger than the others,
is formed as a thin, convoluted layer of gray matter, and communicates exclusively with the lateral parts of the
cerebellar cortex. The flocculonodular lobe is the only part of the cerebellar cortex that does not project to the
deep nuclei — its output goes to the vestibular nuclei instead.
The majority of neurons in the deep nuclei have large cell bodies and spherical dendritic trees with a radius of
about 400 μm, and use glutamate as their neurotransmitter. These cells project to a variety of targets outside
the cerebellum. Intermixed with them is a lesser number of small cells, which use GABA as neurotransmitter
and project exclusively to the inferior olivary nucleus, the source of climbing fibers. Thus, the nucleo-olivary
projection provides an inhibitory feedback to match the excitatory projection of climbing fibers to the nuclei.
There is evidence that each small cluster of nuclear cells projects to the same cluster of olivary cells that send
climbing fibers to it; there is strong and matching topography in both directions.
When a Purkinje cell axon enters one of the deep nuclei, it branches to make contact with both large and small
nuclear cells, but the total number of cells contacted is only about 35 (in cats). On the converse, a single deep
nuclear cell receives input from approximately 860 Purkinje cells (again in cats).
Compartmentalization
Schematic illustration of the structure of zones and microzones in the cerebellar cortex
From the viewpoint of gross anatomy, the cerebellar cortex appears to be a homogeneous sheet of tissue, and,
from the viewpoint of microanatomy, all parts of this sheet appear to have the same internal structure. There
are, however, a number of respects in which the structure of the cerebellum is compartmentalized. There are
large compartments that are generally known as zones; these can be decomposed into smaller compartments
known asmicrozones.
The first indications of compartmental structure came from studies of the receptive fields of cells in various
parts of the cerebellum cortex. Each body part maps to specific points in the cerebellum, but there are
numerous repetitions of the basic map, forming an arrangement that has been called "fractured somatotopy". A
clearer indication of compartmentalization is obtained by immunostaining the cerebellum for certain types of
protein. The best-known of these markers are called "zebrins", because staining for them gives rise to a
complex pattern reminiscent of the stripes on a zebra. The stripes generated by zebrins and other
compartmentalization markers are oriented perpendicular to the cerebellar folds — that is, they are narrow in
the mediolateral direction, but much more extended in the longitudinal direction. Different markers generate
different sets of stripes, and the widths and lengths vary as a function of location, but they all have the same
general shape.
Oscarsson in the late 1970s proposed that these cortical zones can be partitioned into smaller units called
microzones. A microzone is defined as a group of Purkinje cells all having the same somatotopic receptive
field. Microzones were found to contain on the order of 1000 Purkinje cells each, arranged in a long, narrow
strip, oriented perpendicular to the cortical folds. Thus, as the adjoining diagram illustrates, Purkinje cell
dendrites are flattened in the same direction as the microzones extend, while parallel fibers cross them at right
angles.
It is not only receptive fields that define the microzone structure: The climbing fiber input from the inferior
olivary nucleus is equally important. The branches of a climbing fiber (usually numbering about 10) usually
innervate Purkinje cells belonging to the same microzone. Moreover, olivary neurons that send climbing fibers
to the same microzone tend to be coupled by gap junctions, which synchronize their activity, causing Purkinje
cells within a microzone to show correlated complex spike activity on a millisecond time scale. Also, the
Purkinje cells belonging to a microzone all send their axons to the same small cluster of output cells within
the deep cerebellar nuclei. Finally, the axons of basket cells are much longer in the longitudinal direction than
in the mediolateral direction, causing them to be confined largely to a single microzone. The consequence of all
this structure is that cellular interactions within a microzone are much stronger than interactions between
different microzones.
In 2005, Richard Apps and Martin Garwicz summarized evidence that microzones themselves form part of a
larger entity they call a multizonal microcomplex. Such a microcomplex includes several spatially separated
cortical microzones, all of which project to the same group of deep cerebellar neurons, plus a group of coupled
olivary neurons that project to all of the included microzones as well as to the deep nuclear area.
Function
The strongest clues to the function of the cerebellum have come from examining the consequences of damage
to it. Animals and humans with cerebellar dysfunction show, above all, problems with motor control. They
continue to be able to generate motor activity, but it loses precision, producing erratic, uncoordinated, or
incorrectly timed movements. A standard test of cerebellar function is to reach with the tip of the finger for a
target at arm's length: A healthy person will move the fingertip in a rapid straight trajectory, whereas a person
with cerebellar damage will reach slowly and erratically, with many mid-course corrections. Deficits in non-
motor functions are more difficult to detect. Thus, the general conclusion reached decades ago is that the basic
function of the cerebellum is not to initiate movements, or to decide which movements to execute, but rather to
calibrate the detailed form of a movement.
Prior to the 1990s, the function of the cerebellum was almost universally believed to be purely motor-related,
but newer findings have brought that view strongly into question. Functional imaging studies have shown
cerebellar activation in relation to language, attention, and mental imagery; correlation studies have shown
interactions between the cerebellum and non-motoric areas of the cerebral cortex; and a variety of non-motor
symptoms have been recognized in people with damage that appears to be confined to the cerebellum.
Kenji Doya has argued that the function of the cerebellum is best understood not in terms of what behaviors it
is involved in but rather in terms of what neural computations it performs; the cerebellum consists of a large
number of more or less independent modules, all with the same geometrically regular internal structure, and
therefore all, it is presumed, performing the same computation. If the input and output connections of a module
are with motor areas (as many are), then the module will be involved in motor behavior; but, if the connections
are with areas involved in non-motor cognition, the module will show other types of behavioral correlates. The
cerebellum, Doya proposes, is best understood as a device for supervised learning, in contrast to the basal
ganglia, which perform reinforcement learning, and the cerebral cortex, which performs unsupervised learning.
Principles
The comparative simplicity and regularity of the cerebellar anatomy led to an early hope that it might imply a
similar simplicity of computational function, as expressed in one of the first books on cerebellar
electrophysiology, The Cerebellum as a Neuronal Machine byJohn C. Eccles, Masao Ito, and Janos
Szentágothai. Although a full understanding of cerebellar function has remained elusive, at least four principles
have been identified as important: (1) feedforward processing, (2) divergence and convergence, (3) modularity,
and (4) plasticity.
1. Feedforward processing: The cerebellum differs from most other parts of the brain (especially the cerebral
cortex) in that the signal processing is almost entirely feedforward - that is, signals move unidirectionally
through the system from input to output, with very little recurrent internal transmission. The small amount of
recurrence that does exist consists of mutual inhibition; there are no mutually excitatory circuits. This
feedforward mode of operation means that the cerebellum, in contrast to the cerebral cortex, cannot generate
self-sustaining patterns of neural activity. Signals enter the circuit, are processed by each stage in sequential
order, and then leave. As Eccles, Ito, and Szentágothai wrote, "This elimination in the design of all possibility of
reverberatory chains of neuronal excitation is undoubtedly a great advantage in the performance of the
cerebellum as a computer, because what the rest of the nervous system requires from the cerebellum is
presumably not some output expressing the operation of complex reverberatory circuits in the cerebellum but
rather a quick and clear response to the input of any particular set of information."
2. Divergence and convergence: In the human cerebellum, information from 200 million mossy fiber inputs is
expanded to 40 billiongranule cells, whose parallel fiber outputs then converge onto 15 million Purkinje
cells. Because of the way that they are lined up longitudinally, the 1000 or so Purkinje cells belonging to a
microzone may receive input from as many as 100 million parallel fibers, and focus their own output down to a
group of less than 50 deep nuclear cells. Thus, the cerebellar network receives a modest number of inputs,
processes them very extensively through its rigorously structured internal network, and sends out the results
via a very limited number of output cells.
3. Modularity: The cerebellar system is functionally divided into more or less independent modules, which
probably number in the hundreds to thousands. All modules have a similar internal structure, but different
inputs and outputs. A module (a multizonal microcompartment in the terminology of Apps and Garwicz)
consists of a small cluster of neurons in the inferior olivary nucleus, a set of long narrow strips of Purkinje cells
in the cerebellar cortex (microzones), and a small cluster of neurons in one of the deep cerebellar nuclei.
Different modules share input from mossy fibers and parallel fibers, but in other respects they appear to
function independently — the output of one module does not appear to significantly influence the activity of
other modules.
4. Plasticity: The synapses between parallel fibers and Purkinje cells, and the synapses between mossy fibers
and deep nuclear cells, are both susceptible to modification of their strength. In a single cerebellar module,
input from as many as a billion parallel fibers converges onto a group of less than 50 deep nuclear cells, and
the influence of each parallel fiber on those nuclear cells is adjustable. This arrangement gives tremendous
flexibility for fine-tuning the relationship between cerebellar inputs and outputs.
Learning
There is considerable evidence that the cerebellum plays an essential role in some types of motor learning.
The tasks where the cerebellum most clearly comes into play are those in which it is necessary to make fine
adjustments to the way an action is performed. There has, however, been much dispute about whether
learning takes place within the cerebellum itself, or whether it merely serves to provide signals that promote
learning in other brain structures. Most theories that assign learning to the circuitry of the cerebellum are
derived from early ideas of David Marr and James Albus, who postulated that climbing fibers provide a
teaching signal that induces synaptic modification inparallel fiber—Purkinje cell synapses. Marr assumed that
climbing fiber input would cause synchronously activated parallel fiber inputs to be strengthened. Most later
cerebellar-learning models, however, have followed Albus in assuming that climbing fiber activity would be
anerror signal, and would cause synchronously activated parallel fiber inputs to be weakened. Some of these
later models, such as theAdaptive Filter model of Fujita made attempts to understand cerebellar function in
terms of optimal control theory.
The idea that climbing fiber activity functions as an error signal has been examined in many experimental
studies, with some supporting it but others casting doubt. In a pioneering study by Gilbert and Thach from
1977, Purkinje cells from monkeys learning a reaching task showed increased complex spike activity — which
is known to reliably indicate activity of the cell's climbing fiber input — during periods when performance was
poor. Several studies of motor learning in cats observed complex spike activity when there was a mismatch
between an intended movement and the movement that was actually executed. Studies of the vestibulo-ocular
reflex (which stabilizes the visual image on the retina when the head turns) found that climbing fiber activity
indicated "retinal slip", although not in a very straightforward way.
One of the most extensively studied cerebellar learning tasks is the eyeblink conditioning paradigm, in which a
neutral conditioned stimulus such as a tone or a light is repeatedly paired with an unconditioned stimulus, such
as an air puff, that elicits a blink response. After such repeated presentations of the CS and US, the CS will
eventually elicit a blink before the US, a conditioned response or CR. Experiments showed that lesions
localized either to a specific part of the interpositus nucleus (one of the deep cerebellar nuclei or to a few
specific points in the cerebellar cortex would abolish learning of a correctly timed blink response. If cerebellar
outputs are pharmacologically inactivated while leaving the inputs and intracellular circuits intact, learning takes
place even while the animal fails to show any response, whereas, if intracerebellar circuits are disrupted, no
learning takes place — these facts taken together make a strong case that the learning, indeed, occurs inside
the cerebellum.
Theories and computational models

Model of a cerebellar perceptron, as formulated by James Albus

The large base of knowledge about the anatomical structure and behavioral functions of the cerebellum have
made it a fertile ground for theorizing — there are perhaps more theories of the function of the cerebellum than
of any other part of the brain. The most basic distinction among them is between "learning theories" and
"performance theories" — that is, theories that make use of synaptic plasticity within the cerebellum to account
for its role in learning, versus theories that account for aspects of ongoing behavior on the basis of cerebellar
signal processing. Several theories of both types have been formulated as mathematical models and simulated
using computers.
Perhaps the earliest "performance" theory was the "delay line" hypothesis of Valentino Braitenberg. The
original theory put forth by Braitenberg and Atwood in 1958 proposed that slow propagation of signals along
parallel fibers imposes predictable delays that allow the cerebellum to detect time relationships within a certain
window. Experimental data did not support the original form of the theory, but Braitenberg continued to argue
for modified versions. The hypothesis that the cerebellum functions essentially as a timing system has also
been advocated by Richard Ivry. Another influential "performance" theory is the Tensor Network Theory of
Pellionisz and Llinás, which provided an advanced mathematical formulation of the idea that the fundamental
computation performed by the cerebellum is to transform sensory into motor coordinates.
Theories in the "learning" category almost all derive from early publications by David Marr and James
Albus. Marr's 1969 paper proposed that the cerebellum is a device for learning to associate elemental
movements encoded by climbing fibers with mossy fiber inputs that encode the sensory context. Albus
proposed that a cerebellar Purkinje cell functions as a perceptron, a neurally inspired abstract learning device.
The most basic difference between the Marr and Albus theories is that Marr assumed that climbing fiber activity
would cause parallel fiber synapses to be strengthened, whereas Albus proposed that they would be
weakened. Albus also formulated his version as a software algorithm he called a CMAC (Cerebellar Model
Articulation Controller), which has been tested in a number of applications.
Pathology

Altered walking gait of a woman with cerebellar disease

The most salient symptoms of cerebellar dysfunction are motor-related — the specific symptoms depend on
which part of the cerebellum is involved and how it is disrupted. Damage to the flocculonodular lobe
(the vestibular part) may show up as a loss of equilibrium and, in particular, an altered walking gait, with a wide
stance that indicates difficulty in balancing. Damage to the midline portion may disrupt whole-body movements,
whereas damage localized more laterally is more likely to disrupt fine movements of the hands or limbs.
Damage to the upper part of the cerebellum tends to cause gait impairments and other problems with leg
coordination; damage to the lower part is more likely to cause uncoordinated or poorly aimed movements of the
arms and hands, as well as difficulties in speed. This complex of motor symptoms is called "ataxia". To identify
cerebellar problems, the neurological examination includes assessment of gait (a broad-based gait being
indicative of ataxia), finger-pointing tests and assessment of posture. If cerebellar dysfunction is indicated,
a magnetic resonance imaging scan can be used to obtain a detailed picture of any structural alterations that
may exist.

The lower trace shows an attempt by a patient with cerebellar disease to reproduce the upper trace.
The list of medical problems that can produce cerebellar damage is long: it includes stroke; hemorrhage;
tumors; alcoholism; physical trauma such as gunshot wounds; and chronic degenerative conditions such
as olivopontocerebellar atrophy. Some forms of migraine headache may also produce temporary dysfunction of
the cerebellum, of variable severity.
Aging
The human cerebellum changes with age. These changes may differ from those of other parts of the brain, for
example the gene expression pattern in the human cerebellum shows less age-related alteration than in
the cerebral cortex. Some studies have reported reductions in numbers of cells or volume of tissue, but the
amount of data relating to this question is not very large.
Ataxia
Ataxia (from Greek α- [used as a negative prefix] + -τάξις [order], meaning "lack of order") is
a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a
non-specific clinical manifestation implying dysfunction of the parts of thenervous system that coordinate
movement, such as the cerebellum. Several possible causes exist for these patterns of neurological
dysfunction. The term "dystaxia" is a rarely-used synonym.
The International Ataxia Awareness Day is observed on September 25 each year.
Types
Cerebellar
The term cerebellar ataxia is employed to indicate ataxia that is due to dysfunction of the cerebellum. This
causes a variety of elementary neurological deficits, such as
antagonist hypotonia, asynergy, dysmetria, dyschronometria, and dysdiadochokinesia. How and where these
abnormalities manifest themselves depends on which cerebellar structures have been damaged, and whether
the lesion is bilateral or unilateral.
 Dysfunction of the vestibulocerebellum impairs the balance and the control of eye movements.
This presents itself with postural instability, in which the person tends to separate his/her feet upon
standing, in order to gain a wider base and to avoid bodily oscillations (especially forward-backward ones).
The instability is therefore worsened when standing with the feet together, regardless of whether the eyes
are open or closed. This is a negative Romberg's test], or more accurately, it denotes the individual's
inability to carry out the test, because the individual feels unstable even with open eyes).
 Dysfunction of the spinocerebellum presents itself with a wide-based "drunken sailor" gait,
characterised by uncertain start and stop, lateral deviations, and unequal steps. This part of the cerebellum
regulates body and limb movements.
 Dysfunction of the cerebrocerebellum presents with disturbances in carrying out voluntary, planned
movements. These include:
 intention tremor (coarse trembling, accentuated over the execution of voluntary movements,
possibly involving the head and eyes as well as the limbs and torso);
 peculiar writing abnormalities (large, unequal letters, irregular underlining);
 a peculiar pattern of dysarthria (slurred speech, sometimes characterised by explosive
variations in voice intensity despite a regular rhythm).
Sensory
The term sensory ataxia is employed to indicate ataxia due to loss of proprioception - the loss of sensitivity to
the positions of joint and body parts. This is generally caused by dysfunction of the dorsal columns of the spinal
cord, because they carry proprioceptive information up to the brain. In some cases, the cause of sensory ataxia
may instead be dysfunction of the various parts of the brain which receive positional information, including the
cerebellum, thalamus, and parietal lobes.
Sensory ataxia presents itself with an unsteady "stomping" gait with heavy heel strikes, as well as a postural
instability that is usually worsened when the lack of proprioceptive input cannot be compensated for by visual
input, such as in poorly lit environments.
Physicians can find evidence of sensory ataxia during physical examination by having the patient stand with
his/her feet together and eyesshut. In affected patients, this will cause the instability to worsen markedly,
producing wide oscillations and possibly a fall. This is called a positive Romberg's test. Worsening of the finger-
pointing test with the eyes closed is another feature of sensory ataxia. Also, when the patient is standing with
arms and hands extended toward the physician, if the eyes are closed, the patient's finger will tend to "fall
down" and then be restored to the horizontal extended position by sudden muscular contractions (the "ataxic
hand").
Vestibular
The term vestibular ataxia is employed to indicate ataxia due to dysfunction of the vestibular system, which in
acute and unilateral cases is associated with prominent vertigo, nausea and vomiting. In slow-onset, chronic
bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent,
and dysequilibrium may be the sole presentation.
Causes
The three types of ataxia have overlapping causes, and therefore can either coexist or occur in isolation.
Focal lesions
Any type of focal lesion of the central nervous system (such as stroke, brain tumour, multiple sclerosis) will
cause the type of ataxia corresponding to the site of the lesion: cerebellar if in the cerebellum, sensory if in the
dorsal spinal cord (and rarely in the thalamus orparietal lobe), vestibular if in the vestibular system (including
the vestibular areas of the cerebral cortex).
Exogenous substances
Exogenous substances that cause ataxia mainly do so because they have a depressant effect on central
nervous system function. The most common example is ethanol, that is, alcohol, which is capable of causing
reversible cerebellar and vestibular ataxia. Other examples include various prescription drugs (e.g.
most antiepileptic drugs have cerebellar ataxia as a possible adverse effect), Lithium level over
1.5mEq/L,cannabis ingestion and various other recreational drugs (e.g. ketamine, PCP or dextromethorphan,
all of which are NMDA receptor antagonists that produce a dissociative state at high doses). Exposure to high
levels of methylmercury, through consumption of fish with high mercury concentrations, is also a known cause
of ataxia and other neurological disorders
Vitamin B12 deficiency
Vitamin B12 deficiency may cause, among several neurological abnormalities, overlapping cerebellar and
sensory ataxia.
Causes of isolated sensory ataxia
Peripheral neuropathies may cause generalised or localised sensory ataxia (e.g. a limb only) depending on the
extent of the neuropathic involvement. Spinal disorders of various types may cause sensory ataxia from the
lesioned level below, when they involve the dorsal columns.
Non-hereditary cerebellar degeneration
Non-hereditary causes of cerebellar degeneration include chronic ethanol abuse, paraneoplastic cerebellar
degeneration, high altitude cerebral oedema, coeliac disease, normal pressure hydrocephalus and cerebellitis.
Hereditary ataxias
Ataxia may depend on hereditary disorders consisting of degeneration of the cerebellum and/or of the spine;
most cases feature both to some extent, and therefore present with overlapping cerebellar and sensory ataxia,
even though one is often more evident than the other. Hereditary disorders causing ataxia include autosomal
dominant ones such as spinocerebellar ataxia, episodic ataxia, anddentatorubropallidoluysian atrophy, as well
as autosomal recessive disorders such as Friedreich's ataxia (sensory and cerebellar, with the former
predominating) and Niemann Pick disease, ataxia-telangiectasia (sensory and cerebellar, with the latter
predominating), andabetalipoproteinaemia. An example of X-linked ataxic condition is the rare fragile X-
associated tremor/ataxia syndrome.
Arnold-Chiari Malformation
Arnold-Chiari malformation is a malformation of the brain. It consists of a downward displacement of
the cerebellar tonsils and the medullathrough the foramen magnum, sometimes causing hydrocephalus as a
result of obstruction of cerebrospinal fluid outflow.
Treatment
The movement disorders related to ataxia are primarily treated with physical therapy. As ataxia involves a loss
of coordinated and efficient action of stabilising muscles in the trunk, exercise training typically includes a focus
on stability exercise. There is often an array of other motor deficits requiring exercise treatment including
weakness, balance impairment and decreased endurance. It is also possible that treatment will include
strategies to manage difficulties with everyday activities, such as a cane or walker to decrease the risk of falls
associated with a balance impairment, or prescription of a wheelchair.
Aphasia
Aphasia from the Greek root word "aphatos", meaning speechless, is an acquired language disorder in which
there is an impairment of any language modality. This may include difficulty in producing or comprehending
spoken or written language.
Traditionally, aphasia suggests the total impairment of language ability, and dysphasia a degree of impairment
less than total. However, the term dysphasia is commonly confused withdysphagia, a swallowing disorder, and
thus aphasia has come to mean both partial and total language impairment in common use.
Depending on the area and extent of brain damage, someone suffering from aphasia may be able to speak but
not write, or vice versa, or display any of a wide variety of other deficiencies in language comprehension and
production, such as being able to sing but not speak. Aphasia may co-occur with speech disorders such
as dysarthria or apraxia of speech, which also result from brain damage.
Aphasia can be assessed in a variety of ways, from quick clinical screening at the bedside to several-hour-long
batteries of tasks that examine the key components of language and communication. The prognosis of those
with aphasia varies widely, and is dependent upon age of the patient, site and size of lesion, and type of
aphasia.
Classification
Classifying the different subtypes of aphasia is difficult and has led to disagreements among experts. The
localizationist model is the original model, but modern anatomical techniques and analyses have shown that
precise connections between brain regions and symptom classification don't exist. The neural organization of
language is complicated; language is a comprehensive and complex behavior and it makes sense that it isn't
the product of some small, circumscribed region of the brain.
No classification of patients in subtypes and groups of subtypes is adequate. Only about 60% of patients will fit
in a classification scheme such as fluent/nonfluent/pure aphasias. There is a huge variation among patients
with the same diagnosis, and aphasias can be highly selective. For instance, patients with naming deficits
(anomic aphasia) might show an inability only for naming buildings, or people, or colors.
Localizationist model

Cortex
The localizationist model attempts to classify the aphasia by major characteristics and then link these to areas
of the brain in which the damage has been caused. The initial two categories here were devised by early
neurologists working in the field, namely Paul Broca and Carl Wernicke. Other researchers have added to the
model, resulting in it often being referred to as the "Boston-Neoclassical Model". The most prominent writers on
this topic have been Harold Goodglass andEdith Kaplan.
 Individuals with Broca's aphasia (also termed expressive aphasia) were once thought to have ventral
temporal damage, though more recent work by Dr. Nina Dronkers using imaging and 'lesion analysis' has
revealed that patients with Broca's aphasia have lesions to the medial insular cortex. Broca missed these
lesions because his studies did not dissect the brains of diseased patients, so only the more temporal
damage was visible. Dronkers and Dr. Odile Plaisant scanned Broca's original patients' brains using a non-
invasive MRI scanner to take a closer look. Individuals with Broca's aphasia often have right-sided
weakness or paralysis of the arm and leg, because the frontal lobe is also important for body movement.
 In contrast to Broca's aphasia, damage to the temporal lobe may result in a fluent aphasia that is
called Wernicke's aphasia (also termedsensory aphasia). These individuals usually have no body
weakness, because their brain injury is not near the parts of the brain that control movement.
 Working from Wernicke's model of aphasia, Ludwig Lichtheim proposed five other types of aphasia,
but these were not tested against real patients until modern imaging made more indepth studies available.
The other five types of aphasia in the localizationist model are:
1. Pure word deafness
2. Conduction aphasia
3. Apraxia of speech, which is now considered a separate disorder in itself.
4. Transcortical motor aphasia
5. Transcortical sensory aphasia
 Anomia is another type of aphasia proposed under what is commonly known as the Boston-
Neoclassical model, which is essentially a difficulty with naming. A final type of aphasia, global aphasia,
results from damage to extensive portions of the perisylvian region of the brain.
Other ways to Classify Aphasia
Fluent, non-fluent and "pure" aphasias
The different types of aphasia can be divided into three categories: fluent, non-fluent and "pure" aphasias.
 Fluent aphasias, also called receptive aphasias, are impairments related mostly to the input or
reception of language, with difficulties either in auditory verbal comprehension or in the repetition of words,
phrases, or sentences spoken by others. Speech is easy and fluent, but there are difficulties related to the
output of language as well, such as paraphasia. Examples of fluent aphasias are: Wernicke's
aphasia, Transcortical sensory aphasia, Conduction aphasia, Anomic aphasia
 Nonfluent aphasias, also called expressive aphasias are difficulties in articulating, but in most cases
there is relatively good auditory verbal comprehension. Examples of nonfluent aphasias are: Broca's
aphasia, Transcortical motor aphasia, Global aphasia
 "Pure" aphasias are selective impairments in reading, writing, or the recognition of words. These
disorders may be quite selective. For example, a person is able to read but not write, or is able to write but
not read. Examples of pure aphasias are: Pure alexia, Agraphia,Pure word deafness
Primary and secondary aphasia
Aphasia can be divided into primary and secondary aphasia.
 Primary aphasia is due to problems with language-processing mechanisms.
 Secondary aphasia is the result of other problems, like memory impairments, attention disorders, or
perceptual problems.
Cognitive neuropsychological model
The cognitive neuropsychological model builds on cognitive neuropsychology. It assumes that language
processing can be broken down into a number of modules, each of which has a specific function. Hence there
is a module which recognises phonemes as they are spoken and a module which stores formulated phonemes
before they are spoken. Use of this model clinically involves conducting a battery of assessments (usually from
the PALPA), each of which tests one or a number of these modules. Once a diagnosis is reached as to where
the impairment lies, therapy can proceed to treat the individual module.
Signs and symptoms
People with aphasia may experience any of the following behaviors due to an acquired brain injury, although
some of these symptoms may be due to related or concomitant problems such as dysarthria or apraxia and not
primarily due to aphasia.
 inability to comprehend language
 inability to pronounce, not due to muscle paralysis or weakness
 inability to speak spontaneously
 inability to form words
 inability to name objects
 poor enunciation
 excessive creation and use of personal neologisms
 inability to repeat a phrase
 persistent repetition of phrases
 paraphasia (substituting letters, syllables or words)
 agrammatism (inability to speak in a grammatically correct fashion)
 dysprosody (alterations in inflexion, stress, and rhythm)
 incompleted sentences
 inability to read
 inability to write
 limited verbal output
 difficulty in naming
The following table summarizes some major characteristics of different types of aphasia:
Type of Auditory
Repetition Naming Fluency Presentation
aphasia comprehension
Individuals with Wernicke's
aphasia may speak in long
sentences that have no
meaning, add unnecessary
Wernicke's mild– fluent
mild–mod defective words, and even create new
aphasia severe paraphasic
"words" (neologisms). For
example, someone with
Wernicke's aphasia may say,
"You know that smoodle
 pinkered and that I want to get
him round and take care of him
like you want before", meaning
"The dog needs to go out so I
will take him for a walk". They
have poor auditory and reading
comprehension, and fluent, but
nonsensical, oral and written
expression. Individuals with
Wernicke's aphasia usually have
great difficulty understanding the
speech of both themselves and
others and are therefore often
unaware of their mistakes.
Transcortical Similar deficits as in Wernicke's
mod–
sensory good poor fluent aphasia, but repetition ability
severe
aphasia remains intact.
Conduction aphasia is caused
by deficits in the connections
between the speech-
comprehension and speech-
production areas. This might be
damage to the arcuate
fasciculus, the structure that
transmits information between
Conduction
poor poor relatively good fluent Wernicke's area and Broca's
aphasia
area. Similar symptoms,
however, can be present after
damage to the insula or to
the auditory cortex. Auditory
comprehension is near normal,
and oral expression is fluent
with occasional paraphasic
errors. Repetition ability is poor.
Anomic aphasia, is essentially a
difficulty with naming. The
patient may have difficulties
naming certain words, linked by
their grammatical type (e.g.
difficulty naming verbs and not
nouns) or by
Nominal or
mod– their semanticcategory (e.g.
Anomic mild mild fluent
severe difficulty naming words relating
aphasia
to photography but nothing else)
or a more general naming
difficulty. Patients tend to
produce grammatic, yet empty,
speech. Auditory
comprehension tends to be
preserved.
Individuals with Broca's aphasia
frequently speak short,
meaningful phrases that are
produced with great effort.
non-fluent,
Broca's mod– Broca's aphasia is thus
mod–severe mild difficulty effortful,
aphasia severe characterized as a nonfluent
slow
aphasia. Affected people often
omit small words such as "is",
"and", and "the". For example, a
person with Broca's aphasia
 may say, "Walk dog" which
could mean "I will take the dog
for a walk", "You take the dog
for a walk" or even "The dog
walked out of the yard".
Individuals with Broca's aphasia
are able to understand the
speech of others to varying
degrees. Because of this, they
are often aware of their
difficulties and can become
easily frustrated by their
speaking problems. It is
associated with
right hemiparesis, meaning that
there can be paralysis of the
patient's right face and arm.
Similar deficits as Broca's
aphasia, except repetition ability
remains intact. Auditory
comprehension is generally fine
Transcortical for simple conversations, but
mild–
motor good mild non-fluent declines rapidly for more
severe
aphasia complex conversations. It is
associated with right
hemiparesis, meaning that there
can be paralysis of the patient's
right face and arm.
Individuals with global aphasia
have severe communication
difficulties and will be extremely
limited in their ability to speak or
comprehend language. They
Global may be totally nonverbal, and/or
poor poor poor non-fluent
aphasia only use facial expressions and
gestures to communicate. It is
associated with right
hemiparesis, meaning that there
can be paralysis of the patient's
right face and arm.
Mixed Similar deficits as in global
transcortical moderate poor poor non-fluent aphasia, but repetition ability
aphasia remains intact.
Characteristics and symptoms
depend upon the site and size of
Subcortical subcortical lesion. Possible sites
aphasias of lesions include the thalamus,
internal capsule, and basal
ganglia.
Jargon aphasia is a fluent or receptive aphasia in which the patient's speech is incomprehensible, but appears
to make sense to them. Speech is fluent and effortless with intact syntax and grammar, but the patient has
problems with the selection of nouns. They will either replace the desired word with another that sounds or
looks like the original one, or has some other connection, or they will replace it withsounds. Accordingly,
patients with jargon aphasia often use neologisms, and may perseverate if they try to replace the words they
can't find with sounds.
Commonly, substitutions involve picking another (actual) word starting with the same sound (e.g. clocktower -
colander), picking another semantically related to the first (e.g. letter - scroll), or picking one phonetically similar
to the intended one (e.g. lane - late).
Causes
Aphasia usually results from lesions to the language-relevant areas of the frontal, temporal and parietal lobes
of the brain, such as Broca's area, Wernicke's area, and the neural pathways between them. These areas are
almost always located in the left hemisphere, and in most people this is where the ability to produce and
comprehend language is found. However, in a very small number of people, language ability is found in the
right hemisphere. In either case, damage to these language areas can be caused by a stroke, traumatic brain
injury, or otherbrain injury. Aphasia may also develop slowly, as in the case of a brain tumor or
progressive neurological disease, e.g., Alzheimer's orParkinson's disease. It may also be caused by a
sudden hemorrhagic event within the brain. Certain chronic neurological disorders, such
asepilepsy or migraine, can also include transient aphasia as a prodromal or episodic symptom. Aphasia is
also listed as a rare side effect of the fentanyl patch, an opioid used to control chronic pain.
Treatment
There is no one treatment proven to be effective for all types of aphasias. Melodic intonation therapy is often
used to treat non-fluent aphasia and has proved to be very effective in some cases.
Apraxia
Apraxia is a disorder caused by damage to specific areas of the cerebrum, characterized by loss of the ability
to execute or carry out learned purposeful movements, despite having the desire and the physical ability to
perform the movements. It is a disorder of motor planningwhich may be acquired or developmental, but may
not be caused by incoordination, sensory loss, or failure to comprehend simple commands (which can be
tested by asking the person to recognize the correct movement from a series). Apraxia should not be confused
with aphasia, an inability to produce and/or comprehend language; abulia, the lack of desire to carry out an
action; or allochiria, in which patients perceive stimuli to one side of the body as occurring on the other.
The root word of apraxia is praxis, Greek for an act, work, or deed. It is preceded by a privative a,
meaning without.
Types
There are several types of apraxia including:
 ideomotor (inability to carry out a motor command; for example, "act as if you are brushing your teeth"
or "salute") - the form most frequently encountered by physicians;
 limb apraxia when movements of the arms and legs are involved;
 nonverbal-oral or buccofacial (inability to carry out facial movements on command; e.g.,
lick lips, whistle, cough, or wink);
 ideational (inability to create a plan for or idea of a specific movement; for example, "pick up this pen
and write down your name");
 limb-kinetic (inability to make fine, precise movements with a limb);
 verbal (difficulty planning the movements necessary for speech), also known as Apraxia of Speech
(see below);
 constructional (inability to draw or construct simple configurations), such as intersecting pentagons;
 oculomotor (difficulty moving the eye, especially with saccade movements).
 gait apraxia
Each type may be tested at decreasing levels of complexity; if the person tested fails to execute the
commands, you can make the movement yourself and ask that the person mimic it, or you can even give them
a real object (like a toothbrush) and ask them to use it.
Apraxia may be accompanied by a language disorder called aphasia.
Apraxia of speech
Symptoms of Acquired Apraxia of speech (AOS) and Childhood Apraxia of Speech (CAS) include inconsistent
articulatory errors, groping oral movements to locate the correct articulatory position, and increasing errors with
increasing word and phrase length. AOS often co-occurs with Oral Apraxia (during both speech and non-
speech movements) and Limb Apraxia.
Childhood Apraxia of Speech (CAS) presents in children who have no evidence of difficulty with strength or
range of motion of the articulators, but are unable to execute speech movements because of motor planning
and coordination problems. This is not to be confused with phonological impairments in children with normal
coordination of the articulators during speech.
Acquired apraxia of speech involves the loss of previously acquired speech levels. It occurs in both children
and adults who have (prior to the onset of apraxia) acquired some level of speaking ability. Unlike Childhood
Apraxia of Speech, AOS is typically the result of a stroke, tumor, or other known neurological illness or injury.
Causes
Ideomotor apraxia is almost always caused by lesions in the language-dominant (usually left) hemisphere of
the brain; and, as such, these patients often have concomitant aphasia, especially of
the Broca or conduction type. Left-side ideomotor apraxia may be caused by a lesion of the anterior corpus
callosum.
Ideational apraxia is commonly associated with confusion states and dementia.
Constructional apraxia is associated with hepatic encephalopathy due to cerebral edema.
Treatment
Recommended treatment for individuals with apraxia includes physical therapy, occupational
therapy and/or speech therapy.
Prognosis
The prognosis for individuals with apraxia varies. With therapy, some patients improve significantly, while
others may show very little improvement. Some individuals with apraxia may benefit from the use of
a communication aid.
Alexia
Alexia is a type ofaphasia where damage to the brain causes a patient to lose the ability to read. It is also
called word blindness, text blindness or visual aphasia.
Those who suffer from "alexia" and "dyslexia" can have similar difficulties, however, "alexia" refers to an
acquired reading disability, where reading ability had previously been developed, usually occurring in adulthood
conditions, while "dyslexia" refers to developmental reading disability.
Classification
There are two groups of alexia.
 The first or main group is "the central dyslexia" group which includes surface dyslexia, semantic
dyslexia, phonological dyslexia, anddeep dyslexia.
 The second group, "the peripheral dyslexia" group, includes neglect dyslexia, attentional dyslexia,
and pure alexia which is also known as alexia without agraphia.
Causes
Alexia typically occurs following damage to the left hemisphere of the brain or to the areas of
the occipital and parietal lobes, which are responsible for processing auditory, phonological and visual aspects
of language. The region at the junction of occipital and temporal lobes (sometimes called the occipito-temporal
junction) coordinates information that is gathered from visual and auditory processing and assigns meaning to
the stimulus. Alexia can also occur following damage to the inferior frontal. Damage to these different areas of
the cortex result in somewhat different patterns of difficulty in affected individuals. In some cases, a stroke can
cause alexia.
Presentation
Alexia may be accompanied by expressive and/or receptive aphasia (the inability to produce or comprehend
spoken language). Alexia can also co-occur with agraphia, the specific loss of the ability to produce written
language even when other manual motor abilities are intact. In other cases, damage is restricted to areas
responsible for input processing. The result is known as pure alexia. In this scenario, an individual's ability to
produce written language is spared even though they are unable to understand written text.
Alexia without agraphia results from a left occipital splenium of the corpus callosum lesion.
Dementia
Dementia (taken from Latin, originally meaning "madness", from de- "without" + ment, the root of mens "mind")
is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from
normal aging. It may be static, the result of a unique global brain injury, or progressive, resulting in long-term
decline due to damage or disease in the body. Although dementia is far more common in
the geriatric population, it may occur in any stage of adulthood.
The overwhelming factor emerging from genetic studies of the dementias and other central nervous system
neurodegenerative conditions is abnormalities of protein handling.
This age cutoff is defining, as similar sets of symptoms due to organic brain syndrome or dysfunction, are given
different names in populations younger than adult. Up to the end of the nineteenth century, dementia was a
much broader clinical concept. Well into the second half of the twentieth century, dementia of the elderly was
called senile dementia or senilityand viewed as a normal aspect of growing old rather than as being caused
by any specific diseases, while Alzheimer's disease was seen as a rare disease of middle age, until the
neurologist Robert Katzmann signaled a link between "senile dementia" and Alzheimer's.
Dementia is a non-specific illness syndrome (set of signs and symptoms) in which affected areas of cognition
may be memory, attention,language, and problem solving. It is normally required to be present for at least 6
months to be diagnosed; cognitive dysfunction that has been seen only over shorter times, in particular less
than weeks, must be termed delirium. In all types of general cognitive dysfunction, higher mental functions are
affected first in the process.
Especially in the later stages of the condition, affected persons may be disoriented in time (not knowing what
day of the week, day of the month, or even what year it is), in place (not knowing where they are), and in
person (not knowing who they are or others around them). Dementia, though often treatable to some degree, is
usually due to causes that are progressive and incurable.
Symptoms of dementia can be classified as either reversible or irreversible, depending upon the etiology of the
disease. Less than 10% of cases of dementia are due to causes that may presently be reversed with treatment.
Causes include many different specific disease processes, in the same way that symptoms of organ
dysfunction such as shortness of breath, jaundice, or pain are attributable to many etiologies.
Without careful assessment of history, the short-term syndrome of delirium (often lasting days to weeks) can
easily be confused with dementia, because they have all symptoms in common, save duration. Some mental
illnesses, including depression and psychosis, may also produce symptoms that must be differentiated from
both delirium and dementia.
Chronic use of substances such as alcohol can also predispose the patient to cognitive changes suggestive of
dementia, although moderate intake may have a protective effect.
Signs and symptoms
Comorbidities
Dementia is not merely a problem of memory. It reduces the ability to learn, reason, retain or recall past
experience and there is also loss of patterns of thoughts, feelings and activities (Gelder et al 2005). Additional
mental and behavioral problems often affect people who have dementia, and may influence quality of life,
caregivers, and the need for institutionalization.As dementia worsens individuals may neglect themselves and
may become disinhibited,the individual may become incontinent as their condition worsens (Gelder et al 2005).
Depression affects 20–30% of people who have dementia, and about 20% have anxiety. Psychosis (often
delusions of persecution) and agitation/aggression also often accompany dementia. Each of these needs to be
assessed and treated independent of the underlying dementia.
Risk to self and others
The Canadian Medical Association Journal has reported that driving with dementia could lead to severe injury
or even death to self and others. Doctors should advise appropriate testing on when to quit driving.
In the United States, Florida's Baker Act allows law enforcement and the judiciary to force mental evaluation for
those suspected of suffering from dementia or other mental incapacities.
In the United Kingdom, as with all mental disorders, where a sufferer could potentially be a danger to
themselves or others, they can be detained under the Mental Health Act 1983 for the purposes of assessment,
care and treatment. This is a last resort, and usually avoided if the patient has family or friends who can ensure
care.
The United Kingdom DVLA (Driving & Vehicle Licensing Agency) states that dementia sufferers who
specifically suffer with poor short term memory, disorientation, lack of insight or judgment are almost certainly
not fit to drive—and in these instances, the DVLA must be informed so said license can be revoked. They do
however acknowledge low-severity cases and early sufferers, and those drivers may be permitted to drive
pending medical report.
Causes
Fixed cognitive impairment
Various types of brain injury, occurring as a single event, may cause irreversible but fixed cognitive
impairment. Traumatic brain injury may cause generalized damage to the white matter of the brain (diffuse
axonal injury), or more localized damage (as also may neurosurgery). A temporary reduction in the brain's
supply of blood or oxygen may lead to hypoxic-ischemic injury. Strokes (ischemic stroke, or intracerebral,
subarachnoid, subdural or extradural hemorrhage) or infections (meningitis and/or encephalitis) affecting the
brain, prolonged epilepticseizures and acute hydrocephalus may also have long-term effects on cognition.
Excessive alcohol use may cause alcohol dementia,Wernicke's encephalopathy and/or Korsakoff's psychosis,
and certain other recreational drugs may cause substance-induced persisting dementia; once overuse ceases,
the cognitive impairment is persistent but not progressive.
Slowly progressive dementia
Dementia which begins gradually and worsens progressively over several years is usually caused
by neurodegenerative disease; that is, by conditions affecting only or primarily the neurons of the brain and
causing gradual but irreversible loss of function of these cells. Less commonly, a non-degenerative condition
may have secondary effects on brain cells, which may or may not be reversible if the condition is treated.
The causes of dementia depend on the age at which symptoms begin. In the elderly population (usually
defined in this context as over 65 years of age), a large majority of cases of dementia are caused
by Alzheimer's disease, vascular dementia or both. Dementia with Lewy bodies is another fairly common
cause, which again may occur alongside either or both of the other causes. Hypothyroidismsometimes causes
slowly progressive cognitive impairment as the main symptom, and this may be fully reversible with
treatment. Normal pressure hydrocephalus, though relatively rare, is important to recognize since treatment
may prevent progression and improve other symptoms of the condition. However, significant cognitive
improvement is unusual.
Dementia is much less common under 65 years of age. Alzheimer's disease is still the most frequent cause,
but inherited forms of the disease account for a higher proportion of cases in this age group. Frontotemporal
lobar degeneration and Huntington's disease account for most of the remaining cases. Vascular dementia also
occurs, but this in turn may be due to underlying conditions (includingantiphospholipid
syndrome, CADASIL, MELAS, homocystinuria, moyamoya and Binswanger's disease). People who receive
frequent head trauma, such as boxers or some martial artists, are at risk of dementia pugilistica.
In young adults (up to 40 years of age) who were previously of normal intelligence, it is very rare to develop
dementia without other features of neurological disease, or without features of disease elsewhere in the body.
Most cases of progressive cognitive disturbance in this age group are caused by psychiatric illness, alcohol or
other drugs, or metabolic disturbance. However, certain genetic disorders can cause true neurodegenerative
dementia at this age. These include familial Alzheimer's
disease, SCA17 (dominant inheritance); adrenoleukodystrophy (X-linked); Gaucher's disease type
3, metachromatic leukodystrophy, Niemann-Pick disease type C, pantothenate kinase-associated
neurodegeneration, Tay-Sachs disease and Wilson's disease (all recessive). Wilson's disease is particularly
important since cognition can improve with treatment.
At all ages, a substantial proportion of patients who complain of memory difficulty or other cognitive symptoms
are suffering from depressionrather than a neurodegenerative disease. Vitamin deficiencies and chronic
infections may also occur at any age; they usually cause other symptoms before dementia occurs, but
occasionally mimic degenerative dementia. These include deficiencies of vitamin B12, folate or niacin, and
infective causes including cryptococcal meningitis, HIV, Lyme disease, progressive multifocal
leukoencephalopathy, subacute sclerosing panencephalitis, syphilis and Whipple's disease.
Rapidly progressive dementia
Creutzfeldt-Jakob disease typically causes a dementia which worsens over weeks to months, being caused
by prions. The common causes of slowly progressive dementia also sometimes present with rapid
progression: Alzheimer's disease, dementia with Lewy bodies,frontotemporal lobar
degeneration (including corticobasal degeneration and progressive supranuclear palsy).
On the other hand, encephalopathy or delirium may develop relatively slowly and resemble dementia. Possible
causes include brain infection (viral encephalitis, subacute sclerosing panencephalitis, Whipple's disease) or
inflammation (limbic encephalitis, Hashimoto's encephalopathy, cerebral vasculitis); tumors such
as lymphoma or glioma; drug toxicity (e.g. anticonvulsant drugs); metabolic causes such as liver
failure or kidney failure; and chronic subdural hematoma.
Dementia as a feature of other conditions
There are many other medical and neurological conditions in which dementia only occurs late in the illness, or
as a minor feature. For example, a proportion of patients with Parkinson's disease develop dementia, though
widely varying figures are quoted for this proportion. When dementia occurs in Parkinson's disease, the
underlying cause may be dementia with Lewy bodies orAlzheimer's disease, or both. Cognitive impairment also
occurs in the Parkinson-plus syndromes of progressive supranuclear palsy andcorticobasal degeneration (and
the same underlying pathology may cause the clinical syndromes of frontotemporal lobar degeneration).
Chronic inflammatory conditions of the brain may affect cognition in the long term, including Behçet's
disease, multiple sclerosis,sarcoidosis, Sjögren's syndrome and systemic lupus erythematosus. Although the
acute porphyrias may cause episodes of confusion and psychiatric disturbance, dementia is a rare feature of
these rare diseases.
Aside from those mentioned above, inherited conditions which may cause dementia alongside other features
include:
 Alexander disease
 Canavan disease
 Cerebrotendinous xanthomatosis
 DRPLA
 Fragile X-associated tremor/ataxia syndrome
 Glutaric aciduria type 1
 Krabbe's disease
 Maple syrup urine disease
 Niemann Pick disease type C
 Kufs' disease
 Neuroacanthocytosis
 Organic acidemias
 Pelizaeus-Merzbacher disease
 Urea cycle disorders
 Sanfilippo syndrome type B
 Spinocerebellar ataxia type 2
Diagnosis
Proper differential diagnosis between the types of dementia (cortical and subcortical) will require, at the least,
referral to a specialist, e.g., a geriatric internist, geriatric psychiatrist, neurologist, neuropsychologist or
geropsychologist. Duration of symptoms must evident for at least six months for a diagnosis of dementia or
organic brain syndrome to be made (ICD-10).
Cognitive testing
There exist some brief tests (5–15 minutes) Sensitivity and specificity of common tests for dementia
that have reasonable reliability and can be
used in the office or other setting to screen Test Sensitivity Specificity Reference
cognitive status. Examples of such tests MMSE 71%-92% 56%-96%
include theabbreviated mental test
score (AMTS), the mini mental state 3MS 83%-93.5% 85%-90%
examination (MMSE), Modified Mini-Mental
AMTS 73%-100% 71%-100%
State Examination (3MS), the Cognitive
Abilities Screening Instrument (CASI), and
the clock drawing test. Scores must be interpreted in the context of the person's educational and other
background, and the particular circumstances; for example, a person highly depressed or in great pain will not
be expected to do well on many tests of mental ability.
While many tests have been studied, and some may emerge as better alternatives to the MMSE, presently the
MMSE is the best studied and most commonly used.
Another approach to screening for dementia is to ask an informant (relative or other supporter) to fill out a
questionnaire about the person's everyday cognitive functioning. Informant questionnaires provide
complementary information to brief cognitive tests. Probably the best known questionnaire of this sort is
the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). On the other hand the General
Practitioner Assessment Of Cognition combines both, a patient assessment and an informant interview. It was
specifically designed for the use in the primary care setting and is also available as a web-based test. It can be
accessed at www.gpcog.com.au.
Further evaluation includes retesting at another date, and administration of other tests of mental function.
Laboratory tests
Routine blood tests are also usually performed to rule out treatable causes. These tests include vitamin
B12, folic acid, thyroid-stimulating hormone (TSH), C-reactive protein, full blood
count, electrolytes, calcium, renal function, and liver enzymes. Abnormalities may suggestvitamin
deficiency, infection or other problems that commonly cause confusion or disorientation in the elderly. The
problem is complicated by the fact that these cause confusion more often in persons who have early dementia,
so that "reversal" of such problems may ultimately only be temporary.
Testing for alcohol and other known dementia-inducing drugs may be indicated.
Imaging
A CT scan or magnetic resonance imaging (MRI scan) is commonly performed, although these modalities do
not have optimal sensitivity for the diffuse metabolic changes associated with dementia in a patient that shows
no gross neurological problems (such as paralysis or weakness) on neurological exam. CT or MRI may
suggest normal pressure hydrocephalus, a potentially reversible cause of dementia, and can yield information
relevant to other types of dementia, such as infarction (stroke) that would point at a vascular type of dementia.
The functional neuroimaging modalities of SPECT and PET are more useful in assessing long-standing
cognitive dysfunction, since they have shown similar ability to diagnose dementia as a clinical exam. The ability
of SPECT to differentiate the vascular cause from the Alzheimer's disease cause of dementias, appears to be
superior to differentiation by clinical exam.
Recent research has established the value of PET imaging using carbon-11 Pittsburgh Compound B as a
radiotracer (PIB-PET) in predictive diagnosis of various kinds of dementia, in particular Alzheimer's disease.
Studies from Australia have found PIB-PET to be 86% accurate in predicting which patients with mild cognitive
impairment would develop Alzheimer's disease within two years. In another study, carried out using 66 patients
seen at the University of Michigan, PET studies using either PIB or another radiotracer, carbon-11
dihydrotetrabenazine (DTBZ), led to more accurate diagnosis for more than one-fourth of patients with mild
cognitive impairment or mild dementia.
Prevention
It appears that the regular moderate consumption of alcohol (beer, wine, or distilled spirits) and
a Mediterranean diet may reduce risk. A study has shown a link between high blood pressure and developing
dementia. The study, published in the Lancet Neurology journal July 2008, found that blood pressure lowering
medication reduced dementia by 13%.
Brain-derived neurotrophic factor (BDNF) expression is associated with some dementia types.
A Canadian study found that a lifetime of bilingualism delays the onset of dementia by an average of four years
when compared tomonolingual patients.
Management
Except for the treatable types listed above, there is no cure to this illness. Cholinesterase inhibitors are often
used early in the disease course. Cognitive and behavioral interventions may also be appropriate. Educating
and providing emotional support to the caregiver (or carer) is of importance as well (see also elderly care).
Pain and dementia
As they age, people experience more health problems, and most health problems associated with aging carry a
substantial burden of pain; so, between 25% and 50% of older adults experience persistent pain. Seniors with
dementia experience the same prevalence of conditions likely to cause pain as seniors without dementia. Pain
is often overlooked in older adults and, when screened for, often poorly assessed, especially among those with
dementia. Beyond the issue of humane care, unrelieved pain has functional implications. Persistent pain can
lead to decreased ambulation, depressed mood, sleep disturbances, impaired appetite and exacerbation of
cognitive impairment, and pain-related interference with activity is a factor contributing to falls in the elderly.
Although persistent pain in the person with dementia is difficult to communicate, diagnose and treat, failure to
address persistent pain has profound functional, psychosocial and quality of life implications for this vulnerable
population. Health professionals often lack the skills and usually lack the time needed to recognize, accurately
assess and adequately monitor pain in people with dementia. Family members and friends can make a
valuable contribution to the care of a person with dementia by learning to recognize and assess their pain.
Educational resources (such as the Understand Pain and Dementia tutorial) and observational assessment
tools are available.
Medications
 Acetylcholinesterase inhibitors: Tacrine (Cognex), donepezil (Aricept), galantamine (Razadyne),
and rivastigmine (Exelon) are approved by the United States Food and Drug Administration (FDA) for
treatment of dementia induced by Alzheimer's disease. They may be useful for other similar diseases
causing dementia such as Parkinsons or vascular dementia.
 N-methyl-D-aspartate Blockers. Memantine (Namenda) is a drug representative of this class. It can be
used in combination with acetylcholinesterase inhibitors.
Off label
 Amyloid deposit inhibitors: Minocycline and Clioquinoline, antibiotics, may help
reduce amyloid deposits in the brains of persons with Alzheimer's disease.
 Antidepressant drugs: Depression is frequently associated with dementia and generally worsens the
degree of cognitive and behavioralimpairment. Antidepressants effectively treat the cognitive and
behavioral symptoms of depression in patients with Alzheimer's disease, but evidence for their use in other
forms of dementia is weak.
 Anxiolytic drugs: Many patients with dementia experience anxiety symptoms.
Although benzodiazepines like diazepam (Valium) have been used for treating anxiety in other situations,
they are often avoided because they may increase agitation in persons with dementia and are likely to
worsen cognitive problems or are too sedating. Buspirone (Buspar) is often initially tried for mild-to-
moderate anxiety. There is little evidence for the effectiveness of benzodiazepines in dementia, whereas
there is evidence for the effectivess of antipsychotics (at low doses).
 Selegiline, a drug used primarily in the treatment of Parkinson's disease, appears to slow the
development of dementia. Selegiline is thought to act as an antioxidant, preventing free radical damage.
However, it also acts as a stimulant, making it difficult to determine whether the delay in onset of dementia
symptoms is due to protection from free radicals or to the general elevation of brain activity from the
stimulant effect.
 Antipsychotic drugs: Both typical antipsychotics (such as Haloperidol) and atypical antipsychotics such
as (risperidone) increase the risk of death in dementia-associated psychosis. This means that any use of
antipsychotic medication for dementia-associated psychosis is off-label and should only be considered
after discussing the risks and benefits of treatment with these drugs, and after other treatment modalities
have failed. In the UK around 144,000 dementia sufferers are unnecessarily prescribed antipsychotic
drugs, around 2000 patients die as a result of taking the drugs each year.
Services
Adult daycare centers as well as special care units in nursing homes often provide specialized care for
dementia patients. Adult daycare centers offer supervision, recreation, meals, and limited health care to
participants, as well as providing respite for caregivers.
While some preliminary studies have found that music therapy may be useful in helping patients with dementia,
their quality has been low and no reliable conclusions can be drawn from them.
Epidemiology

Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2002.
no data ≤ 50 50-70 70-90 90-110 110-130 130-150 150-170 170-190 190-210 210-230 230-250 ≥ 250
In a study issued by European researchers, it is estimated that about 35 million people have dementia
worldwide. They said that figure is likely to double every 20 years, to nearly 66 million in 2030 and 115 million
in 2050.
Alzheimer's disease

Alzheimer's disease (AD)—also called Alzheimer disease, senile dementia of the Alzheimer
type (SDAT), primary degenerative dementia of the Alzheimer's type(PDDAT), or Alzheimer's—is the
most common form of dementia. This incurable, degenerative, and terminal disease was first described by
German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, it is
diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much
earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people
globally by 2050.
Although the course of Alzheimer's disease is unique for every individual, there are many common
symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or
manifestations of stress. In the early stages, the most commonly recognised symptom is inability to acquire
new memories, such as difficulty in recalling recently observed facts. When AD is suspected, the diagnosis is
usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan if available.
As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language
breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses
decline. Gradually, bodily functions are lost, ultimately leading to death.Individual prognosis is difficult to
assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming
fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is
approximately seven years. Fewer than three percent of individuals live more than fourteen years after
diagnosis.
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the
disease is associated with plaquesand tangles in the brain. Currently used treatments offer a small
symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available. As of
2008, more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it
is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive,
life-style habits have been suggested for the prevention of Alzheimer's disease, but there is a lack of adequate
evidence for a link between these recommendations and reduced degeneration. Mental stimulation, exercise,
and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.
Because AD cannot be cured and is degenerative, management of patients is essential. The role of the
main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a
great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and
economic elements of the caregiver's life. In developed countries, AD is one of the most costly diseases to
society.
Characteristics
The disease course is divided into four stages, with progressive patterns
of cognitive and functional impairments.
Pre-dementia
The first symptoms are often mistaken as related to aging or stress. Detailed neuropsychological testing can
reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of
AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is
memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new
information.
Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or
impairments in semantic memory(memory of meanings, and concept relationships), can also be symptomatic
of the early stages of AD. Apathy can be observed at this stage, and remains the most
persistent neuropsychiatric symptom throughout the course of the disease. The preclinical stage of the disease
has also been termed mild cognitive impairment, but whether this term corresponds to a different diagnostic
stage or identifies the first step of AD is a matter of dispute.
Early
In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis.
In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of
movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities
equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit
memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser
degree than new facts or memories.
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which
lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is
usually capable of adequately communicating basic ideas. While performing fine motor tasks such as writing,
drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they
are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks
independently, but may need assistance or supervision with the most cognitively demanding activities.
Moderate
Progressive deterioration eventually hinders independence; with subjects being unable to perform most
common activities of daily living.Speech difficulties become evident due to an inability to recall vocabulary,
which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also
progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so
the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise
close relatives. Long-term memory, which was previously intact, becomes impaired.
Behavioural and neuropsychiatric changes become more prevalent. Common manifestations
are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or
resistance to caregiving. Sundowning can also appear. Approximately 30% of patients develop illusionary
misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and
limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and
caretakers, which can be reduced by moving the person from home care to other long-term care facilities.
Advanced
During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to
simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal
language abilities, patients can often understand and return emotional signals. Although aggressiveness can
still be present, extreme apathy and exhaustion are much more common results. Patients will ultimately not be
able to perform even the most simple tasks without assistance. Muscle mass and mobility deteriorate to the
point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness with the
cause of death typically being an external factor such as infection of pressure ulcers or pneumonia, not the
disease itself.
Causes

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylatedtau protein

Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most
currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused
by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained
widespread support, largely because medications intended to treat acetylcholine deficiency have not been very
effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation
of amyloid, leading to generalised neuroinflammation.
In 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the
disease. Support for this postulate comes from the location of the gene for theamyloid beta precursor
protein (APP) on chromosome 21, together with the fact that people withtrisomy 21 (Down Syndrome) who
have an extra gene copy almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk
factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition
precedes clinical AD.Further evidence comes from the finding that transgenic mice that express a mutant form
of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial
learning deficits.
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any
significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of
many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-
derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the
synapse, thereby disrupting neuronal communication. One receptor for Aβ oligomers may be the prion protein,
the same protein that has been linked to mad cow disease and the related human condition,Creutzfeldt-Jakob
disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of
Alzheimer's disease.
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not
necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-
related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be
triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-
APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by
one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called
death receptor 6 (DR6, also known asTNFRSF21). DR6 is highly expressed in the human brain regions most
affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to
cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss. This
observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. In
this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they
form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing
the neuron's transport system. This may result first in malfunctions in biochemical communication between
neurons and later in the death of the cells. Herpes simplex virus type 1 has also been proposed to play a
causative role in people carrying the susceptible versions of the apoE gene.
Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain.
Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released
during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes
contribute to the development of proteinaceous deposits such as amyloid-beta and tau.
Oxidative stress is a significant cause in the formation of the pathology.
AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its
neurotransmitter role) that locally diffuses from "varicosities" as an endogenous antiinflammatory agent in the
microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has
been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines
and their phagocytosis of Aβ. This suggests that degeneration of the locus ceruleus might be responsible for
increased Aβ deposition in AD brains.
Pathophysiology

Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset.
Silver impregnation.
Neuropathology
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain
subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in
the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Studies
using MRI and PET have documented reductions in the size of specific brain regions in patients as they
progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from
healthy older adults.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by
AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptideand cellular material outside and
around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau
which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older
individuals develop some plaques and tangles as a consequence of aging, the brains of AD patients have a
greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in AD
patient's brains.
Biochemistry
Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the
formation of senile plaques in AD.
Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation
of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino
acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger
protein called amyloid precursor protein (APP), atransmembrane protein that penetrates through the neuron's
membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an
unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of
these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense
formations known as senile plaques.

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has
a cytoskeleton, an internal support structure partly made up of structures called microtubules. These
microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of
the axon and back. A protein called tau stabilizes the microtubules whenphosphorylated, and is therefore called
a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it
then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport
system.
Disease mechanism
Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology
of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as
the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are
believed to be the toxic form of the protein responsible for disrupting the cell's calciumion homeostasis,
induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in
the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation
of glucose by neurons.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's
disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to
tissue damage in AD or a marker of an immunological response.
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as
the brain derived neurotrophic factor (BDNF) have been described in AD.
Genetics
The vast majority of cases of Alzheimer's disease are sporadic, meaning that they are not genetically inherited
although some genes may act as risk factors. On the other hand, around 0.1% of the cases are familial forms
of autosomal-dominant inheritance, which usually have an onset before age 65.
Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid
precursor protein (APP) andpresenilins 1 and 2. Most mutations in the APP and presenilin genes increase the
production of a small protein called Aβ42, which is the main component of senile plaques. Some of the
mutations merely alter the size ratio between Aβ42 and the other major forms—e.g., Aβ40—without increasing
Aβ42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of
Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its
fragments other than Aβ.
Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD.
Nevertheless genetic differences may act as risk factors. The best known genetic risk factor is the inheritance
of the ε4 allele of the apolipoprotein E(APOE). Between 40 and 80% of patients with AD possess at least one
apoE4 allele. The APOE4 allele increases the risk of the disease by three times in heterozygotes and by 15
times in homozygotes. Geneticists agree that numerous other genes also act as risk factors or have protective
effects that influence the development of late onset Alzheimer's disease. Over 400 genes have been tested for
association with late-onset sporadic AD, most with null results.
Diagnosis

PET scan of the brain of a person with AD showing a loss of function in the temporal lobe
Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and
clinical observations, based on the presence of characteristic neurological andneuropsychological features and
the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic
resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron
emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of
dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to
Alzheimer's disease.
Assessment of intellectual functioning including memory testing can further characterise the state of the
disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process
for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain
material is available and can be examined histologically.[8
Criteria
The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and theAlzheimer's
Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established
the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984,[8 extensively updated in
2007.[8 These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome,
be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD.
A histopathologicconfirmation including a microscopic examination of brain tissue is required for a definitive
diagnosis. Good statistical reliability and validityhave been shown between the diagnostic criteria and definitive
histopathological confirmation.[8 Eight cognitive domains are most commonly impaired in AD—
memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional
abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.[8[8
Techniques

Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the
one shown in the picture, remember words, read, and subtract serial numbers.
Neuropsychological tests such as the mini-mental state examination (MMSE), are widely used to evaluate the
cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability
of results, particularly in the earliest stages of the disease.[8[8 Neurological examination in early AD will usually
provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from
other diseases processes, including other causes of dementia.
Further neurological examinations are crucial in the differential diagnosis of AD and other diseases.Interviews
with family members are also utilised in the assessment of the disease. Caregivers can supply important
information on the daily living abilities, as well as on the decrease, over time, of the person's mental function. A
caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his
own deficits.[8 Many times, families also have difficulties in the detection of initial dementia symptoms and may
not communicate accurate information to a physician.[8
Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau
proteins,[8 both total tau protein and phosphorylated tau181P protein concentrations. Searching for these proteins
using a spinal tap can predict the onset of Alzheimer's with a sensitivity of between 94% and 100%. When used
in conjunction with existing neuroimaging techniques, doctors can identify patients with significant memory loss
who are already developing the disease.Spinal fluid tests are commercially available, unlike the latest
neuroimaging technology. Alzheimer's was diagnosed in one-third of the people who did not have any
symptoms in a 2010 study, meaning that disease progression occurs well before symptoms occur.
Supplemental testing provides extra information on some features of the disease or is used to rule out other
diagnoses. Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be
reversible. It is common to perform thyroid function tests, assess B12, rule out syphillis, rule out metabolic
problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals
(e.g. lead, mercury) and anemia. (See differential diagnosis for Dementia). (It is also necessary to rule
outdelirium).
Psychological tests for depression are employed, since depression can either be concurrent with AD, an early
sign of cognitive impairment, or even the cause.
Imaging
When available as a diagnostic tool, single photon emission computed tomography (SPECT) and positron
emission tomography (PET) neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with
evaluations involving mental status examination. In a person already having dementia, SPECT appears to be
superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts
employing mental testing and medical history analysis. Advances have led to the proposal of new diagnostic
criteria.[8
A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid
deposits in vivo using a tracer thatbinds selectively to the A-beta deposits. The PiB-PET compound
uses carbon-11 PET scanning. Recent studies suggest that PiB-PET is 86% accurate in predicting which
people with mild cognitive impairment will develop Alzheimer's disease within two years, and 92% accurate in
ruling out the likelihood of developing Alzheimer's.0
A similar PET scanning radiopharmaceutical compound called (E)-4-(2-(6-(2-(2-(2-(8F]-
18
fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine, or F AV-45, or florbetapir-fluorine-18,
or simply florbetapir, contains the longer-lasting radionuclide fluorine-18, has recently been created, and tested
as a possible diagnostic tool in Alzheimer's patients.0000 Florbetapir, like PiB, binds to beta-amyloid, but due to
its use of fluorine-18 has a half-life of 110 minutes, in contrast to PiB's radioactive half life of 20 minutes.
Wong et al.found that the longer life allowed the tracer to accumulate significantly more in the brains of the AD
patients, particularly in the regions known to be associated with beta-amyloid deposits.0
One review predicted that amyloid imaging is likely to be used in conjunction with other markers rather than as
an alternative.0
Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during
the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive
than other imaging methods currently under study.0
Recent studies suggest that brain metabolite levels may be utilized as biomarkers for Alzheimer's disease. 0
Prevention

Intellectual activities such as playingchess or regular social interaction have been linked to a reduced risk of AD in
epidemiological studies, although no causal relationship has been found.
At present, there is no definitive evidence to support that any particular measure is effective in preventing
AD.0 Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results.
However, epidemiological studies have proposed relationships between certain modifiable factors, such as
diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's
likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can
help to prevent AD.0
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are
associated with a higher risk of onset and course of AD, 11 statins, which arecholesterol lowering drugs, have
not been effective in preventing or improving the course of the disease. 11 The components of a Mediterranean
diet, which include fruit and vegetables,bread, wheat and other cereals, olive oil, fish, and red wine, may all
individually or together reduce the risk and course of Alzheimer's disease.1 Its beneficial cardiovascular effect
has been proposed as the mechanism of action.1 There is limited evidence that light to moderate use of
alcohol, particularly red wine, is associated with lower risk of AD.1
Reviews on the use of vitamins have not found enough evidence of efficacy to recommend vitamin C,1 E,11 or
folic acid with or without vitamin B12,1 as preventive or treatment agents in AD. Additionally vitamin E is
associated with important health risks.1 Trials examining folic acid (B9) and other B vitamins failed to show any
significant association with cognitive decline.1 Docosahexaenoic acid, an Omega 3 fatty acid, has not been
found to slow decline.2
Long-term usage of non-steroidal anti-inflammatory drug (NSAIDs) is associated with a reduced likelihood of
developing AD.2 Humanpostmortem studies, in animal models, or in vitro investigations also support the notion
that NSAIDs can reduce inflammation related to amyloid plaques. 2 However trials investigating their use as
palliative treatment have failed to show positive results while no prevention trial has been
completed.2 Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain
damage in mouse modelsdue to its anti-inflammatory properties.22 Hormone replacement therapy, although
previously used, is no longer thought to prevent dementia and in some cases may even be related to it. 22 There
is inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and
dementia,2 and a recent study concludes that it has no effect in reducing the rate of AD incidence. 2A 21-year
study found that coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-
life.2
People who engage in intellectual activities such as reading, playing board games, completing crossword
puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's
disease.2 This is compatible with the cognitive reservetheory, which states that some life experiences result in
more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia
manifestations.2 Education delays the onset of AD syndrome, but is not related to earlier death after
diagnosis.3 Physical activity is also associated with a reduced risk of AD.3
Some studies have shown an increased risk of developing AD with environmental factors such the intake
of metals, particularlyaluminium,33 or exposure to solvents.3 The quality of some of these studies has been
criticised,3 and other studies have concluded that there is no relationship between these environmental factors
and the development of AD.3333
While some studies suggest that Extremely low frequency electromagnetic fields may increase the risk for
Alzheimer's disease, reviewers found that further epidemiological and laboratory investigations of this
hypothesis are needed.3 Smoking is a significant AD risk factor.4Systemic markers of the innate immune
system are risk factors for late-onset AD.4
Management
There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but
remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and
caregiving.
Pharmaceutical

Three-dimensional molecular model ofdonepezil, an acetylcholinesterase inhibitorused in the treatment of AD symptoms

Molecular structure of memantine, a medication approved for advanced AD symptoms

Four medications are currently approved by regulatory agencies such as the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) to treat the cognitive manifestations of AD:
three are acetylcholinesterase inhibitors and the other is memantine, anNMDA receptor antagonist. No drug
has an indication for delaying or halting the progression of the disease.
Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's
disease.4 Acetylcholinesterase inhibitors are employed to reduce the rate at whichacetylcholine (ACh) is broken
down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the
death of cholinergic neurons.4 As of 2008, the cholinesterase inhibitors approved for the management of AD
symptoms are donepezil (brand name Aricept),4 galantamine (Razadyne),4 and rivastigmine (branded
as Exelon4 andExelon Patch4). There is evidence for the efficacy of these medications in mild to moderate
Alzheimer's disease,44 and some evidence for their use in the advanced stage. Only donepezil is approved for
treatment of advanced AD dementia.5 The use of these drugs in mild cognitive impairment has not shown any
effect in a delay of the onset of AD.5 The most common side effects are nausea and vomiting, both of which are
linked to cholinergic excess. These side effects arise in approximately 10–20% of users and are mild to
moderate in severity. Less common secondary effects include muscle cramps, decreased heart
rate (bradycardia), decreased appetite and weight, and increased gastric acid production.5
Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in
the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of
glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological
diseases such as Parkinson's disease and multiple sclerosis.5 Memantine (brand
5
names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda), is a noncompetitive NMDA receptor
antagonist first used as an anti-influenza agent. It acts on theglutamatergic system by blocking NMDA
receptors and inhibiting their overstimulation by glutamate.5 Memantine has been shown to be moderately
efficacious in the treatment of moderate to severe Alzheimer's disease. Its effects in the initial stages of AD are
unknown.5 Reported adverse events with memantine are infrequent and mild,
including hallucinations,confusion, dizziness, headache and fatigue.5 The combination of memantine and
donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".5
Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer's patients with
behavioural problems, but are associated with serious adverse effects, such
as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine
use.55 When used in the long-term, they have been shown to associate with increased mortality.5
Medical marijuana appears to be effective in delaying Alzheimer's Disease. The active ingredient in
marijuana, THC, prevents the formation of deposits in the brain associated with Alzheimer's disease. THC was
found to inhibit acetylcholinesterase more effectively than commercially marketed drugs. THC was also found
to delay amylogenesis.66
Psychosocial intervention

A specifically designed room for sensory integration therapy, also called snoezelen; an emotion-oriented psychosocial
intervention for people with dementia
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within
behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and
rarely specific to AD, focusing instead on dementia in general.6
Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem
behaviours. This approach has not shown success in improving overall functioning, 6but can help to reduce
some specific problem behaviours, such as incontinence.6 There is a lack of high quality data on the
effectiveness of these techniques in other behaviour problems such as wandering.66
Emotion-oriented interventions include reminiscence therapy, validation therapy,
supportivepsychotherapy, sensory integration, also called snoezelen, and simulated presence therapy.
Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in
helping mildly impaired patients adjust to their illness.6 Reminiscence therapy (RT) involves the discussion of
past experiences individually or in group, many times with the aid of photographs, household items, music and
sound recordings, or other familiar items from the past. Although there are few quality studies on the
effectiveness of RT, it may be beneficial for cognitionand mood. 6 Simulated presence therapy (SPT) is based
on attachment theories and involves playing a recording with voices of the closest relatives of the person with
Alzheimer's disease. There is partial evidence indicating that SPT may reduce challenging behaviours.6 Finally,
validation therapy is based on acceptance of the reality and personal truth of another's experience, while
sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the
usefulness of these therapies.67
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the
reduction of cognitive deficits. Reality orientation consists in the presentation of information about time, place or
person in order to ease the understanding of the person about its surroundings and his or her place in them.
On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities.
Both have shown some efficacy improving cognitive capacities,77 although in some studies these effects were
transient and negative effects, such as frustration, have also been reported.6
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind
of recreational activities. Stimulation has modest support for improving behaviour, mood, and, to a lesser
extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation
therapies is the change in the person's routine. 6
Caregiving
Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs,
caregiving essentially is the treatment and must be carefully managed over the course of the disease.
During the early and moderate stages, modifications to the living environment and lifestyle can increase patient
safety and reduce caretaker burden.77 Examples of such modifications are the adherence to simplified routines,
the placing of safety locks, the labelling of household items to cue the person with the disease or the use of
modified daily life objects.677 The patient may also become incapable of feeding themselves, so they require
food in smaller pieces or pureed.7 When swallowing difficulties arise, the use of feeding tubes may be required.
In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the
caregivers and family members.77 The use of physical restraints is rarely indicated in any stage of the disease,
although there are situations when they are necessary to prevent harm to the person with AD or their
caregivers.6
As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure
ulcers, malnutrition, hygieneproblems, or respiratory, skin, or eye infections. Careful management can prevent
them, while professional treatment is needed when they do arise.88 During the final stages of the disease,
treatment is centred on relieving discomfort until death.8
A small recent study in the US concluded that patients whose caregivers had a realistic understanding of the
prognosis and clinical complications of late dementia were less likely to receive aggressive treatment near the
end of life. 8
Prognosis

Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2004.
no data ≤ 50 50–70 70–90 90–110 110–130 130–150 150–170 170–190 190–210 210–230 230–250 ≥ 250
The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once
cognitive impairment compromises daily living activities, although the person may still be living independently.
The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of
cognitive and non-cognitive disturbances, eliminating any possibility of independent living.
Life expectancy of the population with the disease is reduced.88 The mean life expectancy following diagnosis
is approximately seven years. Fewer than 3% of patients live more than fourteen years. Disease features
significantly associated with reduced survival are an increased severity of cognitive impairment, decreased
functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases
such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival.888 While
the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when
compared to the healthy population among those who are younger.8 Men have a less favourable survival
prognosis than women.8
The disease is the underlying cause of death in 70% of all cases. Pneumonia and dehydrationare the most
frequent immediate causes of death, while cancer is a less frequent cause of death than in the general
population.8
Epidemiology
Incidence rates Two main measures are used in epidemiological studies: incidence and
after age 658 prevalence. Incidence is the number of new cases per unit of person–time at risk
(usually number of new cases per thousand person–years); while prevalence is the
New affected total number of cases of the disease in the population at any given time.
Age per thousand Regarding incidence, cohort longitudinal studies (studies where a disease-free
person–years population is followed over the years) provide rates between 10 and 15 per
thousand person–years for all dementias and 5–8 for AD,89 which means that half of
65–69 3
new dementia cases each year are AD. Advancing age is a primary risk factor for
70–74 6 the disease and incidence rates are not equal for all ages: every five years after the
age of 65, the risk of acquiring the disease approximately doubles, increasing from
75–79 9 3 to as much as 69 per thousand person years.89 There are also sex differences in
80–84 23 the incidence rates, women having a higher risk of developing AD particularly in the
population older than 85.99
85–89 40 Prevalence of AD in populations is dependent upon different factors including
90– 69 incidence and survival. Since the incidence of AD increases with age, it is
particularly important to include the mean age of the population of interest. In the
United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall and in the 65–74 age
group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than 84
group.9 Prevalence rates in less developed regions are lower.[dead link]9 The World Health Organization estimated
that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would increase to 0.441% in
2015 and to 0.556% in 2030.9 Other studies have reached similar conclusions.9 Another study estimated that in
2006, 0.40% of the world population (range 0.17–0.89%; absolute number 26.6 million, range 11.4–59.4
million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would
quadruple by 2050.
History

Alois Alzheimer's patient Auguste Deterin 1902. Hers was the first described case of what became known as Alzheimer's
disease.
The ancient Greek and Roman philosophers and physicians associated old age with increasingdementia. It
was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as
Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alzheimer followed her until she died in
1906, when he first reported the case publicly.9 During the next five years, eleven similar cases were reported
in the medical literature, some of them already using the term Alzheimer's disease. The disease was first
described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and
hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste
D.9 He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile
dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.9
For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the
ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a
conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia
were almost identical, although the authors also added that this did not rule out the possibility that they had
different causes.9 This eventually led to the diagnosis of Alzheimer's disease independently of age.9 The
term senile dementia of the Alzheimer type(SDAT) was used for a time to describe the condition in those over
65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease
was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common
symptom pattern, disease course, and neuropathology.0
Multi-infarct dementia
Multi-infarct dementia, also known as vascular dementia, is the second most common form
of dementia after Alzheimer's disease (AD) in older adults. The term refers to a group of syndromes caused by
different mechanisms all resulting in vascular lesions in the brain. Early detection and accurate diagnosis are
important, as vascular dementia is at least partially preventable.
The main subtypes of this disease are: mild cognitive impairment, multi-infarct dementia, vascular dementia
due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or
the cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (which includes
vascular dementia due to lacunar lesions and Binswanger's disease), and mixed Alzheimer's and vascular
dementia.
Vascular lesions can be the result of diffuse cerebrovascular disease or focal lesions (or a combination of both,
which is what is observed in the majority of cases). Mixed dementia is diagnosed when patients have evidence
of AD and cerebrovascular disease, either clinically or based on neuroimaging evidence of ischemic lesions. In
fact vascular dementia and Alzheimer's disease often coexist, especially in older patients with dementia.

arrows: lacunar infarcts

Epidemiology
Vascular dementia is the second most common cause of dementia in the United States and Europe in the
elderly, but it is the most common form in some parts of Asia. The prevalence of the illness is 1.5% in Western
countries and approximately 2.2% in Japan. It accounts for 50% of all dementias in Japan, 20% to 40% in
Europe and 15% in Latin America. The incidence of dementia is 9 times higher in patients who have had a
stroke than in controls. 25% of stroke patients develop new-onset dementia within 1 year of their stroke.
The relative risk of incident dementia is 5.5% within 4 years of suffering a stroke.
The prevalence of vascular dementia is higher in men than in women and it increases with age.
Mortality/morbidity
The 5-year survival rate is 39% for patients with vascular dementia compared with 75% for age-matched
controls. Vascular dementia is associated with a higher mortality than "Alzheimer's", presumably because of
the excess in cardiovascular risk factors.
Clinical presentation
Patients suffering from vascular dementia present with cognitive impairment, acutely or subacutely, after an
acute cerebrovascular event. After the onset a stepwise progression is typical. However stepwise progression
may not be observed in small vessel disease, Binswanger's disease or vascular dementia due to small lacunar
infarcts.
In small vessel disease the incidence peaks between the 4th and the 7th decades of life and 80% will have a
history of hypertension. Patients develop progressive cognitive, motor and behavioral signs and symptoms. A
significant proportion of them also develop affective symptoms. These changes occur over a period of 5–10
years. If the frontal lobes are affected, which is often the case, patients may present as apatheticor abulic. This
is often accompanied by problems with attention, orientation and urinary incontinence.
As already stated, small vessel disease and focal lesions often overlap, so these two patterns may be evident
in the same individual concurrently.
Rare genetic disorders which result in vascular lesions in the brain have other patterns of presentation. As a
rule of thumb they tend to present earlier in life and have a more aggressive course.
Diagnosis
Several specific diagnostic criteria can be used to diagnose vascular dementia, including the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the International Classification of
Diseases, Tenth Edition (ICD-10) criteria, the National Institute of Neurological Disorders and Stroke-
Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria, the
Alzheimer's Disease Diagnostic and Treatment Center criteria, and the Hachinski ischemic score.
Lateralizing signs such as hemiparesis, bradykinesia, hyperreflexia, extensor plantar
reflexes, ataxia, pseudobulbar palsy, and gait andswallowing difficulties may be observed.
In terms of cognitive testing patients have patchy deficits. They tend to have better free recall and fewer recall
intrusions compared with patients with Alzheimer's disease. As small vessel disease often affects the frontal
lobes, apathy early in the disease is more suggestive of vascular dementia because it usually occurs in the
later stages of Alzheimer's. Consequently patients with vascular dementia perform worse than their Alzheimer's
disease counterparts in frontal lobe tasks such as verbal fluency. They also tend to exhibit more perseverative
behavior. They may also present with general slowing of processing ability, difficulty shifting sets and
impairment in abstract thinking. In the more severe patients, or those patients affected by strategic infarcts in
the Wernicke or Broca areas, dysarthrias, dysphasias and aphasias may be present.
Etiology
Risk factors for vascular dementia include hypertension, smoking, hypercholesterolemia, diabetes mellitus, and
cardiovascular and cerebrovascular disease.
Investigations
The recommended investigations for cognitive impairment should be carried out, including a dementia
screening blood test, chest X-Ray, CAT scan and EKG. The screening blood test should typically include full
blood count, liver function tests, thyroid function tests, lipid profile,erythrocyte sedimentation rate, C reactive
protein, syphilis serology, calcium serum level, fasting glucose, urea and electrolytes, vitamin B-12, folate. In
selected patients HIV serology and autoantibody testing may be done.
Treatment
The aim of the management is the prevention of further cerebrovascular lesions. This includes administering
antiplatelet drugs and controlling major vascular risk factors (hypertension, hypercholesterolemia, smoking and
diabetes mellitus to mention a few).
The general management of dementia includes referral to community services, judgment and decision-making
regarding legal and ethical issues (e.g., driving, capacity, advance directives), and consideration of caregiver
stress.
Cholinesterase inhibitors such as galantamine have shown to be helpful in various randomized controlled trials.
However their use is not licensed yet for this indication.
Behavioral and affective symptoms are particularly important in this patient group and deserve special
consideration. These problems, if they develop, tend to be resistant to conventional psychopharmacological
treatment and in many cases lead to hospital admission and placement in permanent care. Agents that may be
useful include antidepressants, neuroleptics and mood-stabilizers. Electroconvulsive therapy may be indicated
in extreme cases provided a medical contraindication does not exist.
Epilepsy

Epilepsy (from the Ancient Greek ἐπιληψία (epilēpsía) — "to seize") is a common chronicneurological
disorder characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms
of abnormal, excessive or synchronous neuronal activity in the brain. About 50 million people worldwide have
epilepsy, with almost 90% of these people being in developing countries. Epilepsy is more likely to occur in
young children, or people over the age of 65 years; however, it can occur at any time. As a consequence of
brain surgery, epileptic seizures may occur in recovering patients.
Epilepsy is usually controlled, but cannot be cured with medication, although surgery may be considered in
difficult cases. However, over 30% of people with epilepsy do not have seizure control even with the best
available medications. Not all epilepsy syndromes are lifelong – some forms are confined to particular stages of
childhood. Epilepsy should not be understood as a single disorder, but rather as syndromic with vastly
divergent symptoms but all involving episodic abnormal electrical activity in the brain.
Classification
Epilepsies are classified in five ways:
1. By their first cause (or etiology).
2. By the observable manifestations of the seizures, known as semiology.
3. By the location in the brain where the seizures originate.
4. As a part of discrete, identifiable medical syndromes.
5. By the event that triggers the seizures, as in primary reading epilepsy or musicogenic epilepsy.
In 1981, the International League Against Epilepsy (ILAE) proposed a classification scheme for individual
seizures that remains in common use. This classification is based on observation (clinical and EEG) rather than
the underlying pathophysiology or anatomy and is outlined later on in this article. In 1989, the ILAE proposed a
classification scheme for epilepsies and epileptic syndromes. This can be broadly described as a two-axis
scheme having the cause on one axis and the extent of localization within the brain on the other. Since 1997,
the ILAE have been working on a new scheme that has five axes:
1. ictal phenomenon, (pertaining to an epileptic seizure)
2. seizure type,
3. syndrome,
4. etiology,
5. impairment.
Seizure types
Seizure types are organized firstly according to whether the source of the seizure within the brain is localized
(partial or focal onset seizures) or distributed (generalized seizures). Partial seizures are further divided on the
extent to which consciousness is affected. If it is unaffected, then it is a simple partial seizure; otherwise it is
a complex partial (psychomotor) seizure. A partial seizure may spread within the brain - a process known
as secondary generalization. Generalized seizures are divided according to the effect on the body but all
involve loss of consciousness. These include absence (petit mal), myoclonic, clonic, tonic, tonic-clonic (grand
mal) and atonic seizures.
Children may exhibit behaviors that are easily mistaken for epileptic seizures but are not caused by epilepsy.
These include:
 Inattentive staring
 Benign shudders (among children younger than age 2, usually when they are tired or excited)
 Self-gratification behaviors (nodding, rocking, head banging)
 Conversion disorder (flailing and jerking of the head, often in response to severe personal stress such
as physical abuse)
Conversion disorder can be distinguished from epilepsy because the episodes never occur during sleep and do
not involve incontinence or self-injury.
Seizure types
The numerous epileptic seizure types are most commonly defined and grouped according to a scheme
proposed by the International League Against Epilepsy (ILAE) in 1981. Distinguishing between seizure
types is important since different types of seizure may have different causes, prognosis and treatments.
International classification of seizure types (1981)
This classification is based on observation (clinical and EEG) rather than the
underlying pathophysiology or anatomy.
I Partial seizures (Older term: focal seizures)
A Simple partial seizures - consciousness is not impaired
1 With motor signs
2 With sensory symptoms
3 With autonomic symptoms or signs
4 With psychic symptoms
B Complex partial seizures - consciousness is impaired (Older terms: temporal lobe or psychomotor
seizures)
1 Simple partial onset, followed by impairment of consciousness
2 With impairment of consciousness at onset
C Partial seizures evolving to secondarily generalized seizures
1 Simple partial seizures evolving to generalized seizures
2 Complex partial seizures evolving to generalized seizures
3 Simple partial seizures evolving to complex partial seizures evolving to generalized seizures
II Generalized seizures
A Absence seizures (Older term: petit mal)
1 Typical absence seizures
2 Atypical absence seizures
B Myoclonic seizures
C Clonic seizures
D Tonic seizures
E Tonic–clonic seizures (Older term: grand mal)
F Atonic seizures
III Unclassified epileptic seizures
In terms of their origin within the brain, seizures may be described as either partial (focal) or generalized.
Partial seizures only involve a localized part of the brain, whereas generalized seizures involve the whole of
both hemispheres. The term 'secondary generalisation' may be used to describe a partial seizure that later
spreads to the whole of the cortex and becomes generalized.
Whilst most seizures can be neatly split into partial and generalized, there exists some that don't fit. For
example: the seizure may be generalized only within one hemisphere. Alternatively there may be many focal
points (multifocal seizures) that are distributed in a symmetrical or asymmetrical pattern.
Partial seizures
Partial seizures may be further subdivided into both simple and complex seizures. This refers to the effect of
such a seizure onconsciousness; simple seizures cause no interruption to consciousness (although they may
cause sensory distortions or other sensations), whereas complex seizures interrupt consciousness to varying
degrees. This does not necessarily mean that the person experiencing this sort of seizure will fall unconscious
(like fainting). For example, a complex partial seizure may involve the unconscious repetition of simple
actions, gestures or verbal utterances, or simply a blank stare and apparent unawareness of the occurrence of
the seizure, followed by no memory of the seizure. Other patients may report a feeling of tunnel vision or
dissociation, which represents a diminishment of awareness without full loss of consciousness. Still other
patients can perform complicated actions, such as travel or shopping, while in the midst of a complex partial
seizure.
The effects of partial seizures can be quite dependent on the area of the brain in which they are active. For
example, a partial seizure in areas involved in perception may cause a particular sensory experience (for
example, the perception of a scent, music or flashes of light) whereas, when centred in the motor cortex, a
partial seizure might cause movement in particular groups of muscles. This type of seizure may also produce
particular thoughts or internal visual images or even experiences which may be distinct but not easily
described. Seizures centered on the temporal lobes are known to produce mystical or ecstatic experiences
in some people. These may result in a misdiagnosis ofpsychosis or even schizophrenia,[citation needed] if
other symptoms of seizure are disregarded and other tests are not performed. Unfortunately for those with
epilepsy, anti-psychotic medications prescribed without anticonvulsants in this case can actually lower the
seizure threshold further and worsen the symptoms.
When the effects of a partial seizure appear as a 'warning sign' before a larger seizure, they are known as
an aura: it is frequently the case that a partial seizure will spread to other parts of the brain and eventually
become generalized, resulting in a tonic-clonic convulsion. The subjective experience of an aura, like other
partial seizures, will tend to reflect the function of the affected part of the brain.
Generalized seizures
Primarily generalized seizures can be sub-classified into a number of categories, depending on their
behavioural effects:
 Absence seizures involve an interruption to consciousness where the person experiencing the
seizure seems to become vacant and unresponsive for a short period of time (usually up to 30
seconds). Slight muscle twitching may occur.
 Myoclonic seizures involve an extremely brief (< 0.1 second) muscle contraction and can result in
jerky movements of muscles or muscle groups.
 Clonic seizures are myoclonus that are regularly repeating at a rate typically of 2-3 per second.
 Tonic–clonic seizures involve an initial contraction of the muscles (tonic phase) which may
involve tongue biting, urinary incontinence and the absence of breathing. This is followed by
rhythmic muscle contractions (clonic phase). This type of seizure is usually what is referred to when
the term 'epileptic fit' is used colloquially.
 Atonic seizures involve the loss of muscle tone, causing the person to fall to the ground. These are
sometimes called 'drop attacks' but should be distinguished from similar looking attacks that may occur
in narcolepsy or cataplexy.
Mixed seizures
Mixed seizure is defined as the existence of both generalized and partial seizures in the same patient. For
example, someone who periodically has myoclonic seizures may have a tonic-clonic seizure triggered e.g.
by a mild fever.
Continuous seizures
Status epilepticus refers to continuous seizure activity with no recovery between successive seizures. When
the seizures are convulsive, it is a life-threatening condition and emergency medical assistance should be
called immediately if this is suspected. A tonic-clonic seizure lasting longer than 5 minutes (or two minutes
longer than a given person's usual seizures) is usually considered grounds for calling the emergency services.
Epilepsia partialis continua is a rare type of focal motor seizure (hands and face) which recurs every few
seconds or minutes for extended periods (days or years). It is usually due to strokes in adults and focal cortical
inflammatory processes in children (Rasmussen's encephalitis), possibly caused by chronic viral
infections or autoimmune processes.
Future classifications
In 1997, the ILAE began work on revising the classification of seizures, epilepsies and epileptic
syndromes. This revision remains in gestation and has not superseded the 1981 classification.
Proposed changes to terminology include:
 Replace partial with the older term focal to describe seizures that originate in one part of the brain
(though not necessarily a small or well defined area). The word partial was regarded as ambiguous.
 Drop the terms simple partial and complex partial - grouping based on the effect to consciousness is
no longer regarded as useful.
 Replace cryptogenic with probably symptomatic.
The hierarchy presented has the structure:
Self limiting seizure types
Generalized seizures
Tonic-clonic seizures (includes variations beginning with a clonic or myoclonic phase)
Clonic seizures (with and without tonic features)
Typical absence seizures
Atypical absence seizures
Myoclonic absence seizures
Tonic seizures
Spasms
Myoclonic seizures
Massive bilateral myoclonus
Eyelid myoclonia (with and without absences)
Myoclonic atonic seizures
Negative myoclonus
Atonic seizures
Reflex seizures in generalized epilepsy syndromes
Seizures of the posterior neocortex
Neocortical temporal lobe seizures
Focal seizures
Focal sensory seizures
Focal motor seizures
Gelastic seizures
Hemiclonic seizures
Secondarily generalized seizures
Reflex seizures in focal epilepsy syndromes
Continuous seizure types
Generalized status epilepticus
Generalized tonic-clonic status epilepticus
Clonic status epilepticus
Absence status epilepticus
Tonic status epilepticus
Myoclonic status epilepticus
Focal status epilepticus
Epilepsia partialis continua of Kojevnikov
Aura continua
Limbic status epilepticus (psychomotor status)
Hemiconvulsive status with hemiparesis
Earlier classifications
The 1981 classification was a revision of the one devised by Henri Gastaut for the ILAE and published in
1970. A significant difference was the distinction between simple and complex partial seizures. In the 1970
classification, the distinction was whether the symptoms involved elementary sensory or motor functions
(simple) or whether "higher functions" were involved (complex). This was changed to consider whether
consciousness was fully retained or not. As a result, studies that group patients according to these
classifications are not directly comparable from one generation to another. The 1970 classification was
important for standardising the modern terms for many seizure types. Prior to this, terms such as petit
mal, grand mal, Jacksonian, psychomotor and temporal-lobe seizures were used.
The earliest classification of seizures can be attributed to Babylonian scholars who inscribed their medical
knowledge into stone tablets know as the Sakikku (meaning All Diseases). This dates from the reign of
the Babylonian king Adad-apla-iddina of the Second Dynasty of Isin - estimated to be between 1067 and
1046 BC. Many types of seizures are described, each attributed to a certain demon or departed spirit and
given a prognosis.

Epilepsy syndromes
There are over 40 different types of epilepsy, including: Absence seizures, atonic seizures, benign Rolandic
epilepsy, childhood absence,clonic seizures, complex partial seizures, frontal lobe epilepsy, febrile
seizures, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, hot water epilepsy, Lennox-
Gastaut syndrome, Landau-Kleffner syndrome , myoclonic seizures, mitochondrial disorders,progressive
myoclonic epilepsy, psychogenic seizures, reflex epilepsy, Rasmussen's syndrome, simple partial seizures,
secondarily generalized seizures, temporal lobe epilepsy, tonic-clonic seizures, tonic seizures, psychomotor
seizures, limbic epilepsy, partial-onset seizures, Rett syndrome, generalized-onset seizures, status
epilepticus, abdominal epilepsy, akinetic seizures, autonomic seizures, massive
bilateral myoclonus, catamenial epilepsy, drop seizures, emotional seizures, focal seizures, gelastic seizures,
Jacksonian seizure disorder, Lafora disease, motor seizures, multifocal seizures, neonatal seizures, nocturnal
seizures, photosensitive epilepsy,pseudoseizures, sensory seizures, subtle seizures, Sylvan
seizures, withdrawal seizures and visual reflex seizures, among others.
Each type of epilepsy presents with its own unique combination of seizure type, typical age of onset, EEG
findings, treatment, and prognosis. The most widespread classification of the epilepsies divides epilepsy
syndromes by location or distribution of seizures (as revealed by the appearance of the seizures and by EEG)
and by cause. Syndromes are divided into localization-related epilepsies, generalized epilepsies, or epilepsies
of unknown localization.
Localization-related epilepsies, sometimes termed partial or focal epilepsies, arise from an epileptic focus, a
small portion of the brain that serves as the irritant driving the epileptic response. Generalized epilepsies, in
contrast, arise from many independent foci (multifocal epilepsies) or from epileptic circuits that involve the
whole brain. Epilepsies of unknown localization remain unclear whether they arise from a portion of the brain or
from more widespread circuits.
Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic, and cryptogenic.
Idiopathic epilepsies are generally thought to arise from genetic abnormalities that lead to alteration of basic
neuronal regulation. Symptomatic epilepsies arise from the effects of an epileptic lesion, whether that lesion is
focal, such as a tumor, or a defect in metabolism causing widespread injury to the brain. Cryptogenic epilepsies
involve a presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.
The genetic component to epilepsy is receiving particular interest from the scientific community. Conditions
such as ring chromosome 20 syndrome (r(20))are gaining acknowledgment, and although only 60 cases have
been reported in the literature since 1976, "more widespread cytogenetic chromosomal karyotyping in
nonetiological cases of epilepsy" is likely.
Some epileptic syndromes are difficult to fit within this classification scheme and fall in the unknown
localization/etiology category. People who only have had a single seizure, or those with seizures that occur
only after specific precipitants ("provoked seizures"), have "epilepsies" that fall into this category. Febrile
convulsions are an example of seizures bound to a particular precipitant. Landau-Kleffner syndrome is another
epilepsy which, because of its variety of EEG distributions, falls uneasily in clear categories. More confusingly,
certain syndromes,such as West syndrome, featuring seizures such as infantile spasms can be classified as
idiopathic, syndromic, or cryptogenic depending on cause and can arise from both focal or generalized epileptic
lesions.
Below are some common seizure syndromes:
 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic localization-related
epilepsy that is an inherited epileptic disorder that causes seizures during sleep. Onset is usually in
childhood. These seizures arise from the frontal lobes and consist of complex motor movements, such as
hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or
crying are also common. ADNFLE is often misdiagnosed as nightmares. ADNFLE has a genetic
basis. These genes encode various nicotinic acetylcholine receptors.
 Benign centrotemporal lobe epilepsy of childhood or benign Rolandic epilepsy is an idiopathic
localization-related epilepsy that occurs in children between the ages of 3 and 13 years, with peak onset in
prepubertal late childhood. Apart from their seizure disorder, these patients are otherwise normal. This
syndrome features simple partial seizures that involve facial muscles and frequently cause drooling.
Although most episodes are brief, seizures sometimes spread and generalize. Seizures are typically
nocturnal and confined to sleep. The EEG may demonstrate spike discharges that occur over the
centrotemporal scalp over the central sulcus of the brain (the Rolandic sulcus) that are predisposed to
occur during drowsiness or light sleep. Seizures cease near puberty. Seizures may
requireanticonvulsant treatment, but sometimes are infrequent enough to allow physicians to defer
treatment.
 Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy and
consists of an evolving group of syndromes. Most authorities include two subtypes, an early subtype with
onset between three and five years, and a late onset between seven and 10 years. Seizures in BOEC
usually feature visual symptoms such as scotoma or fortifications (brightly colored spots or lines) or
amaurosis (blindness or impairment of vision). Convulsions involving one half the body, hemiconvulsions,
or forced eye deviation or head turning are common. Younger patients typically experience symptoms
similar to migraine with nausea and headache, and older patients typically complain of more visual
symptoms. The EEG in BOEC shows spikes recorded from the occipital (back of head) regions. The EEG
and genetic pattern suggest an autosomal dominant transmission as described by Ruben Kuzniecky, et
al. Lately, a group of epilepsies termed Panayiotopoulos syndrome that share some clinical features of
BOEC but have a wider variety of EEG findings are classified by some as BOEC.
 Catamenial epilepsy (CE) is when seizures cluster around certain phases of a woman's menstrual
cycle.
 Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy that affects children
between the ages of four and 12 years of age, although peak onset is around five to six years old. These
patients have recurrent absence seizures, brief episodes of unresponsive staring, sometimes with minor
motor features such as eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz spike
and wave discharges. Some go on to develop generalized tonic-clonic seizures. This condition carries a
good prognosis because children do not usually show cognitive decline or neurological deficits, and the
seizures in the majority cease spontaneously with onging maturation.
 Dravet's syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a
neurodevelopmental disorder beginning in infancy and characterized by severe epilepsy that does not
respond well to treatment. This syndrome was described by Charlotte Dravet, French psychiatrist and
epileptologist (born July 14, 1936). Dravet described this syndrome while working at the Centre Saint Paul
at the University of Marseille. At Centre Saint Paul, one of her supervisors was Henri Gastaut, who
described the Lennox-Gastaut syndrome. She described this condition in 1978 Estimates of the
prevalence of this rare disorder have ranged from 1:20,000 to 1:40,000 births, though the incidence may
be found to be greater as the syndrome becomes better recognized and new genetic evidence is
discovered. It is thought to occur with similar frequency in both genders, and knows no geographic or
ethnic boundaries.
The course of Dravet syndrome is highly variable from person to person. Seizures begin during the
first year of life and development is normal prior to their onset. In most cases, the first seizures occur
with fever and are generalized tonic-clonic (grand mal) or unilateral (one-sided) convulsions. These
seizures are often prolonged, and may lead to status epilepticus, a medical emergency. In time,
seizures increase in frequency and begin to occur without fever. Additional seizure types appear, most
often these are myoclonic, atypical absence, and complex-partial seizures.
Additional features that are seen in significant numbers of patients with Dravet syndrome may
include sensory integration disorders and other autism spectrum characteristics, orthopedic or
movement disorders, frequent or chronic upper respiratory and ear infections, sleep
disturbance, dysautonomia, and problems with growth and nutrition.
 Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from
lesions causing seizures that occur in the frontal lobes of the brain. These epilepsies can be difficult to
diagnose because the symptoms of seizures can easily be confused with nonepileptic spells and, because
of limitations of the EEG, be difficult to "see" with standard scalp EEG.
 Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset than CAE, typically
in prepubertal adolescence, with the most frequent seizure type being absence seizures. Generalized
 tonic-clonic seizures can occur. Often, 3 Hz spike-wave or multiple spike discharges can be seen on EEG.
The prognosis is mixed, with some patients going on to a syndrome that is poorly distinguishable from
JME.
 Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy that occurs in patients aged
8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common
seizures are myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur
as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized
4–6 Hz spike wave discharges or multiple spike discharges. Interestingly, these patients are often first
diagnosed when they have their first generalized tonic-clonic seizure later in life, when they experience
sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol
withdrawal can also be a major contributing factor in breakthrough seizures, as well. The risk of the
tendency to have seizures is lifelong; however, the majority have well-controlled seizures with
anticonvulsant medication and avoidance of seizure precipitants.
 Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental
delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of
approximately 2 Hz "slow" spike-waves. Onset occurs between two and 18 years. As in West syndrome,
LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West
syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic
seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes,
complex partial seizures. Anticonvulsants are usually only partially successful in treatment.
 Ohtahara syndrome is a rare, but mild, form of epilepsy syndrome combined with cerebral palsy, and
characterised with frequent seizures which typically start in the first few days of life.
 Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy.
Reading in susceptible individuals triggers characteristic seizures.
 Progressive myoclonic epilepsies define a group of symptomatic generalized epilepsies
characterized by progressive dementia and myoclonic seizures. Tonic-clonic seizures may occur as well.
Diseases usually classified in this group are Unverricht-Lundborg disease, myoclonus epilepsy with ragged
red fibers (MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.
 Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a progressive,
inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate simple
partial or complex partial seizures and may progress to epilepsia partialis continua (simple partial status
epilepticus). Neuroimaging shows inflammatory encephalitis on one side of the brain that may spread if not
treated. Dementia and hemiparesis are other problems. The cause is hypothesized to involve an
immulogical attack against glutamate receptors, a common neurotransmitter in the brain.
 Symptomatic localization-related epilepsies are divided by the location in the brain of the epileptic
lesion, since the symptoms of the seizures are more closely tied to the brain location rather than the cause
of the lesion. Tumors, atriovenous malformations, cavernous malformations, trauma, and cerebral infarcts
can all be causes of epileptic foci in different brain regions.
 Temporal lobe epilepsy (TLE), a symptomatic localization-related epilepsy, is the most common
epilepsy of adults who experience seizures poorly controlled with anticonvulsant medications. In most
cases, the epileptogenic region is found in the midline (mesial) temporal structures (e.g.,
the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and
adolescence. Most of these patients have complex partial seizures sometimes preceded by an aura, and
some TLE patients also suffer from secondary generalized tonic-clonic seizures. If the patient does not
respond sufficiently to medical treatment, epilepsy surgery may be considered.
 Tuberous Sclerosis (TSC) is a genetic disorder that causes tumors to form in many different organs,
primarily in the brain, eyes, heart, kidney, skin and lungs. Several types of brain lesions can occur in
individuals with TSC and 60% - 90% of people with TSC develop epilepsy.
 West syndrome is a triad of developmental delay, seizures termed infantile spasms,
and EEG demonstrating a pattern termedhypsarrhythmia. Onset occurs between three months and two
years, with peak onset between eight and 9 months. West syndrome may arise from idiopathic,
symptomatic, or cryptogenic causes. The most common cause is tuberous sclerosis. The prognosis varies
with the underlying cause. In general, most surviving patients remain with significant cognitive impairment
and continuing seizures and may evolve to another eponymic syndrome, Lennox-Gastaut syndrome.
Causes
The diagnosis of epilepsy usually requires that the seizures occur spontaneously. Nevertheless, certain
epilepsy syndromes require particular precipitants or triggers for seizures to occur. These are termed reflex
epilepsy. For example, patients with primary reading epilepsy have seizures triggered by
reading. Photosensitive epilepsy can be limited to seizures triggered by flashing lights. Other precipitants
can trigger an epileptic seizure in patients who otherwise would be susceptible to spontaneous seizures.
For example, children with childhood absence epilepsy may be susceptible to hyperventilation. In fact,
flashing lights and hyperventilation are activating procedures used in clinical EEG to help trigger seizures
to aid diagnosis. Finally, other precipitants can facilitate, rather than obligately trigger, seizures in
susceptible individuals. Emotional stress, sleep deprivation, sleep itself, heat stress, alcohol and febrile
illness are examples of precipitants cited by patients with epilepsy. Notably, the influence of various
 precipitants varies with the epilepsy syndrome. Likewise, the menstrual cycle in women with epilepsy can
influence patterns of seizure recurrence. Catamenial epilepsy is the term denoting seizures linked to
the menstrual cycle.
There are different causes of epilepsy that are common in certain age groups.
 During the neonatal period and early infancy the most common causes include hypoxic-ischemic
encephalopathy, CNS infections, trauma, congenital CNS abnormalities, and metabolic disorders.
 During late infancy and early childhood, febrile seizures are fairly common. These may be caused by
many different things, some thought to be things such as CNS infections and trauma.
 During childhood, well-defined epilepsy syndromes are generally seen.
 During adolescence and adulthood, the causes are more likely to be secondary to any CNS lesion.
Further, idiopathic epilepsy is less common. Other causes associated with these age groups are stress,
trauma, CNS infections, brain tumors, illicit drug use and alcohol withdrawal.
 In older adults, cerebrovascular disease is a very common cause. Other causes are CNS tumors,
head trauma, and other degenerative diseases which are common in the older age group, such
as dementia.

Pathophysiology
Mutations in several genes have been linked to some types of epilepsy. Several genes that code
for protein subunits of voltage-gated andligand-gated ion channels have been associated with forms of
generalized epilepsy and infantile seizure syndromes. Several ligand-gated ion channels have been linked
to some types of frontal and generalized epilepsies. One speculated mechanism for some forms of
inherited epilepsy are mutations of the genes which code for sodium channel proteins; these defective
sodium channels stay open for too long thus making the neuron hyper-excitable. Glutamate, an excitatory
neurotransmitter, may thereby be released from these neurons in large amounts which—by binding with
nearby glutamatergic neurons—triggers excessive calcium (Ca2+) release in these post-synaptic cells.
Such excessive calcium release can be neurotoxic to the affected cell. The hippocampus, which contains a
large volume of just such glutamanergic neurons (and NMDA receptors, which are permeable to Ca2+ entry
after binding of both sodium and glutamate), is especially vulnerable to epileptic seizure, subsequent
spread of excitation, and possible neuronal death. Another possible mechanism involves mutations leading
to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related
mutations in some non-ion channel genes have also been identified.
Epileptogenesis is the process by which a normal brain develops epilepsy after an insult. One interesting
finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent
increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This
phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was
discovered by Dr. Graham Goddard in 1967. It is important to note that these "kindled" animals do not
experience spontaneous seizures. Chemical stimulation can also induce seizures; repeated exposures to
some pesticides have been shown to induce seizures in both humans and animals. One mechanism
proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy
are currently hotly debated.
Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal mass of tissue in an
area of the brain.
The complexity of understanding what seizures are have led to considerable efforts to use computational
models of epilepsy to both interpret experimental and clinical data, as well as guide strategies for therapy.
Management
Epilepsy is usually treated with medication prescribed by a physician; primary caregivers, neurologists,
and neurosurgeons all frequently care for people with epilepsy. However, it has been stressed that
accurate differentiation between generalized and partial seizures is especially important in determining the
appropriate treatment. In some cases the implantation of a stimulator of the vagus nerve, or a special diet
can be helpful. Neurosurgical operations for epilepsy can be palliative, reducing the frequency or severity
of seizures; or, in some patients, an operation can be curative.
The proper initial response to a generalized tonic-clonic epileptic seizure is to prevent the person from self-
injury by moving them away from sharp edges, placing something soft beneath the head, and rolling the
person into the recovery position. Should the person regurgitate, this should be allowed to drip out the side
of the person's mouth. If a seizure lasts longer than 5 minutes, or if more than one seizure occurs without
regaining consciousness emergency medical services should be contacted.
Medications
Anticonvulsant
The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication
treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants
and their effectiveness differs by epilepsy syndrome. Mechanisms, effectiveness for particular epilepsy
syndromes, and side effects differ among the individual anticonvulsant medications. Some general findings
about the use of anticonvulsants are outlined below.
Availability- Currently there are 20 medications approved by the Food and Drug Administration for the use of
treatment of epileptic seizures in the US: carbamazepine (common US brand name
Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide (Zarontin),felbamate (Felbatol), fo
sphenytoin (Cerebyx), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (
Keppra),oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primid
one (Mysoline), tiagabine (Gabitril),topiramate (Topamax), valproate semisodium (Depakote), valproic
acid (Depakene), and zonisamide (Zonegran). Most of these appeared after 1990.
Medications commonly available outside the US but still labelled as "investigational" within the US
are clobazam (Frisium) and vigabatrin(Sabril). Medications currently under clinical trial under the
supervision of the FDA include retigabine, brivaracetam, and seletracetam.
Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these
include diazepam (Valium, Diastat) andlorazepam (Ativan). Drugs used only in the treatment of
refractory status epilepticus include paraldehyde (Paral), midazolam (Versed),
andpentobarbital (Nembutal).
Some anticonvulsant medications do not have primary FDA-approved uses in epilepsy but are used in limited
trials, remain in rare use in difficult cases, have limited "grandfather" status, are bound to particular severe
epilepsies, or are under current investigation. These
includeacetazolamide (Diamox), progesterone, adrenocorticotropic hormone (ACTH, Acthar), various
corticotropic steroid hormones (prednisone), orbromide.
Effectiveness - The definition of "effective" varies. FDA-approval usually requires that 50% of the patient
treatment group had at least a 50% improvement in the rate of epileptic seizures. About 20% of patients
with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment.
Safety and Side Effects - 88% of patients with epilepsy, in a European survey, reported at least one
anticonvulsant related side effect.Most side effects are mild and "dose-related" and can often be avoided
or minimized by the use of the smallest effective amount. Some examples include mood changes,
sleepiness, or unsteadiness in gait. Some anticonvulsant medications have "idiosyncratic" side effects that
can not be predicted by dose. Some examples include drug rashes, liver toxicity (hepatitis), or aplastic
anemia. Safety includes the consideration of teratogenicity (the effects of medications on fetal
development) when women with epilepsy become pregnant.
Principles of Anticonvulsant Use and Management - The goal for individual patients is, no seizures and
minimal side effects, and the job of the physician is to aid the patient to find the best balance between the
two during the prescribing of anticonvulsants. Most patients can achieve this balance best
with monotherapy, the use of a single anticonvulsant medication. Some patients, however,
require polypharmacy; the use of two or more anticonvulsants.
Serum levels of AEDs can be checked to determine medication compliance, to assess the effects of new drug-
drug interactions upon previous stable medication levels, or to help establish if particular symptoms such
as instability or sleepiness can be considered a drug side effect or are due to different causes. Children or
impaired adults who may not be able to communicate side effects may benefit from routine screening of
drug levels. Beyond baseline screening, however, trials of recurrent, routine blood or urine monitoring
show no proven benefits and may lead to unnecessary medication adjustments in most older children and
adults using routine anticonvulsants.
If a person's epilepsy cannot be brought under control after adequate trials of two or three (experts vary here)
different drugs, that person's epilepsy is generally said to be medically refractory. A study of patients with
previously untreated epilepsy demonstrated that 47% achieved control of seizures with the use of their first
single drug. 14% became seizure free during treatment with a second or third drug. An additional 3%
became seizure-free with the use of two drugs simultaneously. Other treatments, in addition to or instead
of, anticonvulsant medications may be considered by those people with continuing seizures.
Surgery
Epilepsy surgery is an option for patients whose seizures remain resistant to treatment with anticonvulsant
medications who also have symptomatic localization-related epilepsy; a focal abnormality that can be
located and therefore removed. The goal for these procedures is total control of epileptic
seizures, although anticonvulsant medications may still be required.
The evaluation for epilepsy surgery is designed to locate the "epileptic focus" (the location of the epileptic
abnormality) and to determine if resective surgery will affect normal brain function. Physicians will also
confirm the diagnosis of epilepsy to make sure that spells arise from epilepsy (as opposed to non-epileptic
seizures). The evaluation typically includes neurological examination, routine EEG, Long-term video-EEG
monitoring, neuropsychological evaluation, and neuroimaging such as MRI, Single photon emission
computed tomography (SPECT),positron emission tomography (PET). Some epilepsy centers
use intracarotid sodium amobarbital test (Wada test), functional MRI orMagnetoencephalography (MEG)
as supplementary tests.
Certain lesions require Long-term video-EEG monitoring with the use of intracranial electrodes if noninvasive
testing was inadequate to identify the epileptic focus or distinguish the surgical target from normal brain
tissue and function. Brain mapping by the technique of cortical electrical stimulation
or Electrocorticography are other procedures used in the process of invasive testing in some patients.
The most common surgeries are the resection of lesions like tumors or arteriovenous malformations which, in
the process of treating the underlying lesion, often result in control of epileptic seizures caused by these
lesions.
Other lesions are more subtle and feature epilepsy as the main or sole symptom. The most common form of
intractable epilepsy in these disorders in adults is temporal lobe epilepsy with hippocampal sclerosis, and
the most common type of epilepsy surgery is the anterior temporal lobectomy, or the removal of the front
portion of the temporal lobe including the amygdala and hippocampus. Some neurosurgeons recommend
selective amygdalahippocampectomy because of possible benefits in postoperative memory or language
function. Surgery for temporal lobe epilepsy is effective, durable, and results in decreased health care
costs. Despite the efficacy of epilepsy surgery, some patients decide not to undergo surgery owing to fear
or the uncertainty of having a brain operation.
Palliative surgery for epilepsy is intended to reduce the frequency or severity of seizures. Examples
are callosotomy or commissurotomy to prevent seizures from generalizing (spreading to involve the entire
brain), which results in a loss of consciousness. This procedure can therefore prevent injury due to the
person falling to the ground after losing consciousness. It is performed only when the seizures cannot be
controlled by other means. Multiple subpial transection can also be used to decrease the spread of
seizures across the cortex especially when the epileptic focus is located near important functional areas of
the cortex. Resective surgery can be considered palliative if it is undertaken with the expectation that it will
reduce but not eliminate seizures.
Hemispherectomy involves removal or a functional disconnection of most or all of one half of the cerebrum. It is
reserved for people suffering from the most catastrophic epilepsies, such as those due to Rasmussen
syndrome. If the surgery is performed on very young patients (2–5 years old), the remaining hemisphere
may acquire some rudimentary motor control of the ipsilateral body; in older patients, paralysis results on
the side of the body opposite to the part of the brain that was removed. Because of these and other side
effects it is usually reserved for patients who have exhausted other treatment options.
Other
A ketogenic diet (high fat, low carbohydrate) was developed in the 1920s, and was largely forgotten with the
advent of effectiveanticonvulsants, but was resurrected in the 1990s. The mechanism of action is
unknown. It is used mainly in the treatment of children with severe, medically intractable epilepsies, and
the New York Times reported that use is supported by peer-reviewed research that found that the diet
reduced seizures among drug-resistant epileptics by >50% in 38% of patients and by >90% in 7% of
patients.
While far from a cure, operant-based biofeedback based on conditioning of EEG waves has some
experimental support (see Professional practice of behavior analysis). Overall, the support is based on a
handful of studies reviewed by Barry Sterman. These studies report a 30% reduction in weekly seizures.
Electrical stimulation methods of anticonvulsant treatment are both currently approved for treatment and
investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices
include the responsive neurostimulation system (RNS) and deep brain stimulation (DBS).
 Vagus nerve stimulation (US manufacturer Cyberonics) consists of a computerized electrical device
similar in size, shape and implant location to a heart pacemaker that connects to the vagus nerve in
the neck. The device stimulates the vagus nerve at preset intervals and intensities of current. Efficacy has
been tested in patients with localization-related epilepsies, demonstrating 50% of patients experience a
50% improvement in seizure rate. Case series have demonstrated similar efficacies in certain generalized
epilepsies, such as Lennox-Gastaut syndrome. Although success rates are not usually equal to that of
epilepsy surgery, it is a reasonable alternative when the patient is reluctant to proceed with any required
invasive monitoring, when appropriate presurgical evaluation fails to uncover the location of epileptic foci,
or when there are multiple epileptic foci.
 Responsive neurostimulator system (US manufacturer Neuropace) consists of a computerized
electrical device implanted in the skull, with electrodes implanted in presumed epileptic foci within the
brain. The brain electrodes send EEG signals to the device which contains seizure-detection software.
When certain EEG seizure criteria are met, the device delivers a small electrical charge to other electrodes
near the epileptic focus, which disrupt the seizure. The efficacy of the RNS is under current investigation
with the goal of FDA approval.
 Deep brain stimulation (US manufacturer Medtronic) consists of a computerized electrical device
implanted in the chest in a manner similar to the VNS, but electrical stimulation is delivered to deep brain
structures through depth electrodes implanted through the skull. In epilepsy, the electrode target is
the anterior nucleus of the thalamus. The efficacy of the DBS in localization-related epilepsies is currently
under investigation.
Noninvasive surgery using the gamma knife or other devices used in radiosurgery is currently being
investigated as analternative to traditional open surgery in patients who would otherwise qualify for anterior
temporal lobectomy.
Avoidance therapy consists of minimizing or eliminating triggers in patients whose seizures are particularly
susceptible to seizure precipitants (see above). For example, sunglasses that counter exposure to
particular light wavelengths can improve seizure control in certain photosensitive epilepsies.
Canine warning system is where a seizure response dog, a form of service dog, is trained to summon help or
ensure personal safety when a seizure occurs. These are not suitable for everybody, and not all dogs can
 be so trained. Rarely, a dog may develop the ability to sense a seizure before it occurs. Development of
electronic forms of seizure detection systems are currently under investigation.
Seizure prediction-based devices using long-term EEG recordings is presently being evaluated as a new
way to stop epileptic seizures before they appear clinically.
Alternative or complementary medicine,
including acupuncture, psychological interventions, vitamins and yoga, was evaluated in a number
of systematic reviews by the Cochrane Collaboration into treatments for epilepsy, and found there is no
reliableevidence to support the use of these as treatments for epilepsy. Exercise or other physical
activity have also been proposed as efficacious strategies for preventing or treating epilepsy.
The Memorial Sloan-Kettering Cancer Center says dimethylglycine dietary supplement (DMG) will
"enhance oxygen utilization during hypoxia, reduce lactic acid build-up in the blood during stressful
events," and reduce the number of seizures experienced in epilepsy.
Epidemiology

Disability-adjusted life year for epilepsy per 100,000 inhabitants in 2002.

no data less than 50 50-72.5 72.5-95 95-117.5 117.5-140 140-162.5 162.5-185 185-207.5 207.5-230 230-
252.5 252.5-275 more than 275
Epilepsy is one of the most common of the serious neurological disorders. Genetic, congenital,
and developmental conditions are mostly associated with it among younger patients; tumors are more
likely over age 40; head trauma and central nervous system infections may occur at any age.
The prevalence of active epilepsy is roughly in the range 5–10 per 1000 people. Up to 5% of people
experience non febrile seizures at some point in life; epilepsy's lifetime prevalence is relatively high
because most patients either stop having seizures or (less commonly) die of it. Epilepsy's approximate
annual incidence rate is 40–70 per 100,000 in industrialized countries and 100–190 per 100,000 in
resource-poor countries; socioeconomically deprived people are at higher risk. In industrialized countries
the incidence rate decreased in children but increased among the elderly during the three decades prior to
2003, for reasons not fully understood.
Beyond symptoms of the underlying diseases that can be a part of certain epilepsies, people with epilepsy are
at risk for death from four main problems: status epilepticus (most often associated
with anticonvulsant noncompliance), suicide associated with depression, trauma from seizures, and
sudden unexpected death in epilepsy (SUDEP) Those at highest risk for epilepsy-related deaths usually
have underlying neurological impairment or poorly controlled seizures; those with more benign epilepsy
syndromes have little risk for epilepsy-related death.
The NICE National Sentinel Audit of Epilepsy-Related Deaths, led by "Epilepsy Bereaved" drew attention to this
important problem. The Audit revealed; "1,000 deaths occur every year in the UK as a result of epilepsy"
and most of them are associated with seizures and 42% of deaths were potentially avoidable".
Certain diseases also seem to occur in higher than expected rates in people with epilepsy, and the risk of these
"comorbidities" often varies with the epilepsy syndrome. These diseases include depression and anxiety
disorders, migraine and other headaches, infertility and low sexual libido. Attention-deficit/hyperactivity
disorder (ADHD) affects three to five times more children with epilepsy than children in the general
population. Epilepsy is prevalent in autism.
History
The word epilepsy is derived from the Ancient Greek ἐπιληψία epilēpsía, which was from
ἐπιλαμβάνειν epilambánein "to take hold of", which in turn was combined from ἐπί epí "upon" and
λαμβάνειν lambánein "to take". In the past, epilepsy was associated with religiousexperiences and
even demonic possession. In ancient times, epilepsy was known as the "Sacred Disease" because people
thought that epileptic seizures were a form of attack by demons, or that the visions experienced by persons
with epilepsy were sent by the gods. Amonganimist Hmong families, for example, epilepsy was understood
as an attack by an evil spirit, but the affected person could become revered as a shaman through these
otherworldly experiences.
However, in most cultures, persons with epilepsy have been stigmatized, shunned, or even imprisoned; in
the Salpêtrière, the birthplace of modern neurology, Jean-Martin Charcot found people with epilepsy side-
by-side with the mentally retarded, those with chronic syphilis, and the criminally insane. In Tanzania to
this day, as with other parts of Africa, epilepsy is associated with possession by evil spirits, witchcraft, or
poisoning and is believed by many to be contagious. In ancient Rome, epilepsy was known as the Morbus
Comitialis ('disease of the assembly hall') and was seen as a curse from the gods.
Stigma continues to this day, in both the public and private spheres, but polls suggest it is generally decreasing
with time, at least in the developed world; Hippocrates remarked that epilepsy would cease to be
considered divine the day it was understood.
Society and culture
Legal implications
Many jurisdictions forbid certain activities to persons suffering from epilepsy. The most commonly prohibited
activities involve operation of vehicles or machinery, or other activities in which continuous vigilance is
required. However, there are usually exceptions for those who can prove that they have stabilized their
condition. Those few whose seizures do not cause impairment of consciousness, have a lengthy aura
preceding impairment of consciousness, or whose seizures only arise from sleep, may be exempt from
such restrictions, depending on local laws. There is an ongoing debate in bioethics over who should bear
the burden of ensuring that an epilepsy patient does not drive a car or fly an airplane.
Wilson's disease

Wilson's disease
Classification and external resources

A Kayser-Fleischer ring (the brown ring on the edge of

the iris) is common in Wilson's disease, especially when
neurological symptoms are present
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in
which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms
and liver disease. It is treated with medication that reduces copper absorption or removes the excess
copper from the body, but occasionally a liver transplant is required.
The condition is due to mutations in the Wilson disease protein (ATP7B) gene. A single abnormal copy of
the gene is present in 1 in 100 people, who do not develop any symptoms (they are carriers). If a child
inherits the gene from both parents, they may develop Wilson's disease. Symptoms usually appear
between the ages of 6 and 20 years, but cases in much older patients have been described. Wilson's
disease occurs in 1 to 4 per 100,000 people. Wilson's disease is named after Samuel Alexander Kinnier
Wilson (1878–1937), the British neurologist who first described the condition in 1912.
Signs and symptoms
The main sites of copper accumulation are the liver and the brain, and consequently liver disease and
neuropsychiatric symptoms are the main features that lead to diagnosis. Patients with liver problems tend
to come to medical attention earlier, generally as children or teenagers, than those with neurological and
psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because
relatives have been diagnosed with Wilson's disease; many of these patients, when tested, turn out to
have been experiencing symptoms of the condition but haven't received a diagnosis.
Liver disease
Liver disease may present as tiredness, increased bleeding tendency or confusion (due to hepatic
encephalopathy) and portal hypertension. The latter, a condition in which the pressure in the portal vein is
markedly increased, leads to esophageal varices (blood vessels in the esophagus) that may bleed in a
life-threatening fashion, splenomegaly (enlargement of the spleen) and ascites (accumulation of fluid in
the abdominal cavity). On examination, signs of chronic liver disease such as spider naevi (small
distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has
caused cirrhosis of the liver in most patients by the time they develop symptoms. While most people with
cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in
Wilson's disease.
About 5% of all patients are diagnosed only when they develop fulminant acute liver failure, often in the
context of a hemolytic anemia (anemia due to the destruction of red blood cells). This leads to
abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The
deranged protein metabolism leads to the accumulation of waste products such as ammonia in the
bloodstream. When these irritate the brain, the patient develops hepatic encephalopathy (confusion,
coma, seizures and finally life-threatening swelling of the brain).
Neuropsychiatric symptoms
About half the patients with Wilson's have neurological or psychiatric problems. Most patients initially
have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological
symptoms then follow, often in the form of parkinsonism (increased rigidity and slowing of routine
movements) with or without a typical hand tremor, masked facial expressions, slurred
speech, ataxia (lack of coordination) or dystonia (twisting and repetitive movements of part of the
body). Seizures and migraine appear to be more common in Wilson's disease.
Psychiatric problems due to Wilson's disease may include behavioral
changes, depression, anxiety and psychosis.
Other organ systems
Various medical conditions have been linked with copper accumulation in Wilson's disease:
 Eyes: Kayser–Fleischer rings (KF rings) may be visible around the iris. They are due to copper
deposition in Descemet's membrane of the cornea. They do not occur in all patients and may only be
visible on slit lamp examination. Wilson's disease is also associated with sunflower cataracts, brown
or green pigmentation of the anterior and posterior lens capsule. Neither cause significant visual
loss. KF rings occur in 66% of cases, more often in those with neurological than with liver problems.
 Kidneys: renal tubular acidosis, a disorder of bicarbonate handling by the proximal tubules leads
to nephrocalcinosis (calcium accumulation in the kidneys), weakening of the bone (due to calcium
and phosphate loss) and occasionally aminoaciduria (loss of amino acids, needed for protein
synthesis).
 Heart: cardiomyopathy (weakness of the heart muscle) is a rare but recognized problem in
Wilson's disease; it may lead to heart failure (fluid accumulation due to decreased pump function)
and cardiac arrhythmias (episodes of irregular and/or abnormally fast or slow heart beat).
 Hormones: hypoparathyroidism (failure of the parathyroid glands, leading to low calcium
levels), infertility and habitual abortion.
Genetics

Wilson's disease has an autosomal recessive pattern of inheritance.

The Wilson's disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is expressed
primarily in the liver, kidney, andplacenta. The gene codes for a P-type (cation transport
enzyme) ATPase that transports copper into bile and incorporates it intoceruloplasmin. Mutations can be
detected in 90% of patients. Most (60%) are homozygous for ATP7B mutations (two abnormal copies),
and 30% have only one abnormal copy. Ten per cent have no detectable mutation.
Although 300 mutations of ATP7B have been described, in most populations the cases of Wilson's
disease are due to a small number of mutations specific for that population. For instance, in Western
populations the H1069Q mutation (replacement of a histidine by a glutamine at position 1069 in the
protein) is present in 37–63% of cases, while in China this mutation is very uncommon and R778L
(arginine to leucine at 778) is found more often. Relatively little is known about the relative impact of
various mutations, although the H1069Q mutation seems to predict later onset and predominantly
neurological problems, according to some studies.
A normal variation in the PRNP gene can modify the course of the disease by delaying the age of onset
and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the
brain and other tissues and also appears to be involved in transporting copper. A role for the ApoE gene
was initially suspected but could not be confirmed.
The condition is inherited in an autosomal recessive pattern. In order to inherit it, both of the parents of an
individual must carry an affected gene. Most patients have no family history of the condition. People with
only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically
insignificant, abnormalities of copper metabolism.
Wilson's disease is the most common of a group of hereditary diseases that cause copper overload in the
liver. All can cause cirrhosis at a young age. The other members of the group are Indian childhood
cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic copper toxicosis. These are not related
to ATP7B mutations: for example, ICC has been linked to mutations in the KRT8 and the KRT18 gene.
Pathophysiology
Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying
copper.
Copper is needed by the body for a number of functions, predominantly as a cofactor for a number of
enzymes such as ceruloplasmin,cytochrome c oxidase, dopamine β-hydroxylase, superoxide
dismutase and tyrosinase.
Copper enters the body through the digestive tract. A transporter protein on the cells of the small
bowel, copper membrane transporter 1(CMT1), carries copper inside the cells, where some is bound
to metallothionein and part is carried by ATOX1 to an organelle known as thetrans-Golgi network. Here,
in response to rising concentrations of copper, an enzyme called ATP7A releases copper into the portal
vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the
cell, but here it is ATP7B that links copper toceruloplasmin and releases it into the bloodstream, as well
as removing excess copper by secreting it into bile. Both functions of ATP7B are impaired in Wilson's
disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks
copper (termed apoceruloplasmin) and rapidly degraded in the bloodstream.
When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative
damage through a process known asFenton chemistry; this damage eventually leads to chronic active
hepatitis, fibrosis (deposition of connective tissue) and cirrhosis. The liver also releases copper into the
bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body but
particularly in the kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia,
particularly in the putamen and globus pallidus(together called the lenticular nucleus); these areas
normally participate in the coordination of movement as well as playing a significant role in neurocognitive
processes such as the processing of stimuli and mood regulation. Damage to these areas, again by
Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson's disease.
It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest that high
levels of free (non-ceruloplasmin bound) copper have a direct effect on either oxidation of hemoglobin,
inhibition of energy-supplying enzymes in the red blood cell, or direct damage to the cell membrane.
Diagnosis

Location of the basal ganglia, the part of the brain affected by Wilson's disease
Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a
close relative has been found to have Wilson's. Most patients have slightly abnormal liver function
tests such as a raised aspartate transaminase, alanine transaminase and bilirubinlevel. If the liver
damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this
protein; likewise, theprothrombin time (a test of coagulation) may be prolonged as the liver is unable to
produce proteins known as clotting factors. Alkaline phosphatase levels are relatively low in patients with
Wilson's-related acute liver failure. If there are neurological symptoms, magnetic resonance
imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called
the basal ganglia in the T2setting. MRI may also demonstrate the characteristic "face of the giant panda"
pattern.
There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in the blood,
as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an
impression of the amount of copper in the body. The gold standard or most ideal test is a liver biopsy.
Ceruloplasmin

Ceruloplasmin
Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at
normal levels in people with ongoing inflammation as it is an acute phase protein. Low ceruloplasmin is
also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than
Wilson's disease.
The combination of neurological symptoms, Kayser–Fleisher rings and a low ceruloplasmin level is
considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are
needed.
Serum and urine copper
Serum copper is paradoxically low but urine copper is elevated in Wilson's disease. Urine is collected for
24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilson's
disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative.High urine copper levels are
not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and
in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).
In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and
urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of
Wilson's disease. This test has not been validated in adults.
Liver biopsy
Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount
of liver tissue through a liver biopsy. This is assessed microscopically for the degree
of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the
severity of the copper accumulation. A level of 250 μg of copper per gram of dried liver tissue confirms
Wilson's disease. Occasionally, lower levels of copper are found; in that case, the combination of the
biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's.
In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material),
increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the
changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration
by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis
is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue
architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting
copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a
diagnosis.
Genetic testing
Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver,
may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease
as part of clinical genetics family counselling.
Treatment
Dietary
In general, a diet low in copper-containing foods is recommended. Patients avoid eating copper-
containing foods like mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.
Medical
Various treatments are available for Wilson's disease. Some increase the removal of copper from the
body, while others prevent the absorption of copper from the diet.
Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of
copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a
sufficiently high dose is taken. Penicillamine is not without problems: about 20% of patients experience a
side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains
and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented
with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While
this phenomenon is also observed in other treatments for Wilson's, it is usually taken as an indication for
discontinuing penicillamine and commencing second-line treatment. Patients intolerant to penicillamine
may instead be commenced on trientine hydrochloride, which also has chelating properties. Some
recommend trientine as first-line treatment, but experience with penicillamine is more extensive. A further
agent with known activity in Wilson's disease is tetrathiomolybdate. This is still regarded as
experimental, although some studies have shown a beneficial effect.
Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called
Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc
stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and
transport to the liver. Zinc therapy is continued unless symptoms recur, or if the urinary excretion of
copper increases.
In rare cases where none of the oral treatments are effective, especially in severe neurological
disease, dimercaprol (British anti-Lewisite) is still occasionally necessary. This treatment is
injected intramuscularly (into a muscle) every few weeks, and has a number of unpleasant side effects
such as pain.
People who are asymptomatic (for instance those diagnosed through family screening or only as a result
of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage
in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.
Liver transplantation
Liver transplantation is the only cure for Wilson's disease, but is used only in particular scenarios because
of the numerous risks and complications associated with the procedure. It is used mainly in patients with
fulminant liver failure who fail to respond to medical treatment, or in patients with advanced chronic liver
disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not
been demonstrated.
History
The disease bears the name of the British physician Samuel Alexander Kinnier Wilson (1878–1937),
a neurologist who described the condition, including the pathological changes in the brain and liver, in
1912. Wilson's work had been predated by, and drew on, reports from German neurologist Carl
Westphal (in 1883), who termed it "pseudosclerosis"; by the British neurologist William Gowers (in 1888);
and by Adolph Strümpell (in 1898), who noted hepatic cirrhosis. Neuropathologist John Nathaniel
Cumings made the link with copper accumulation in both the liver and the brain in 1948. The occurrence
of hemolysis was noted in 1967.
Cumings, and simultaneously the New Zealand neurologist Derek Denny-Brown, working in the United
States, first reported effective treatment with metal chelator British anti-Lewisite in 1951. This treatment
had to be injected but was one of the first therapies available in the field of neurology, a field that
classically was able to observe and diagnose but had few treatments to offer. The first effective oral
chelation agent, penicillamine, was discovered in 1956 by British neurologist John Walshe. In 1982,
Walshe also introduced trientine, and was the first to develop tetrathiomolybdate for clinical use. Zinc
acetate therapy initially made its appearance in the Netherlands, where physicians Schouwink and
Hoogenraad used it in 1961 and in the 1970s, respectively, but it was further developed later by Brewer
and colleagues at the University of Michigan.
The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the 1980s and
1990s by several research groups.
Huntington's disease

Huntington's disease

A microscope image of Medium spiny neurons(yellow)

with nuclear inclusions (orange), which occur as part of
the disease process, image width 360 µm
Huntington's disease, chorea, or disorder (HD), is a neurodegenerative genetic disorder that affects
muscle coordination and leads tocognitive decline and dementia. It typically becomes noticeable in middle
age. HD is the most common genetic cause of abnormal involuntary writhing movements
called chorea and is much more common in people of Western European descent than in those from Asia
or Africa. The disease is caused by an autosomal dominant mutation on either of an individual's two
copies of a gene called Huntingtin, which means any child of an affected parent has a 50% risk of
inheriting the disease. In rare situations where both parents have an affected gene, or either parent has
two affected copies, this risk is greatly increased. Physical symptoms of Huntington's disease can begin
at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases
start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly.
The variant is classified as juvenile, akinetic-rigid or Westphal variant HD.
The Huntingtin gene normally provides the genetic information for a protein that is also called
"Huntingtin". The mutation of the Huntingtin gene codes for a different form of the protein, whose
presence results in gradual damage to specific areas of the brain. The exact way this happens is not fully
understood. Genetic testing can be performed at any stage of development, even before the onset of
symptoms. This raises several ethical debates regarding the age at which an individual is considered
mature enough to choose testing, the right of parents to test their children, and confidentiality and
disclosure of test results. Genetic counseling has developed to inform and aid individuals considering
genetic testing and has become a model for other genetically dominant diseases.
The exact way HD affects an individual varies and can differ even between members of the same family,
but the symptoms progress predictably for most individuals. The earliest symptoms are a general lack of
coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements
become more apparent, along with a decline in mental abilities and behavioral and psychiatricproblems.
Physical abilities are gradually impeded until coordinated movement becomes very difficult, and mental
abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical
injury from falls reduce life expectancy to around twenty years after symptoms begin. There is no cure for
HD, and full-time care is required in the later stages of the disease, but there are emerging treatments to
relieve some of its symptoms.
Self-help support organizations, first founded in the 1960s and increasing in number, have been working
to increase public awareness, to provide support for individuals and their families, and to promote
research. The Hereditary Disease Foundation, a research group born out of the first support organization,
was instrumental in finding the gene in 1993. Since that time there have been important discoveries every
few years and understanding of the disease is improving. Current research directions include determining
the exact mechanism of the disease, improving animal models to expedite research, clinical trials of
pharmaceuticals to treat symptoms or slow the progression of the disease, and studying procedures such
as stem cell therapy with the goal of repairing damage caused by the disease.
Signs and symptoms
Symptoms of Huntington's disease commonly become noticeable between the ages of 35 and 44 years,
but they can begin at any age from infancy. In the early stages, there are subtle changes in
personality, cognition, and physical skills. The physical symptoms are usually the first to be noticed, as
cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the
earlier stages. Almost everyone with Huntington's disease eventually exhibits similar physical symptoms,
but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between
individuals.
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements
called chorea. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or
uncompleted motions, lack of coordination, or slowed saccadic eye movements. These minor motor
abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear
appearance of symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder
progresses. These are signs that the system in the brain that is responsible for movement is
affected. Psychomotor functions become increasingly impaired, such that any action that requires muscle
control is affected. Common consequences are physical instability, abnormal facial expression, and
difficulties chewing, swallowing and speaking. Eating difficulties commonly cause weight loss and may
lead to malnutrition. Sleep disturbances are also associated symptoms. Juvenile HD differs from these
sympto
ms in
that it Reported prevalences of behavioral and psychiatric symptoms in Huntington's disease
generall
y Irritability 38–73%
progres Apathy 34–76%
ses
faster Anxiety 34–61%
and Depressed mood 33–69%
chorea
is Obsessive and compulsive 10–52%
exhibite Psychotic 3–11%
d
briefly, if
at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD.
Cognitive abilities are impaired progressively. Especially affected are executive functions which include
planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting
inappropriate actions. As the disease progresses, memory deficits tend to appear. Reported impairments
range from short-term memory deficits to long-term memory difficulties, including deficits
in episodic (memory of one's life), procedural (memory of the body of how to perform an activity)
and working memory. Cognitive problems tend to worsen over time, ultimately leading to dementia. This
pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical
effects of cortical dementias e.g. Alzheimer's disease.
Reported neuropsychiatric manifestations are anxiety, depression, a reduced display of emotions (blunted
affect), egocentrism, aggression, andcompulsive behavior, the latter of which can cause or
worsen addictions, including alcoholism, gambling, and hypersexuality. Difficulties in recognizing other
people's negative expressions have also been observed. Prevalence of these symptoms is also highly
variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between
33% and 76%. For many sufferers and their families these symptoms are among the most distressing
aspects of the disease, often affecting daily functioning and constituting reason
forinstitutionalisation. Suicidal thoughts and suicide attempts are more common than in the general
population.
Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral
tissues that are directly caused by such expression outside the brain. These abnormalities include muscle
atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy.
Genetics
All humans have the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt). Part of this gene
is a repeated section called a trinucleotide repeat, which varies in length between individuals and may
change length between generations. When the length of this repeated section reaches a certain
threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing
functions of these proteins are the cause of pathological changes which in turn cause the disease
symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant:
mutation of either of a person's HTT genes causes the disease. It is not inherited according to sex, but
the length of the repeated section of the gene, and hence its severity, can be influenced by the sex of the
affected parent.
Genetic mutation
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section
of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at
4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated
multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the genetic code for
the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as
a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.
Classification of the trinucleotide repeat, and resulting disease status, depends on the number
of CAG repeats
Repeat count Classification Disease status
<28 Normal Unaffected
28–35 Intermediate Unaffected
36–40 Reduced Penetrance +/- Affected
>40 Full Penetrance Affected
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production
of the cytoplasmicprotein Huntingtin. However, a sequence of 36 or more glutamines results in the
production of a protein which has different characteristics. This altered form, called mHtt (mutant Htt),
increases the decay rate of certain types of neuron. Regions of the brain have differing amounts and
reliance on these type of neurons, and are affected accordingly. Generally, the number of CAG repeats is
related to how much this process is affected, and accounts for about 60% of the variation of the age of
the onset of symptoms. The remaining variation is attributed to environment and other genes that modify
the mechanism of HD.36–40 repeats result in a reduced-penetrance form of the disease, with a much
later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms
are never noticed. With very large repeat counts, HD has full penetrance and can occur under the age of
20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for
about 7% of HD carriers.
Inheritance

Huntington's disease is inherited in an autosomal dominant fashion. The probability of each offspring
inheriting an affected gene is 50%. Inheritance is independent of gender, and the gene does not skip
generations.
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically
inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected
parent. Since penetrance of the mutation is very high those who have a mutated copy of the gene will
have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50%
risk of inheriting the mutant allele and therefore being affected with the disorder (see figure). This
probability is sex-independent.
Trinucleotide CAG repeats over 28 are unstable during replication and this instability increases with the
number of repeats present.This usually leads to new expansions as generations pass (dynamic
mutations) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of
repeats to change in successive generations, such that an unaffected parent with an "intermediate"
number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an
increase in the number of repeats that produces fully penetrant HD. Such increases in the number of
repeats (and hence earlier age of onsetand severity of disease) in successive generations is known as
genetic anticipation. Instability is greater in spermatogenesis thanoogenesis; maternally inherited alleles
are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of
increasing in length. It is rare for Huntington's disease to be caused by a new mutation, where neither
parent has over 36 CAG repeats.
Individuals with both genes affected are rare, except in large consanguineous families. For some time HD
was thought to be the only disease for which possession of a second mutated gene did not affect
symptoms and progression, but it has since been found that it can affect the phenotype and the rate of
progression. Offspring of an individual who has two affected genes will inherit one of them and therefore
definitely inherit the disease. Offspring where both parents have one affected gene have a 75% risk of
inheriting HD, including a 25% risk of inheriting two affected genes. Identical twins, who have inherited
the same affected gene, typically have differing ages of onset and symptoms.
Mechanism
The Htt protein interacts with over 100 other proteins, and appears to have multiple biological
functions. The behavior of mutated mHtt protein is not completely understood, but it is toxic to certain
types of cells, particularly in the brain. Damage mainly occurs in the striatum, but as the disease
progresses, other areas of the brain are also significantly affected. As the damage accumulates,
symptoms associated with the functions of these brain areas appear. Planning and modulating movement
are the main functions of the striatum, and difficulties with these are initial symptoms.
Htt function
Htt is expressed in all mammalian cells. The highest concentrations are found in the brain and testes, with
moderate amounts in the liver, heart, and lungs. The function of Htt in humans is unclear. It interacts with
proteins which are involved in transcription, cell signaling and intracellular transporting. In
animals genetically modified to exhibit HD, several functions of Htt have been found. In these animals, Htt
is important for embryonic development, as its absence is related to embryonic death. It also acts as
an anti-apoptotic agent preventing programmed cell death and controls the production of brain-derived
neurotrophic factor, a protein which protects neurons and regulates their creation during neurogenesis.
Htt also facilitates vesicular transport and synaptic transmission and controls neuronal gene
transcription. If the expression of Htt is increased and more Htt produced, brain cell survival is improved
and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting
characteristics are more typical of the presence of mHtt. In humans the disruption of the normal gene
does not cause the disease. It is currently concluded that the disease is not caused by inadequate
production of Htt, but by a gain of toxic function of mHtt.
Cellular changes due to mHtt

A microscope image of a neuron with inclusion (stained orange) caused by HD, image width 250 µm
There are multiple cellular changes through which the toxic function of mHtt may manifest and produce
the HD pathology. During the biological process of posttranslational modification of mHtt, cleavage of the
protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion. The polar
nature of glutamine causes interactions with other proteins when it is overabundant in Htt proteins. Thus,
the Htt molecule strands will form hydrogen bonds with one another, forming a protein aggregate rather
than folding into functional proteins. Over time, the aggregates accumulate, ultimately interfering with
neuron function because these fragments can then misfold and coalesce, in a process called protein
aggregation, to form inclusion bodies within cells. Neuronal inclusions run indirect interference. The
excess protein aggregates clump together at axons and dendrites in neurons which mechanically stops
the transmission of neurotransmitters because vesicles (filled with neurotransmitters) can no longer move
through the cytoskeleton. Ultimately, over time, less and less neurotransmitters are available for release
in signaling other neurons as the neuronal inclusions grow. Inclusion bodies have been found in both
the cell nucleus and cytoplasm. Inclusion bodies in cells of the brain are one of the earliest pathological
changes, and some experiments have found that they can be toxic for the cell, but other experiments
have shown that they may form as part of the body's defense mechanism and help protect cells.
Several pathways by which mHtt may cause cell death have been identified. These include: effects
on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases,
which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells;
impairment of energy production within cells; and effects on the expression of genes. The cytotoxic
effects of mHtt are strongly enhanced by interactions with a protein called Rhes, which is expressed
mainly in the striatum. Rhes was found to induce sumoylation of mHtt, which causes the protein clumps to
disaggregate—studies in cell culture showed that the clumps were much less toxic than the
disaggregated form.
An additional theory that explains another way cell function may be disrupted by HD proposes that
damage to mitochondria in striatal cells (numerous accounts of mitochondrial metabolism deficiency have
been found) and the interactions of the altered huntingtin protein with numerous proteins in neurons leads
to an increased vulnerability of glutamine, which, in large amounts, has been found to be an excitotoxin.
Excitotoxins may cause damage to numerous cellular structures. Although glutamine isn't found in
excessively high amounts, its been postulated that because of the increased vulnerability, even normal
amounts glutamine can cause excitotoxins to be expressed. Furthermore, the increase in sensitivity turn
oncapases are activated by the repeat expansion of polyglutamine and the increase in sensitivity. The
huntingtin protein is cleaved into tiny pieces by capases; these nuclear aggregates disrupt transcription
by interfering with the production of proteins by "slipping" into the nucleus of the neuron. Unfortunately,
the cellular stress caused by the interference causes more huntingtin to be broken up until apoptosis
occurs.
Macroscopic changes due to mHtt

Area of the brain damaged by Huntington's disease – striatum(shown in purple)

HD affects specific areas of the brain. The most prominent early effects are in a part of the basal
ganglia called the neostriatum, which is composed of the caudate nucleus and putamen. Other areas
affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, the hippocampus,purkinje
cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus. These areas
are affected according to their structure and the types of neurons they contain, reducing in size as they
lose cells. Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the
external globus pallidus, with interneurons and spiny cells projecting to the internal pallidum being less
affected. HD also causes an abnormal increase in astrocytes.
The basal ganglia—the part of the brain most prominently affected by HD—play a key role in movement
and behavior control. Their functions are not fully understood, but current theories propose that they are
part of the cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large
number of circuits that generate specific movements. To initiate a particular movement, the cerebral
cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal
ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which
results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted
before, or beyond, its intended completion. The accumulating damage to this area causes the
characteristic erratic movements associated with HD.
There are two ways the basal ganglia can be damaged: directly and indirectly. In the direct pathway,
fewer neurotransmitters are sent the internal globus pallidus (IGP), which in turn comprehends this as a
decrease in inhibition, thereby releasing a greater amount of neurotransmitters then normal. The
thalamus, which receives a greater number of neurotransmitters, becomes inhibited, thus sending less
neurotransmitters to the motor cortex. Ultimately, the motor cortex is understimulated and movements are
slower than usual. The indirect pathway starts with the external globus pallidus receiving a lower number
of neurotransmitters, and in turn, responding to this decrease as a signal of less inhibition, releases a
more neurotransmitters. The subthalamic nuclei (STN), which receives the signals from the external
globus pallidus, releases fewer neurotransmitters to the IGP in response to the increase of
neurotransmitters received. The IGP is now considerably inhibited because the job of the STN is to excite
the IGP and therefore, the IGP releases fewer neurotransmitters. In this context, the reception of less
neurotransmitters by the thalamus is perceived as less inhibition. Finally, the motor cortex receives more
neurotransmitters and is overstimulated, causing the jerky movements usual in chorea. Since there are
two different types of neurons in the striatum, a different neuron, with different axons and dendrites
targeted, is stimulated in each pathway (though neurotransmitter GABA is used in both) and thus both
can run at the same time. The indirect pathway is generally affected first, which is why chorea is among
the first symptoms, but eventually, both types of neurons die off and movement is severely limited.
Transcriptional dysregulation
CREB-binding protein (CBP), a transcription factor, is essential for cell function because as a coactivator
at a significant number of promoters, it activates the transcription of genes for survival
pathways. Furthermore, the amino acids that form CBP include a strip 18 glutamines. Thus, the
glutamines on CBP interact directly with the increased numbers of glutamine on the Htt chain and CBP
gets pulled away from its typical location next to the nucleus. Specifically, CRB contains a
acetyltransferase domain that, in an experiment performed by Steffan and colleagues, showed that a Htt
exon 1 with 51 glutamines binded to this domain in CBP. Autopsied brains of those who had Huntington's
disease also have been found to have incredibly reduced amounts of CBP. Plus, when CBP is
overexpressed, polyglutamine-induced death diminished, further demonstrating that CBP plays an
important role in Huntington's disease and neurons in general.
Diagnosis
Medical diagnosis of the onset of HD can be made following the appearance of physical symptoms
specific to the disease. Genetic testing can be used to confirm a physical diagnosis if there is no family
history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual
or embryo carries an expanded copy of the trinucleotide repeat in theHTT gene that causes the
disease. Genetic counseling is available to provide advice and guidance throughout the testing
procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an
individual's psychology, career, family planning decisions, relatives and relationships. Despite the
availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.
Clinical

Coronal section from a MR brain scan of a patient with HD showing atrophy of the heads of the caudate
nuclei, enlargement of the frontal horns of the lateral ventricles, and generalised cortical atrophy.
A physical examination, sometimes combined with a psychological examination, can determine whether
the onset of the disease has begun.Excessive unintentional movements of any part of the body are often
the reason for seeking medical consultation. If these are abrupt and have random timing and distribution,
they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely the first diagnosed; they are
usually only recognized in hindsight or when they develop further. How far the disease has progressed
can be measured using the unified Huntington's disease rating scale which provides an overall rating
system based on motor, behavioral, cognitive, and functional assessments. Medical imaging, such
as computerized tomography (CT) and magnetic resonance imaging (MRI), only shows visiblecerebral
atrophy in the advanced stages of the disease. Functional neuroimaging techniques such
as fMRI and PET can show changes in brain activity before the onset of physical symptoms.
Genetic
Because HD is dominant, there is a strong motivation for individuals who are at risk of inheriting it to seek
a diagnosis. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in
each of the HTT alleles. A positive result is not considered a diagnosis, since it may be obtained decades
before the symptoms begin. However, a negative test means that the individual does not carry the
expanded copy of the gene and will not develop HD.
A pre-symptomatic test is a life-changing event and a very personal decision. The main reason given for
choosing testing for HD is to aid in career and family decisions. Over 95% of individuals at risk of
inheriting HD do not proceed with testing, mostly because there is no treatment. A key issue is the anxiety
an individual experiences about not knowing whether they will eventually develop HD, compared to the
impact of a positive result. Irrespective of the result, stress levels have been found to be lower two years
after being tested, but the risk of suicide is increased after a positive test result. Individuals found to have
not inherited the disorder may experience survivor guilt with regard to family members who are
affected. Other factors taken into account when considering testing include the possibility of
discrimination and the implications of a positive result, which usually means a parent has an affected
gene and that the individual's siblings will be at risk of inheriting it. Genetic counseling in HD can provide
information, advice and support for initial decision-making, and then, if chosen, throughout all stages of
the testing process. Counseling and guidelines on the use of genetic testing for HD have become models
for other genetic disorders, such as autosomal dominant cerebellar ataxias. Presymptomatic testing for
HD has also influenced testing for other illnesses with genetic variants such aspolycystic kidney disease,
familial Alzheimer's disease and breast cancer.
Embryonic
Embryos produced using in vitro fertilisation may be genetically tested for HD using preimplantation
genetic diagnosis. This technique, where a single cell is extracted from a 4 to 8 cell embryo and then
tested for the genetic abnormality, can then be used to ensure embryos with affected HTT genes are not
implanted, and therefore any offspring will not inherit the disease. It is also possible to obtain a prenatal
diagnosis for an embryo or fetus in the womb.
Differential diagnosis
About 90% of HD diagnoses based on the typical symptoms and a family history of the disease are
confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the
remaining are called HD-like disorders. Most of these other disorders are collectively labelled HD-like
(HDL). The cause of most HDL diseases is unknown, but those with known causes are due to mutations
in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene
(HDL3—only found in one family and poorly understood), and the gene encoding the TATA box-binding
protein (HDL4/SCA17). Other autosomal dominant diseases that can be misdiagnosed as HD
are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. There are also autosomal
recessive disorders that resemble sporadic cases of HD. Main examples are chorea
acanthocytosis,pantothenate kinase-associated neurodegeneration and X-linked McLeod syndrome.
Management

Chemical structure of tetrabenazine, an approved compound for the management ofchorea in HD

There is no cure for HD, but there are treatments available to reduce the severity of some of its
symptoms. For many of these treatments, comprehensive clinical trials to confirm their effectiveness in
treating symptoms of HD specifically are incomplete. As the disease progresses and a person's ability to
tend to their own needs reduces, carefully managed multidisciplinary caregiving becomes increasingly
necessary.
Tetrabenazine was developed specifically to reduce the severity of chorea in HD, it was approved in 2008
for this use in the US. Other drugs that help to reduce chorea
include neuroleptics and benzodiazepines. Compounds such as amantadine or remacemide are still
under investigation but have shown preliminary positive results. Hypokinesia and rigidity can be treated
with antiparkinsonian drugs, andmyoclonic hyperkinesia can be treated with valproic acid.
Psychiatric symptoms can be treated with medications similar to those used in the general
population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for
depression, while atypical antipsychotic drugs are recommended for psychosis and behavioural
problems.
Weight loss and eating difficulties due to dysphagia and other muscle discoordination are common,
making nutrition management increasingly important as the disease advances.Thickening agents can be
added to liquids as thicker fluids are easier and safer to swallow. Reminding the patient to eat slowly and
to take smaller pieces of food into the mouth may also be of use to prevent choking. If eating becomes
too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available.
This is a feeding tube, permanently attached through the abdomen into the stomach, which reduces the
risk of aspirating food and provides better nutritional management.
Although there have been relatively few studies of exercises and therapies that help rehabilitate cognitive
symptoms of HD, there is some evidence for the usefulness of physical therapy, occupational therapy,
and speech therapy. However, more rigorous studies are needed for health authorities to endorse
them. A multidisciplinary approach may be important to limit disability. The families of individuals, who
have inherited or are at risk of inheriting HD, have generations of experience of HD which may be
outdated and lack knowledge of recent breakthroughs and improvements in genetic testing, family
planning choices, care management, and other considerations. Genetic counseling benefits these
individuals by updating their knowledge, dispelling any myths they may have and helping them consider
their future options and plans.
Prognosis
The length of the trinucleotide repeat accounts for 60% of the variation in the age of onset and the rate of
progression of symptoms. A longer repeat results in an earlier age of onset and a faster progression of
symptoms. For example, individuals with a trinucleotide repeat greater than sixty repeats often develop
the disease before twenty years of age, and those with less than forty repeats may not develop noticeable
symptoms. The remaining variation is due to environmental factors and other genes that influence the
mechanism of the disease.
Life expectancy in HD is generally around 20 years following the onset of visible symptoms. Most of the
complications that are life-threatening result from muscle coordination issues, or to a lesser extent from
behavioural changes resulting from the decline in cognitive function. The largest risk is pneumonia, which
is the cause of death of one-third of those with HD. As the ability to synchronise movements deteriorates,
difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of
contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of
fatalities of those with HD. Suicide is the next greatest cause of fatalities, with 7.3% of those with HD
taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are
influenced by psychiatric symptoms, as they may be considered to be a response of an individual to
retain a sense of control of their life or to avoid the later stages of the disease . Other associated risks
include choking, physical injury from falls, and malnutrition.
Epidemiology
The late onset of Huntington's disease means it does not usually affect reproduction. The
worldwide prevalence of HD is 5-10 cases per 100,000 persons, but varies greatly geographically as a
result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and
women. The rate of occurrence is highest in peoples of Western European descent, averaging around
seventy per million people, and is lower in the rest of the world, e.g. one per million people of Asian and
African descent. Additionally, some localized areas have a much higher prevalence than their regional
average. One of the highest prevalences is in the isolated populations of the Lake Maracaibo region
ofVenezuela, where HD affects up to seven thousand per million people. Other areas of high localization
have been found in Tasmania and specific regions of Scotland, Wales andSweden. Increased prevalence
in some cases occurs due to a local founder effect, a historical migration of carriers into an area
of geographic isolation. Some of these carriers have been traced back hundreds of years
using genealogical studies. Genetic haplotypes can also give clues for the geographic variations of
prevalence.
Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical
symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These
cases can now be included in statistics and as the test becomes more widely available, estimates of the
prevalence and incidence of the disorder are likely to increase.
History

In 1872 George Huntington described the disorder in his first paper "On Chorea" at the age of 22.
The first definite mention of HD was in a letter by Charles Oscar Waters, published in the first edition
of Robley Dunglison's Practice of Medicine in 1842. Waters described 'a form of chorea, vulgarly called
magrums', including accurate descriptions of the chorea, its progression, and the strong heredity of the
disease. In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized
regions.Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical
College, Johan Christian Lund also produced an early description in 1860. He specifically noted that
in Setesdalen, a secluded area in Norway, there was a high prevalence of dementia associated with a
pattern of jerking movement disorders that ran in families.
The first thorough description of the disease was by George Huntington in 1872. Examining the combined
medical history of several generations of a family exhibiting similar symptoms, he realized their conditions
must be linked; he presented his detailed and accurate definition of the disease as his first paper.
Unknowingly, Huntington described the exact pattern of inheritance of autosomal dominant disease years
before the rediscovery of Mendelian inheritance. "Of its hereditary nature. When either or both the parents
have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from
the disease ... But if by any chance these children go through life without it, the thread is broken and the
grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the
disease.". Sir William Osler was interested in the disorder and chorea in general, and was impressed with
Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease
has been more accurately, more graphically or more briefly described." Osler's continued interest in HD,
combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge
of the disorder throughout the medical community. Great interest was shown by scientists in Europe,
including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph
Jules Dejerine, and until the end of the century, much of the research into HD was European in origin. By
the end of the 19th century, research and reports on HD had been published in many countries and the
disease was recognized as a worldwide condition.
During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively
as an example of autosomal dominant inheritance. The English biologistWilliam Bateson used the
pedigrees of affected families to establish that HD did have an autosomal dominant inheritance
pattern. The strong inheritance pattern prompted several researchers to attempt to trace and connect
family members of previous studies, one of whom was Smith Ely Jelliffe. Jelliffe collected information from
across New York State and published several articles regarding the genealogy of HD in New
England. Jelliffe's research roused the interest of his college friend, Charles Davenport, who
commissioned Elizabeth Muncey to produce the first field study of families with HD, and construct their
pedigrees, on the East Coast of the United States. Davenport used this information to document the
variable age of onset and range of symptoms of HD and make the claim that most cases of HD in the
USA could be traced back to a handful of individuals. This research was further embellished in 1932 by P.
R. Vessie, who popularised the idea that three brothers who left England in 1630, bound for Boston were
the progenators of HD in the USA. The claim that the earliest progenators had been established
and eugenic bias of Muncey's, Davenport, and Vessie's work contributed to misunderstandings and
prejudice about HD. Muncey and Davenport also popularised the idea that in the past some HD sufferers
may have been thought to be possessed by spirits or victims of witchcraft, and were
sometimes shunned or exiledby society. This idea has not been proven, and there is evidence to the
contrary, for example, the community of the family studied by George Huntington openly accommodated
those who exhibited symptoms of HD.
Research into the disorder continued steadily through the 20th century, reaching a major breakthrough in
1983 when the US–Venezuela Huntington's Disease Collaborative Research Project discovered the
approximate location of a causal gene. This was the result of an extensive study begun in 1979, focusing
on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an
unusually high prevalence of the disease. Among other innovations, the project developed DNA marking
methods which were an important step in making the Human Genome Project possible. In 1993 the
research group isolated the precise causal gene at 4p16.3, making this the
first autosomal diseaselocus found using genetic linkage analysis. In the same time frame, key
discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita
Harding's research group on the effects of the gene's length.
Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996,
enabled larger scale experiments. As these animals have faster metabolisms and much shorter lifespans
than humans, results from experiments are received sooner, speeding research. The 1997 discovery that
mHtt fragments misfold led to the discovery of thenuclear inclusions they cause. These advances have
led to increasingly extensive research into the proteins involved with the disease, potential drug
treatments, care methods, and the gene itself.
Research directions
Research into the mechanism of HD has focused on identifying the functioning of Htt, how mHtt differs or
interferes with it, and the brain pathology that the disease produces. Most research is conducted in
animals. Appropriate animal models are critical for understanding the fundamental mechanisms causing
the disease and for supporting the early stages of drug development. Mice and monkeys, chemically
induced to exhibit HD-like symptoms were initially used, but they did not mimic the progressive features of
the disease. Since the Huntingtin gene was identified, transgenic animals (mice,00 Drosophila fruit
flies,0 and more recently monkeys0) exhibiting HD-like syndromes can be generated by inserting a CAG
repeat expansion into the gene. Nematode worms also provide a valuable model when the gene is
expressed.0
Genetically engineered intracellular antibody fragments called intrabodies have been shown to prevent
mortality during the development stages of Drosophila models. Their mechanism of action was an
inhibition of mHtt aggregation.00 As HD has been conclusively linked to a single gene, gene silencing is
potentially possible and by using gene knockdown in mouse models, researchers have shown that when
the influence of mHtt is reduced, symptoms improve.00 Stem cell therapy is the replacement of damaged
neurons by transplantation ofstem cells into affected regions of the brain. Experiments have yielded some
positive results using this technique in animal models and preliminary human clinical trials.0
Numerous drugs have been reported to produce benefits in animals, including creatine, coenzyme
Q10 and the antibiotic minocycline.Some of these have then been tested by humans in clinical trials, and
as of 2009 several are at different stages of these trials.
Multiple sclerosis

Multiple sclerosis
Classification and external resources

Demyelinization by MS. The CD68 colored tissue shows

several macrophages in the area of the lesion. Original
scale 1:100
Multiple sclerosis (abbreviated MS, also known as disseminated sclerosis or encephalomyelitis
disseminata) is an inflammatory disease in which the fatty myelin sheaths around the axons of
the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad
spectrum of signs and symptoms. Disease onset usually occurs in young adults, and it is more common
in females. It has aprevalence that ranges between 2 and 150 per 100,000. MS was first described in
1868 by Jean-Martin Charcot.
MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve
cells communicate by sending electrical signals called action potentials down long fibers called axons,
which are wrapped in an insulating substance called myelin. In MS, the body's own immune system
attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct
signals. The name multiple sclerosis refers to scars (scleroses—better known as plaques or lesions)
particularly in the white matter of the brain and spinal cord, which is mainly composed of myelin. Although
much is known about the mechanisms involved in the disease process, the cause remains unknown.
Theories include genetics or infections. Different environmental risk factors have also been found.
Almost any neurological symptom can appear with the disease, and often progresses to physical
and cognitive disability. MS takes several forms, with new symptoms occurring either in discrete attacks
(relapsing forms) or slowly accumulating over time (progressive forms). Between attacks, symptoms may
go away completely, but permanent neurological problems often occur, especially as the disease
advances.
There is no known cure for MS. Treatments attempt to return function after an attack, prevent new
attacks, and prevent disability. MS medications can have adverse effects or be poorly tolerated, and
many patients pursue alternative treatments, despite the lack of supporting scientific study.
The prognosis is difficult to predict; it depends on the subtype of the disease, the individual patient's
disease characteristics, the initial symptoms and the degree of disability the person experiences as time
advances. Life expectancy of patients is 5 to 10 years lower than that of the unaffected population.
Classification

Progression of MS subtypes
Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the
disease in an attempt to predict the future course. They are important not only for prognosis but also for
therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society standardized four
subtype definitions:
1. relapsing remitting,
2. secondary progressive,
3. primary progressive, and
4. progressive relapsing.
The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months
to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during attacks
may either resolve or leave sequelae, the latter being more common as a function of time. This describes
the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is
sometimes referred to as benign MS, although patients will still accrue some degree of disability in the
long term. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In
CIS, a patient has an attack suggestive of demyelination, but does not fulfill the criteria for multiple
sclerosis. However only 30 to 70% of persons experiencing CIS later develop MS.

Secondary progressive MS (sometimes called "galloping MS") describes around 65% of those with an
initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute
attacks without any definite periods of remission. Occasional relapses and minor remissions may
appear. The median time between disease onset and conversion from relapsing-remitting to secondary
progressive MS is 19 years.
The primary progressive subtype describes the approximately 10–15% of individuals who never have
remission after their initial MS symptoms. It is characterized by progression of disability from onset, with
no, or only occasional and minor, remissions and improvements. The age of onset for the primary
progressive subtype is later than for the relapsing-remitting, but similar to mean age of progression
between the relapsing-remitting and the secondary progressive. In both cases it is around 40 years of
age.
Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline
but also suffer clear superimposed attacks. This is the least common of all subtypes.
Atypical variants of MS with non-standard behavior have been described; these include Devic's
disease, Balo concentric sclerosis, Schilder's diffuse sclerosis and Marburg multiple sclerosis. There is
debate on whether they are MS variants or different diseases. Multiple sclerosis also behaves differently
in children, taking more time to reach the progressive stage. Nevertheless they still reach it at a lower
mean age than adults.
Signs and symptoms
Main symptoms of multiple sclerosis
A person with MS can suffer almost any neurological symptom or sign, including changes in sensation
such as loss of sensitivity or tingling, pricking or numbness (hypoesthesia and paraesthesia), muscle
weakness, clonus, muscle spasms, or difficulty in moving; difficulties with coordination and balance
(ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic
neuritisincluding phosphenes, or diplopia), fatigue, acute or chronic pain, and bladder and bowel
difficulties. Cognitive impairment of varying degrees and emotional symptoms of depression or unstable
mood are also common. Uhthoff's phenomenon, an exacerbation of extant symptoms due to an exposure
to higher than usual ambient temperatures, and Lhermitte's sign, an electrical sensation that runs down
the back when bending the neck, are particularly characteristic of MS although not specific. The main
clinical measure of disability progression and symptom severity is the Expanded Disability Status Scale or
EDSS.
Symptoms of MS usually appear in episodic acute periods of worsening (called relapses, exacerbations,
bouts, attacks, or "flare-ups"), in a gradually progressive deterioration of neurologic function, or in a
combination of both. Multiple sclerosis relapses are often unpredictable, occurring without warning and
without obvious inciting factors with a rate rarely above one and a half per year. Some attacks, however,
are preceded by common triggers. Relapses occur more frequently during spring and summer. Viral
infections such as the common cold, influenza, or gastroenteritis increase the risk of relapse. Stress may
also trigger an attack. Pregnancy affects the susceptibility to relapse, with a lower relapse rate at each
trimester of gestation. During the first few months after delivery, however, the risk of relapse is
increased. Overall, pregnancy does not seem to influence long-term disability. Many potential triggers
have been examined and found not to influence MS relapse rates. There is no evidence that vaccination
and breast feeding, physical trauma, or Uhthoff's phenomenon are relapse triggers.
Causes
Most likely MS occurs as a result of some combination of genetic, environmental and infectious
factors. Epidemiological studies of MS have provided hints on possible causes for the disease. Theories
try to combine the known data into plausible explanations, but none has proved definitive.
Genetics

HLA region of Chromosome 6. Changes in this area increase the probability of suffering MS.
MS is not considered a hereditary disease. However, a number of genetic variations have been shown to
increase the risk of developing the disease.
The risk of acquiring MS is higher in relatives of a person with the disease than in the general population,
especially in the case of siblings, parents, and children. The disease has an overall familial recurrence
rate of 20%. In the case of monozygotic twins, concordance occurs only in about 35% of cases, while it
goes down to around 5% in the case of siblings and even lower in half-siblings. This indicates
susceptibility is partly polygenically driven.
It seems to be more common in some ethnic groups than others.
Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte
antigen (HLA) system—a group of genes in chromosome 6 that serves as the major histocompatibility
complex (MHC) in humans—increase the probability of suffering MS. The most consistent finding is the
association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6. Other loci have
shown a protective effect, such as HLA-C554 and HLA-DRB1*11.
Environmental factors
Different environmental factors, both of infectious and non infectious origin have been proposed as risk
factors for MS. Although some are partly modifiable, only further research—especially clinical trials—will
reveal whether their elimination can help prevent MS.
MS is more common in people who live farther from the equator, although many exceptions
exist. Decreased sunlight exposure has been linked with a higher risk of MS. Decreased vitamin
D production and intake has been the main biological mechanism used to explain the higher risk among
those less exposed to sun.
Severe stress may also be a risk factor although evidence is weak. Smoking has also been shown to be
an independent risk factor for developing MS. Association with occupational exposures and toxins—
mainly solvents—has been evaluated, but no clear conclusions have been reached. Vaccinations were
also considered as causal factors for the disease; however, most studies show no association between
MS and vaccines. Several other possible risk factors, such as diet and hormone intake, have been
investigated; however, more evidence is needed to confirm or refute their relation with the disease.
Gout occurs less than would statistically be expected in people with MS, and low levels of uric acid have
been found in MS patients as compared to normal individuals. This led to the theory that uric acid protects
against MS, although its exact importance remains unknown.
Infections
Many microbes have been proposed as potential infectious triggers of MS, but none has been
substantiated.
Genetic susceptibility can explain some of the geographic and epidemiological variations in MS incidence,
like the high incidence of the disease among some families or the risk decline with genetic distance, but
does not account for other phenomena, such as the changes in risk that occur with migration at an early
age. An explanation for this epidemiological finding could be that some kind of infection, produced by a
widespread microbe rather than a rare pathogen, is the origin of the disease. Different hypotheses have
elaborated on the mechanism by which this may occur. The hygiene hypothesis proposes that exposure
to several infectious agents early in life is protective against MS, the disease being a response to a later
encounter with such agents. The prevalence hypothesis proposes that the disease is due to
a pathogen more common in regions of high MS prevalence. This pathogen is very common, causing in
most individuals an asymptomatic persistent infection. Only in a few cases, and after many years since
the original infection, does it cause demyelination. The hygiene hypothesis has received more support
than the prevalence hypothesis.
Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal
fluid of most patients, the association of several viruses with human demyelination encephalomyelitis, and
induction of demyelination in animals through viral infection. Human herpes viruses are a candidate group
of viruses linked to MS. Individuals who have never been infected by the Epstein-Barr virus have a
reduced risk of having the disease, and those infected as young adults have a greater risk than those
who had it at a younger age. Although some consider that this goes against the hygiene hypothesis, since
the non-infected have probably experienced a more hygienic upbringing, others believe that there is no
contradiction since it is a first encounter at a later moment with the causative virus that is the trigger for
the disease. Other diseases that have also been related with MS aremeasles, mumps and rubella.
Pathophysiology
Blood-brain barrier breakdown
Demyelination in MS. On Klüver-Barrera myelin staining, decoloration in the area of the lesion can be
appreciated (Original scale 1:100).
The blood–brain barrier is a capillary system that should prevent entrance of T cells into the nervous
system. The blood–brain barrier is normally not permeable to these types of cells, unless triggered by
infection or a virus, which decreases the integrity of the tight junctionsforming the barrier. When the
blood–brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped
inside the brain.
Autoimmunology
MS is currently believed to be an immune-mediated disorder mediated by a complex interaction of the
individual's genetics and as yet unidentified environmental insults. Damage is believed to be caused by
the patient's own immune system. The immune system attacks the nervous system, possibly as a result
of exposure to a molecule with a similar structure to one of its own.
Lesions
The name multiple sclerosis refers to the scars (scleroses – better known as plaques or lesions) that form
in the nervous system. MS lesions most commonly involve white matter areas close to the ventricles of
the cerebellum, brain stem, basal ganglia and spinal cord; and the optic nerve. The function of white
matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of
the body. The peripheral nervous system is rarely involved.
More specifically, MS destroys oligodendrocytes, the cells responsible for creating and maintaining a fatty
layer—known as the myelin sheath—which helps the neurons carry electricalsignals. MS results in a
thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron's
extensions or axons. When the myelin is lost, a neuron can no longer effectively conduct electrical
signals. A repair process, called remyelination, takes place in early phases of the disease, but the
oligodendrocytes cannot completely rebuild the cell's myelin sheath. Repeated attacks lead to
successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged
axons.Different lesion patterns have been described.
Inflammation
Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a
strictly immunological explanation of MS, the inflammatory process is caused by T cells, a kind
of lymphocyte. Lymphocytes are cells that play an important role in the body's defenses. In MS, T cells
gain entry into the brain via the previously described blood–brain barrier. Evidence from animal models
also point to a role of B cells in addition to T cells in development of the disease.
The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers
inflammatory processes, stimulating other immune cells and soluble factors likecytokines and antibodies.
Leaks form in the blood–brain barrier, which in turn cause a number of other damaging effects such
as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.
Diagnosis

T1-weighted MRI scans (post-contrast) of the same brain slice at monthly intervals. Bright spots indicate
active lesions.
Multiple sclerosis can be difficult to diagnose since its signs and symptoms may be similar to other
medical problems. Medical organizations have created diagnostic criteria to ease and standardize the
diagnostic process especially in the first stages of the disease.Historically, the Schumacher and Poser
criteria were both popular.
Currently, the McDonald criteria focus on a demonstration with clinical, laboratory and radiologic data of
the dissemination of MS lesions in time and space for non-invasive MS diagnosis, though some have
stated that the only proved diagnosis of MS is autopsy, or occasionally biopsy, where lesions typical of
MS can be detected through histopathological techniques.
Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered separate episodes
of neurologic symptoms characteristic of MS. Since some people seek medical attention after only one
attack, other testing may hasten and ease the diagnosis. The most commonly used diagnostic tools
are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of
the brain and spine shows areas of demyelination (lesions or plaques). Gadolinium can be
administered intravenously as a contrast to highlight active plaques and, by elimination, demonstrate the
existence of historical lesions not associated with symptoms at the moment of the evaluation. Testing
of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation of
the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on
electrophoresis, which are an inflammation marker found in 75–85% of people with MS. The nervous
system of a person with MS responds less actively to stimulation of the optic nerve and sensory
nerves due to demyelination of such pathways. These brain responses can be examined using visual and
sensory evoked potentials.
Management
Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary
aims of therapy are returning function after an attack, preventing new attacks, and preventing disability.
As with any medical treatment, medications used in the management of MS have several adverse
effects. Alternative treatments are pursued by some patients, despite the shortage of supporting,
comparable, replicated scientific study.
Acute attacks
During symptomatic attacks, administration of high doses of intravenous corticosteroids, such
as methylprednisolone, is the routine therapy for acute relapses. Although generally effective in the short
term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-
term recovery. Oral and intravenous administration seem to have similar efficacy. Consequences of
severe attacks which do not respond to corticosteroids might be treated by plasmapheresis.
Disease-modifying treatments

Disease-modifying treatments are expensive and most of these require frequent (up-to-daily) injections.
Others require IV infusions at 1–3 month intervals.
As of 2009, five disease-modifying treatments for MS have been approved by regulatory agencies of
various countries. Interferon beta-1a (trade names Avonex, CinnoVex, ReciGen and Rebif) and interferon
beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon). A third medication is glatiramer
acetate (Copaxone), a non-interferon, non-steroidal immunomodulator. The fourth
medication, mitoxantrone, is animmunosuppressant also used in cancer chemotherapy. The fifth
is natalizumab (marketed as Tysabri). The interferons and glatiramer acetate are delivered by frequent
injections, varying from once-per-day for glatiramer acetate to once-per-week (but intra-muscular)
for Avonex.Natalizumab and mitoxantrone are given by IV infusion at monthly intervals.
All five kinds of medications are modestly effective at decreasing the number of attacks in relapsing-
remitting MS (RRMS) while the capacity of interferons and glatiramer acetate is more controversial.
Studies of their long-term effects are still lacking. Comparisons between immunomodulators (all but
mitoxantrone) show that the most effective is natalizumab, both in terms of relapse rate reduction and
halting disability progression. Mitoxantrone may be the most effective of them all; however, it is generally
not considered as a long-term therapy, as its use is limited by severe secondary effects. The earliest
clinical presentation of RRMS is the clinically isolated syndrome (CIS). Treatment with interferons during
an initial attack can decrease the chance that a patient will develop clinical MS.
Treatment of progressive MS is more difficult than relapsing-remitting MS. Mitoxantrone has shown
positive effects in patients with secondary progressive and progressive relapsing courses. It is moderately
effective in reducing the progression of the disease and the frequency of relapses in patients in short-term
follow-up. No treatment has been proven to modify the course of primary progressive MS.
As with many medical treatments, these treatments have several adverse effects. One of the most
common is irritation at the injection site for glatiramer acetate and the interferon treatments. Over time, a
visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may
develop. Interferons produce symptoms similar to influenza; some patients taking glatiramer experience a
post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and
anxiety, which usually lasts less than thirty minutes. More dangerous but much less common are liver
damage from interferons, severe cardiotoxicity, infertility, and acute myeloid leukaemia of
mitoxantrone, and the putative link between natalizumab and some cases of progressive multifocal
leukoencephalopathy.
Management of the effects of MS
Disease-modifying treatments reduce the progression rate of the disease, but do not stop it. As multiple
sclerosis progresses, the symptomatology tends to increase. The disease is associated with a variety of
symptoms and functional deficits that result in a range of progressive impairments and disability.
Management of these deficits is therefore very important. Both drug therapy and neurorehabilitation have
shown to ease the burden of some symptoms, though neither influences disease progression. Some
symptoms have a good response to medication, such as unstable bladder and spasticity, while
management of many others is much more complicated. As for any patient with neurologic deficits,
amultidisciplinary approach is key to improving quality of life; however, there are particular difficulties in
specifying a 'core team' because people with MS may need help from almost any health profession or
service at some point. Multidisciplinary rehabilitation programmes increase activity and participation of
patients but do not influence impairment level.
Alternative treatments
As with most chronic diseases, alternative treatments are pursued by some patients, despite the shortage
of supporting, comparable, replicated scientific study. Examples are dietaryregimens, herbal medicine,
including the use of medical cannabis, hyperbaric oxygenation and self-infection with hookworm.
Prognosis

Disability-adjusted life year for multiple sclerosis per 100,000 inhabitants in 2004
no data less than 13 13–16 16–19 19–22 22–25 25–28 28–31 31–34 34–
37 37–40 40–43 more than 43
The prognosis (the expected future course of the disease) for a person with multiple sclerosis depends on
the subtype of the disease; the individual's sex, age, and initial symptoms; and the degree of disability the
person experiences. The disease evolves and advances over decades, 30 being the mean years to death
since onset.
Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the
initial years and especially early age at onset, are associated with a better course.
The life expectancy of people with MS is 5 to 10 years lower than that of unaffected people. Almost 40%
of patients reach the seventh decade of life. Nevertheless, two-thirds of the deaths in people with MS are
directly related to the consequences of the disease. Suicide is also a much more important risk of death
than in the healthy population, while infections and complications are especially hazardous for the more
disabled ones.
Although most patients lose the ability to walk prior to death, 90% are still capable of independent walking
at 10 years from onset, and 75% at 15 years.
Epidemiology
Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the
number of new cases per unit of person–time at risk (usually number of new cases per thousand person–
years); while prevalence is the total number of cases of the disease in the population at a given time.
Prevalence is known to depend not only on incidence, but also on survival rate and migrations of affected
people. MS has a prevalence that ranges between 2 and 150 per 100,000 depending on the country or
specific population. Studies on populational and geographical patterns of epidemiological measures have
been very common in MS, and have led to the proposal of different etiological(causal) theories.
MS usually appears in adults in their thirties but it can also appear in children. The primary progressive
subtype is more common in people in their fifties. As with many autoimmune disorders, the disease is
more common in women, and the trend may be increasing. In children, the sex ratio difference is
higher, while in people over fifty, MS affects males and females almost equally.
There is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the
southern hemisphere, with MS being much less common in people living near
the equator. Climate, sunlight and intake of vitamin D have been investigated as possible causes of the
disease that could explain this latitude gradient. However, there are important exceptions to the north–
south pattern and changes in prevalence rates over time; in general, this trend might be
disappearing. This indicates that other factors such as environment or genetics have to be taken into
account to explain the origin of MS. MS is also more common in regions with northern Europe
populations. But even in regions where MS is common, some ethnic groups are at low risk of developing
the disease, including the Samis, Turkmen, Amerindians, Canadian Hutterites, Africans, and New
Zealand Māori.
Environmental factors during childhood may play an important role in the development of MS later in life.
Several studies of migrants show that if migration occurs before the age of 15, the migrant acquires the
new region's susceptibility to MS. If migration takes place after age 15, the migrant retains the
susceptibility of his home country. However, the age–geographical risk for developing multiple sclerosis
may span a larger timescale. A relationship between season of birth and MS has also been found which
lends support to an association with sunlight and vitamin D. For example fewer people with MS are born
in November as compared to May.
History
Medical discovery

Detail of drawing from Carswell book depicting MS lesions in the brain stem andspinal cord (1838)
The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple
sclerosis as a distinct disease in 1868.Summarizing previous reports and adding his own clinical and
pathological observations, Charcot called the disease sclerose en plaques. The three signs of MS now
known as Charcot's triad 1 are nystagmus, intention tremor, and telegraphic speech, though these are not
unique to MS. Charcot also observed cognition changes, describing his patients as having a "marked
enfeeblement of the memory" and "conceptions that formed slowly".
Prior to Charcot, Robert Carswell (1793–1857), a British professor of pathology, and Jean
Cruveilhier (1791–1873), a French professor of pathologic anatomy, had described and illustrated many
of the disease's clinical details, but did not identify it as a separate disease.Specifically, Carswell
described the injuries he found as "a remarkable lesion of the spinal cord accompanied with
atrophy". Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863
that the inflammation-associated lesions were distributed around veins.
After Charcot's description, Eugène Devic (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand
Schilder (1886–1940), and Otto Marburg(1874–1948) described special cases of the disease. During all
the 20th century there was an important development on the theories about the cause and pathogenesis
of MS while efficacious treatments began to appear in 1990.
Historical cases
There are several historical accounts of people who lived before or shortly after the disease was
described by Charcot and probably had MS.
A young woman called Halldora, who lived in Iceland around 1200, suddenly lost her vision and mobility,
but after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380–1433),
a Dutch nun, may be one of the first clearly identifiable MS patients. From the age of 16 until her death at
53, she suffered intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS.Both
cases have led to the proposal of a 'Viking gene' hypothesis for the dissemination of the disease.
Augustus Frederick d'Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady
Augusta Murray and the grandson of George III of the United Kingdom, almost certainly suffered from
MS. D'Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822
and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a
sudden transient visual loss after the funeral of a friend. During the course of his disease, he developed
weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile
dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.
Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce
Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle with
MS. His diary was published in 1919 as The Journal of a Disappointed Man.
Cerebral palsy

Cerebral palsy (CP) is an umbrella term encompassing a group of non-progressive, non-contagious motor
conditions that causephysical disability in human development, chiefly in the various areas of body
movement.
Cerebral refers to the cerebrum, which is the affected area of the brain (although the disorder most likely
involves connections between thecortex and other parts of the brain such as the cerebellum), and palsy
refers to disorder of movement. However, "paralytic disorders" are not cerebral palsy — the condition of
quadriplegia, therefore, should not be confused with spastic quadriplegia, nor Tardive dyskinesia
withdyskinetic cerebral palsy, nor diplegia with spastic diplegia, and so on.
Cerebral palsy's nature as an umbrella term means it is defined mostly via several different subtypes,
especially spastic, and also mixtures of those subtypes.
Cerebral palsy is caused by damage to the motor control centers of the developing brain and can occur
during pregnancy, during childbirth or after birth up to about age three. Resulting limits in movement and
posture cause activity limitation and are often accompanied by disturbances of sensation, depth
perception and other sight-based perceptual problems, communication ability, and sometimes
evencognition; sometimes a form of CP may be accompanied by epilepsy. CP, no matter what the type, is
often accompanied by secondary musculoskeletal problems that arise as a result of the underlying
etiology.
Of the many types and subtypes of CP, none of them has a known cure. Usually, medical intervention is
limited to the treatment and prevention of complications arising from CP's effects. A 2003 study put the
economic cost for people with CP in the US at $921,000 per individual, including lost income. In another
study, the incidence in six countries surveyed was 2.12–2.45 per 1,000 live births, indicating a slight rise
in recent years. Improvements in neonatalology, or the medical specialty which is involved with treatment
of neonates, have helped reduce the number of babies who develop cerebral palsy, but the survival of
babies with very low birth weights has increased, and these babies are more likely to have cerebral palsy.
Classification
Cerebral palsy (CP) is divided into four major classifications to describe different movement impairments.
These classifications also reflect the areas of the brain that are damaged. The four major classifications
are:
Spastic
Spastic cerebral palsy is by far the most common type of overall cerebral palsy, occurring in 70% to 80%
of all cases. Moreover, spastic CP accompanies any of the other types of CP in 30% of all cases.
People with this type of CP are hypertonic and have what is essentially a neuromuscular mobility
impairment (rather than hypotonia or paralysis) stemming from an upper motor neuron lesion in the brain
as well as the corticospinal tract or the motor cortex, this damage impairs the ability of some nerve
receptors in the spine to properly receive gamma amino butyric acid, leading to hypertonia in the muscles
signaled by those damaged nerves.
As compared to other types of CP, and especially as compared to hypotonic or paralytic mobility
disabilities, spastic CP is typically more easily manageable by the person affected, and medical treatment
can be pursued on a multitude of orthopedic and neurological fronts throughout life. Spastic CP is
classified by topography dependent on the region of the body affected; these include:
Spastic hemiplegia is one side being affected. Generally, injury to muscle-nerves controlled by
the brain's left side will cause a right body deficit, and vice versa. Typically, people that have spastic
hemiplegia are the most ambulatory of all the forms, although they generally have dynamic equinus on
the affected side and are primarily prescribed ankle-foot orthosesto prevent said equinus.
Spastic diplegia is the lower extremities affected, with little to no upper-body spasticity. The most
common form of the spastic forms, most people with spastic diplegia are fully ambulatory, but are "tight"
and have a scissors gait. Flexed knees and hips to varying degrees, and moderate to severe adduction
(stemming from tight adductor muscles and comparatively weak abductor muscles), are present. Gait
analysis is often done in early life on a semi-regular basis, and assistive devices are often provided like
walkers, crutches or canes; any ankle-foot orthotics provided usually go on both legs rather than just one.
In addition, these individuals are often nearsighted. The intelligence of a person with spastic diplegia is
unaffected by the condition. Over time, the effects of the spasticity sometimes produce hip problems and
dislocations (see the main article and spasticity for more on spasticity effects). In three-quarters of spastic
diplegics, also strabismus (crossed eyes) can be present as well.
Spastic monoplegia is one single limb being affected.
Spastic triplegia is three limbs being affected.
Spastic quadriplegia is all four limbs more or less equally affected. People with spastic
quadriplegia are the least likely to be able to walk, or if they can, to desire to walk, because their muscles
are too tight and it is too much of an effort to do so. Some children with spastic quadriplegia also have
hemiparetic tremors, an uncontrollable shaking that affects the limbs on one side of the body and impairs
normal movement.
In any form of spastic CP, clonus of the affected limb(s) may sometimes result, as well as muscle spasms
resulting from the pain and/or stress of the tightness experienced. The spasticity can and usually does
also lead to very early onset of muscle-stress symptoms like arthritis and tendinitis, especially in
ambulatory individuals in their mid-20s and early-30s.Physical therapy and also athletic training regimens
of assisted stretching, strengthening, and targeted physical activity and exercise are usually the chief
ways to keep spastic CP well-managed, although if the spasticity is too much for the person to handle,
other remedies may be considered, such as various antispasmodic medications, botox, baclofen, or even
aneurosurgery known as a selective dorsal rhizotomy (which eliminates the spasticity by eliminating the
nerves causing it).
Ataxic
Ataxia type symptoms can be caused by damage to the cerebellum. The forms of ataxia are less common
types of cerebral palsy, occurring in at most 10% of all cases. Some of these individuals have hypotonia
and tremors. Motor skills such as writing, typing, or using scissors might be affected, as well as balance,
especially while walking. It is common for individuals to have difficulty with visual and/or auditory
processing.
Athetoid/dyskinetic
Athetoid or dyskinetic cerebral palsy is mixed muscle tone — People with athetoid CP have trouble
holding themselves in an upright, steady position for sitting or walking, and often showinvoluntary
motions. For some people with athetoid CP, it takes a lot of work and concentration to get their hand to a
certain spot (like scratching their nose or reaching for a cup). Because of their mixed tone and trouble
keeping a position, they may not be able to hold onto objects (such as a toothbrush or pencil). About one
quarter of all people with CP have athetoid CP. The damage occurs to the extrapyramidal motor system
and/or pyramidal tract and to the basal ganglia. It occurs in 10% to 20% of all cases. In newborn infants,
high bilirubin levels in the blood, if left untreated, can lead to brain damage in certain areas (kernicterus).
This may also lead to athetoid cerebral palsy.
Hypotonic
Hypotonia is the opposite of hypertonia; people with hypotonic CP have musculature that is limp, and can
move only a little or not at all. Although physical therapy is usually attempted to strengthen the muscles
(in a similar way to how PT is used to stretch and loosen the tight muscles of hypertonic individuals), it is
not always fundamentally effective.
Signs and symptoms
All types of cerebral palsy are characterized by abnormal muscle tone (i.e. slouching over while sitting),
reflexes, or motor development and coordination. There can be joint and bone deformities and
contractures (permanently fixed, tight muscles and joints). The classical symptoms are spasticities,
spasms, other involuntary movements (e.g. facial gestures), unsteady gait, problems with balance, and/or
soft tissue findings consisting largely of decreased muscle mass. Scissor walking (where the knees come
in and cross) and toe walking (which can contribute to a gait reminiscent of a marionette) are common
among people with CP who are able to walk, but taken on the whole, CP symptomatology is very diverse.
The effects of cerebral palsy fall on a continuum of motor dysfunction which may range from slight
clumsiness at the mild end of the spectrum to impairments so severe that they render coordinated
movement virtually impossible at the other end the spectrum.
Babies born with severe CP often have an irregular posture; their bodies may be either very floppy or very
stiff. Birth defects, such as spinal curvature, a small jawbone, or a small head sometimes occur along with
CP. Symptoms may appear or change as a child gets older. Some babies born with CP do not show
obvious signs right away. Classically, CP becomes evident when the baby reaches the developmental
stage at six and a half to 9 months and is starting to mobilise, where preferential use of limbs, asymmetry
or gross motor developmental delay is seen.
Secondary conditions can include seizures, epilepsy, apraxia, dysarthria or other communication
disorders, eating problems, sensory impairments, mental retardation, learning disabilities, and/or
behavioral disorders.
Speech and language disorders are common in people with Cerebral Palsy. The incidence of dysarthria is
estimated to range from 31% to 88%. Speech problems are associated with poor respiratory control,
laryngeal and velopharyngeal dysfunction as well as oral articulation disorders that are due to restricted
movement in the oral-facial muscles. There are three major types of dysarthria in cerebral palsy: spastic,
dyskinetic (athetosis) and ataxic. Speech impairments in spastic dysarthria involves four major
abnormalities of voluntary movement: spasticity, weakness, limited range of motion and slowness of
movement. Speech mechanism impairment in athetosis involves a disorder in the regulation of breathing
patterns, laryngeal dysfunction (monopitch, low, weak and breathy voice quality). It is also associated with
articulatory dysfunction (large range of jaw movements), inappropriate positioning of the tongue,
instability of velar elevation. Athetoid dysarthria is caused by disruption of the internal sensorimotor
feedback system for appropriate motor commands, which leads to the generation of faulty movements
that are perceived by others as involuntary. Ataxic dysarthria is uncommon in cerebral palsy. The speech
characteristics are: imprecise consonants, irregular articulatory breakdown, distorted vowels, excess and
equal stress, prolonged phonemes, slow rate, monopitch, monoloudness and harsh voice. Overall
language delay is associated with problems of mental retardation, hearing impairment and learned
helplessness. Children with cerebral palsy are at risk of learned helplessness and becoming passive
communicators, initiating little communication. Early intervention with this clientele often targets situations
in which children communicate with others, so that they learn that they can control people and objects in
their environment through this communication, including making choices, decisions and mistakes.
Skeleton
In order for bones to attain their normal shape and size, they require the stresses from normal
musculature. Osseous findings will therefore mirror the specific muscular deficits in a given person with
CP. The shafts of the bones are often thin (gracile) and become thinner during growth. When compared
to these thin shafts (diaphyses), the centers (metaphyses) often appear quite enlarged (ballooning). With
lack of use, articular cartilage may atrophy, leading to narrowed joint spaces. Depending on the degree of
spasticity, a person with CP may exhibit a variety of angular joint deformities. Because vertebral bodies
need vertical gravitational loading forces to develop properly, spasticity and an abnormal gait can hinder
proper and/or full bone and skeletal development. People with CP tend to be shorter in height than the
average person because their bones are not allowed to grow to their full potential. Sometimes bones
grow to different lengths, so the person may have one leg longer than the other.
Pain and sleep disorders
Pain is common, which may result from the inherent deficits associated with the condition, along with the
numerous procedures children typically face. There is also have a high likelihood of suffering from chronic
sleep disorders associated with both physical and environmental factors.
Causes
While in certain cases there is no identifiable cause, typical causes include problems in intrauterine
development (e.g. exposure to radiation, infection), asphyxia before birth, hypoxia of the brain, and birth
trauma during labor and delivery, and complications in the perinatal period or during childhood. CP is also
more common in multiple births.
Studies at the University of Liverpool have led to the hypothesis that many cases of cerebral palsy, and
other conditions that an infant has at birth, are caused by the death in very early pregnancy of an identical
twin. This may occur when twins have a joint circulation through sharing the same placenta. Not all
identical twins share the same blood supply (monochorionic twins), but if they do, the suggestion is that
perturbations in blood flow between them can cause the death of one and damage to the development of
the surviving fetus. It is common knowledge amongst obstetricians and midwives that a small dead fetus
(fetus papyraceus) may sometimes be found attached to a placenta following birth. In the past, this has
not been considered important and knowledge of the so called ‘vanishing twin’ has been suppressed to
avoid triggering feelings of loss, grief, or guilt in mothers and especially the surviving twin. The
pathological consequences depend on the severity and the stage of development of the fetus when the
imbalances in blood flow between the fetuses occur. It has been proposed that such pathology could
account, not just for cerebral palsy, but for developmental abnormalities of the eye, heart, and gut, and
other specific brain abnormalities such as neuronal migration disorders e.g. lissencephaly and
holoprosencephaly.
Between 40% and 50% of all children who develop cerebral palsy were born prematurely. Premature
infants are vulnerable, in part because their organs are not fully developed, increasing the risk of hypoxic
injury to the brain that may manifest as CP. A problem in interpreting this is the difficulty in differentiating
between cerebral palsy caused by damage to the brain that results from inadequate oxygenation and CP
that arises from prenatal brain damage that then precipitates premature delivery.
Recent research has demonstrated that intrapartum asphyxia is not the most important cause, probably
accounting for no more than 10 percent of all cases; rather, infections in the mother, even infections that
are not easily detected, may triple the risk of the child developing the disorder, mainly as the result of the
toxicity to the fetal brain of cytokines that are produced as part of the inflammatory response. Low
birthweight is a risk factor for CP—and premature infants usually have low birth weights, less than 2.0 kg,
but full-term infants can also have low birth weights. Multiple-birth infants are also more likely than single-
birth infants to be born early or with a low birth weight.
After birth, other causes include toxins, severe jaundice, lead poisoning, physical brain injury, shaken
baby syndrome, incidents involving hypoxia to the brain (such as near drowning), and encephalitis or
meningitis. The three most common causes of asphyxia in the young child are: choking on foreign objects
such as toys and pieces of food, poisoning, and near drowning.
Some structural brain anomalies such as lissencephaly may present with the clinical features of CP,
although whether that could be considered CP is a matter of opinion (some people say CP must be due
to brain damage, whereas people with these anomalies didn't have a normal brain). Often this goes along
with rare chromosome disorders and CP is not genetic or hereditary.
Diagnosis
The diagnosis of cerebral palsy has historically rested on the patient's history and physical examination.
Once diagnosed with cerebral palsy, further diagnostic tests are optional. TheAmerican Academy of
Neurology published an article in 2004 reviewing the literature and evidence available on CT and MRI
imaging. They suggested that neuroimaging with CT or MRI is warranted when the etiology of a patient's
cerebral palsy has not been established - an MRI is preferred over CT due to diagnostic yield and safety.
When abnormal, the neuroimaging study can suggest the timing of the initial damage. The CT or MRI is
also capable of revealing treatable conditions, such as hydrocephalus, porencephaly, arteriovenous
malformation,subdural hematomas and hygromas, and a vermian tumor (which a few studies suggest are
present 5 to 22%). Furthermore, an abnormal neuroimaging study indicates a high likelihood of
associated conditions, such as epilepsy and mental retardation.
Treatment
There is no cure, but various forms of therapy can help a person with the disorder to function and live
more effectively. In general, the earlier treatment begins the better chance children have of overcoming
developmental disabilities or learning new ways to accomplish the tasks that challenge them. The earliest
proven intervention occurs during the infant's recovery in theneonatal intensive care unit (NICU).
Treatment may include one or more of the following: physical therapy; occupational therapy; speech
therapy; drugs to control seizures, alleviate pain, or relax muscle spasms (e.g. benzodiazepienes,
baclofen and intrathecal phenol/baclofen); hyperbaric oxygen; the use of Botox to relax contracting
muscles; surgery to correct anatomical abnormalities or release tight muscles; braces and other orthotic
devices; rolling walkers; and communication aids such as computers with attached voice synthesizers.
For instance, the use of a standing frame can help reduce spasticity and improve range of motion for
people with CP who use wheelchairs. Nevertheless, there is only some benefit from therapy. Treatment is
usually symptomatic and focuses on helping the person to develop as many motor skills as possible or to
learn how to compensate for the lack of them. Non-speaking people with CP are often successful availing
themselves of augmentative and alternative communication systems such as Blissymbols.
Interpersonal therapy
Physiotherapy programs are designed to encourage the patient to build a strength base for improved gait
and volitional movement, together with stretching programs to limit contractures. Many experts believe
that life-long physiotherapy is crucial to maintain muscle tone, bone structure, and prevent dislocation of
the joints.
Occupational therapy helps adults and children maximise their function, adapt to their limitations and live
as independently as possible.
Speech therapy helps control the muscles of the mouth and jaw, and helps improve communication. Just
as CP can affect the way a person moves their arms and legs, it can also affect the way they move their
mouth, face and head. This can make it hard for the person to breathe; talk clearly; and bite, chew and
swallow food. Speech therapy often starts before a child begins school and continues throughout the
school years.
Conductive education was developed in Hungary from 1945 based on the work of András Pető. It is a
unified system of rehabilitation for people with neurological disorders including cerebral palsy, Parkinson's
disease and multiple sclerosis, amongst other conditions. It is theorised to improve mobility, self-esteem,
stamina and independence as well as daily living skills and social skills. The conductor is the professional
who delivers CE in partnership with parents and children. Skills learned during CE should be applied to
everyday life and can help to develop age-appropriate cognitive, social and emotional skills. It is available
at specialized centers.
Biofeedback is an alternative therapy in which people with CP learn how to control their affected muscles.
Some people learn ways to reduce muscle tension with this technique. Biofeedback does not help
everyone with CP.
Neuro-cognitive therapy. It is based upon two proven principles. (1) Neural Plasticity. The brain is capable
of altering its own structure and functioning to meet the demands of any particular environment.
Consequently if the child is provided with an appropriate neurological environment, he will have the best
chance of making progress. (2) Learning can lead to development. As early as the early 1900s, this was
being proven by a psychologist named Lev Vygotsky. He proposed that children's learning is a social
activity, which is achieved by interaction with more skilled members of society. There are many studies
which provide evidence for this claim. There are however, as yet no controlled studies on neuro-cognitive
therapy.
Patterning is a controversial form of alternative therapy for people with CP. The method is promoted by
The Institutes for the Achievement of Human Potential (IAHP), a Philadelphia nonprofit, but has been
criticized by the American Academy of Pediatrics. The IAHP's methods have been endorsed by Linus
Pauling, as well as some parents of children treated with their methods.
Massage therapy is designed to help relax tense muscles, strengthen muscles, and keep joints flexible.
More research is needed to determine the health benefits of these therapies for people with CP.
Occupational therapy
Main article: Occupational therapy in the management of cerebral palsy
Occupational Therapy (OT) enables individuals with CP to participate in activities of daily living that are
meaningful to them. A family-centred philosophy is used with children who have CP. Occupational
therapists work closely with families in order to address their concerns and priorities for their child.
Occupational therapists may address issues relating to sensory, cognitive, or motor impairments resulting
from CP that affect the child's participation in self-care, productivity, or leisure. Parent counselling is also
an important aspect of occupational therapy treatment with regard to optimizing the parent's skills in
caring for and playing with their child to support improvement of their child's abilities to do things. The
occupational therapist typically assesses the child to identify abilities and difficulties, and environmental
conditions, such as physical and cultural influences, that affect participation in daily activities.
Occupational therapists may also recommend changes to the play space, changes to the structure of the
room or building, and seating and positioning techniques to allow the child to play and learn effectively.
Medication
Botulinum toxin A (Botox) injections into muscles that are either spastic or have contractures, the aim
being to relieve the disability and pain produced by the inappropriately contracting muscle.
Surgery and orthoses
Surgery usually involves one or a combination of:
Loosening tight muscles and releasing fixed joints, most often performed on the hips, knees,
hamstrings, and ankles. In rare cases, this surgery may be used for people with stiffness of their elbows,
wrists, hands, and fingers.
The insertion of a baclofen pump usually during the stages while a patient is a young adult. This
is usually placed in the left abdomen. It is a pump that is connected to the spinal cord, whereby it sends
bits of Baclofen alleviating the continuous muscle flexion. Baclofen is a muscle relaxant and is often given
PO "per os" (Latin for "by mouth") to patients to help counter the effects of spasticity.
Straightening abnormal twists of the leg bones, i.e. femur (termed femoral anteversion or
antetorsion) and tibia (tibial torsion). This is a secondary complication caused by the spastic muscles
generating abnormal forces on the bones, and often results in intoeing (pigeon-toed gait). The surgery is
called derotation osteotomy, in which the bone is broken (cut) and then set in the correct alignment.
Cutting nerves on the limbs most affected by movements and spasms. This procedure, called a
rhizotomy, "rhizo" meaning root and "tomy" meaning "a cutting of" from the Greek suffix 'tomia' reduces
spasms and allows more flexibility and control of the affected limbs and joints.
Orthotic devices such as ankle-foot orthoses (AFOs) are often prescribed to minimise gait irregularities.
AFOs have been found to improve several measures of ambulation, including reducing energy
expenditure and increasing speed and stride length.
Other
Cooling high-risk full-term babies shortly after birth may significantly reduce disability or death.
Early nutritional support: In one cohort study of 490 premature infants discharged from the NICU, the rate
of growth during hospital stay was related to neurological function at 18 and 22 months of age. The study
found a significant decrease in the incidence of cerebral palsy in the group of premature infants with the
highest growth velocity. This study suggests that adequate nutrition and growth play a protective role in
the development of cerebral palsy.
Hyperbaric oxygen therapy (HBOT), in which pressurized oxygen is inhaled inside a hyperbaric chamber,
has been studied under the theory that improving oxygen availability to damaged brain cells can
reactivate some of them to function normally. A 2007 systematic review concluded that the effect of
HBOT is no different from that of pressurized room air, and that some children undergoing HBOT will
experience adverse events such as seizures and the need for ear pressure equalization tubes; due to
poor quality of data assessment the review also concluded that estimates of the prevalence of adverse
events are uncertain.
Prognosis
CP is not a progressive disorder (meaning the brain damage neither improves nor worsens), but the
symptoms can become more severe over time due to subdural damage. A person with the disorder may
improve somewhat during childhood if he or she receives extensive care from specialists, but once bones
and musculature become more established, orthopedic surgery may be required for fundamental
improvement. People who have CP tend to develop arthritis at a younger age than normal because of the
pressure placed on joints by excessively toned and stiff muscles.
The full intellectual potential of a child born with CP will often not be known until the child starts school.
People with CP are more likely to have some type of learning disability, but this is not related to a
person's intellect or IQ level. Intellectual level among people with CP varies from genius to intellectually
impaired, as it does in the general population, and experts have stated that it is important to not
underestimate a person with CP's capabilities and to give them every opportunity to learn.
The ability to live independently with CP varies widely depending on the severity of each case. Some
individuals with CP will require personal assistant services for all activities of daily living. Others can lead
semi-independent lives, needing support only for certain activities. Still others can live in complete
independence. The need for personal assistance often changes with increasing age and associated
functional decline. However, in most cases persons with CP can expect to have a normal life expectancy;
survival has been shown to be associated with the ability to ambulate, roll, and self-feed. As the condition
does not directly affect reproductive function, some persons with CP have children and parent
successfully.
According to OMIM, only 2% of cases of CP are inherited (with glutamate decarboxylase-1 as one known
enzyme involved.) There is no evidence of an increased chance of a person with CP having a child with
CP.
The common signs and symptoms associated with CP can have a significant impact on participation in
occupations. Occupation is a term used in occupational therapy that refers to all activities a person does
throughout their day. These activities may be grouped into the categories of self-care, productivity and
leisure activities. Impairments related to CP can impact these activities. For example, children with motor
impairments may also experience difficulties moving around their home and community, such as
transportation, moving from room to room or transferring from wheelchair to toilet.
Self-care
Self-care is any activity children do to care for themselves. For many children with CP, parents are
heavily involved in self-care activities. Self-care activities, such as bathing, dressing, grooming and
eating, can be difficult for children with CP as self-care depends primarily on use of the upper limbs. For
those living with CP, impaired upper limb function affects almost 50% of children and is considered the
main factor contributing to decreased activity and participation. Since the hands are used for many self-
care tasks, it is logical that sensory and motor impairments would impact daily self-care. The extent of the
hand impairment depends on the location and degree of brain damage. Sensory impairments can make
getting dressed and brushing teeth difficult. Along with sensory impairments, motor impairments of the
hand are thought to be responsible for difficulties experienced in daily, self-care activities. However,
motor impairments are more important than sensory impairments, with the most prevalent impairment
being finger dexterity (ability to manipulate small objects).Finger dexterity is essential in fastening buttons,
doing up zippers and tying shoelaces. With upper limb spasticity, it may be difficult to get dressed in the
morning. If the individual with CP also has cognitive deficits, this may add an additional challenge to
dressing and grooming.
Children with CP often have oral sensory disturbances meaning that they have too little or too much
sensitivity around and in the mouth. An infant with CP may not be able to suck, swallow or chew and this
can result in difficulty eating. As mentioned in the above paragraph, finger dexterity is the most prevalent
motor impairment. Finger dexterity is essential for manipulating cutlery or bringing food to the mouth. Fine
finger dexterity, like picking up a spoon, is more frequently impaired than gross manual dexterity, like
spooning food onto a plate. Grip strength impairments are less common. Overall, children with CP may
have difficulty chewing and swallowing food, holding utensils, and preparing food due to sensory and
motor impairments.
Productivity
The effects of sensory, motor and cognitive impairments not only affect self-care occupations in children
with CP, but also productivity occupations. Productivity can include, but is not limited to: school, work,
household chores and contributing to the community. Play is also included as a productive occupation as
it is often the primary activity for children.
Play is considered the main occupation for children. If play becomes difficult due to a disability, like CP,
this can cause problems for the child. These difficulties can affect a child’s self-esteem and sense of self-
value and worth. As well, the sensory and motor problems experienced by children with CP affect how the
child interacts with his or her surroundings, including the environment and other people. Not only do
physical limitations affect a child’s ability to play, the limitations perceived by the child’s caregivers and
playmates also impact the child’s play activities. Typically, children with disabilities spend more time
playing by themselves. When a disability prevents a child from playing, there may be social, emotional
and psychological problems, which can lead to being more dependent on others, less motivation and poor
social skills.
In school, students are asked to complete many tasks and activities, many of which involve handwriting.
Many children with CP have the capacity to learn and write in the school environment. However, students
with CP may find it difficult to keep up with the handwriting demands of school and their writing may be
difficult to read. In addition, writing may take longer and require greater effort on the student’s part.
Factors linked to handwriting include: postural stability, sensory and perceptual abilities of the hand and
writing tool pressure.
Also, speech impairments may be seen in children with CP depending on the severity of brain damage.
Communication in a school setting is quite important because communicating with peers and teachers is
very much a part of the “school experience” and enhances social interaction. Problems with language or
motor dysfunction can lead to underestimating a student’s intelligence. In summary, children with CP may
experience difficulties in school, such as difficulty with handwriting, carrying out school activities,
communicating verbally and interacting socially.
Leisure
Leisure occupations are any activities that are done for enjoyment. Enjoyable activities depend on the
child’s personality and environment. Leisure activities can have several positive effects on physical
health, mental health, life satisfaction and psychological growth for children with physical disabilities like
CP. Common benefits identified are stress reduction, development of coping skills, companionship,
enjoyment, relaxation and a positive effect on life satisfaction. In addition, for children with CP, leisure
appears to enhance adjustment to living with a disability.
Leisure can be divided into structured (formal) and unstructured (informal) activities. Studies show that
children with disabilities, like CP, participate mainly in informal activities that are carried out in the family
environment and are organized by adults. Typically, children with disabilities carry out leisure activities by
themselves or with their parents rather than with friends. Therefore, children may experience limited
diversity of activities and social engagements, as well as a more passive lifestyle than their peers.
Although leisure is important for children with CP, they may have difficulties carrying out leisure activities
due to social and physical barriers.
Participation and barriers
Participation is considered involvement in life situations and everyday activities. Participation includes the
domains of self-care, productivity and leisure. In fact, communication, mobility, education, home life,
leisure and social relationships require participation and are indicators of the extent to which a child
functions in his or her environment. Barriers can exist on three levels: micro, meso and macro. Firstly, the
barriers at the micro level involve the person. Barriers at the micro level include the child’s physical
limitations (motor, sensory and cognitive impairments) or their subjective feelings regarding their ability to
participate. For example, the child may not participate in group activities due to lack of confidence.
Secondly, the barriers at the meso level include the family and community. These may include negative
attitudes of people towards disability or lack of support within the family or in the community. One of the
main reasons for this limited support appears to be the result of a lack of awareness and knowledge
regarding the child’s ability to engage in activities despite his or her disability. Thirdly, barriers at the
macro level incorporate the systems and policies that are not in place or hinder children with CP. These
may be environmental barriers to participation such as architectural barriers, lack of relevant assistive
technology and transportation difficulties due to limited wheelchair or public transit that can accommodate
the children with CP. For example, a building without an elevator may prevent the child from accessing
higher floor levels.
Epidemiology
In the industrialized world, the incidence of cerebral palsy is about 2 per 1000 live births. The incidence is
higher in males than in females; the Surveillance of Cerebral Palsy in Europe (SCPE) reports a M:F ratio
of 1.33:1. Variances in reported rates of incidence across different geographical areas in industrialised
countries are thought to be caused primarily by discrepancies in the criteria used for inclusion and
exclusion. When such discrepancies are taken into account in comparing two or more registers of
patients with cerebral palsy (for example, the extent to which children with mild cerebral palsy are
included), the incidence rates converge toward the average rate of 2:1000.
In the United States, approximately 10,000 infants and babies are diagnosed with CP each year, and
1200–1500 are diagnosed at preschool age.
Overall, advances in care of pregnant mothers and their babies has not resulted in a noticeable decrease
in CP. This is generally attributed to medical advances in areas related to the care of premature babies
(which results in a greater survival rate). Only the introduction of quality medical care to locations with
less-than-adequate medical care has shown any decreases. The incidence of CP increases with
premature or very low-weight babies regardless of the quality of care.
Prevalence of cerebral palsy is best calculated around the school entry age of about six years, the
prevalence in the U.S. is estimated to be 2.4 out of 1000 children
The SCPE reported the following incidence of comorbidities in children with CP (the data are from 1980–
1990 and included over 4,500 children over age 4 whose CP was acquired during the prenatal or
neonatal period):
Mental disadvantage (IQ < 50): 31%
Active seizures: 21%
Mental disadvantage (IQ < 50) and not walking: 20%
Blindness: 11%
The SCPE noted that the incidence of comorbidities is difficult to measure accurately, particularly across
centers. For example, the actual rate of an intellectual impairment may be difficult to determine, as the
physical and communicational limitations of people with CP would likely lower their scores on an IQ test if
they were not given a correctly modified version.
Apgar scores have sometimes been used as one factor to predict whether or not an individual will
develop CP.
History
CP, formerly known as "Cerebral Paralysis," was first identified by English surgeon William Little in 1860.
Little raised the possibility of asphyxia during birth as a chief cause of the disorder. It was not until 1897
that Sigmund Freud, then a neurologist, suggested that a difficult birth was not the cause but rather only a
symptom of other effects on fetal development. Research conducted during the 1980s by the National
Institute of Neurological Disorders and Stroke (NINDS) suggested that only a small number of cases of
CP are caused by lack of oxygen during birth.
Society and culture
Economic impact
Access Economics has released a report on the economic impact of cerebral palsy in Australia. Launched
by the Hon. Bill Shorten, MP, the report found that, in 2007, the financial cost of cerebral palsy (CP) in
Australia was $1.47 billion or 0.14% of GDP. When the value of lost well-being (disability and premature
death) was added, the cost rose a further $2.4 billion.
In 2007, the financial cost of CP was $1.47 billion (0.14% of GDP). Of this:
1.03 billion (69.9%) was productivity lost due to lower employment, absenteeism and premature
death of Australians with CP;
141 million (9.6%) was the DWL from transfers including welfare payments and taxation forgone;
131 million (9.0%) was other indirect costs such as direct program services, aides and home
modifications and the bringing-forward of funeral costs;
129 million (8.8%) was the value of the informal care for people with CP; and
40 million (2.8%) was direct health system expenditure.
Additionally, the value of the lost well-being (disability and premature death) was a further $2.4 billion.
In per capita terms, this amounts to a financial cost of $43,431 per person with CP per annum. Including
the value of lost well-being, the cost is over $115,000 per person per annum.
Individuals with CP bear 37% of the financial costs, and their families and friends bear a further 6%.
Federal government bears around one third (33%) of the financial costs (mainly through taxation
revenues forgone and welfare payments). State governments bear under 1% of the costs, while
employers bear 5% and the rest of society bears the remaining 19%. If the burden of disease (lost well-
being) is included, individuals bear 76% of the costs.
Meningitis
Meningitis

Meninges of the central nervous system: dura mater,

arachnoid, and pia mater.
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known
collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other
microorganisms, and less commonly by certain drugs. Meningitis can be life-threatening because of the
inflammation's proximity to the brain and spinal cord; therefore the condition is classified as a medical
emergency.
The most common symptoms of meningitis are headache and neck stiffness associated with fever,
confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud
noises (phonophobia). Sometimes, especially in small children, only nonspecific symptoms may be
present, such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of
meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied by a
characteristic rash.
A lumbar puncture may be used to diagnose or exclude meningitis. This involves inserting a needle into
the spinal canal to extract a sample of cerebrospinal fluid (CSF), the fluid that envelops the brain and
spinal cord. The CSF is then examined in a medical laboratory. The usual treatment for meningitis is the
prompt application of antibiotics and sometimes antiviral drugs. In some situations, corticosteroid drugs
can also be used to prevent complications from overactive inflammation. Meningitis can lead to serious
long-term consequences such as deafness, epilepsy, hydrocephalus and cognitive deficits, especially if
not treated quickly. Some forms of meningitis (such as those associated with meningococci, Haemophilus
influenzae type B, pneumococci or mumps virus infections) may be prevented by immunization.
Signs and symptoms
Clinical features
In adults, a severe headache is the most common symptom of meningitis – occurring in almost 90% of
cases of bacterial meningitis, followed by nuchal rigidity (inability to flex the neck forward passively due to
increased neck muscle tone and stiffness). The classic triad of diagnostic signs consists of nuchal rigidity,
sudden high fever, and altered mental status; however, all three features are present in only 44–46% of
all cases of bacterial meningitis. If none of the three signs is present, meningitis is extremely unlikely.
Other signs commonly associated with meningitis include photophobia (intolerance to bright light) and
phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned
symptoms, and may only be irritable and looking unwell. In infants up to 6 months of age, bulging of the
fontanelle (the soft spot on top of a baby's head) may be present. Other features that might distinguish
meningitis from less severe illnesses in young children are leg pain, cold extremities, and abnormal skin
color.
Nuchal rigidity occurs in 70% of adult cases of bacterial meningitis. Other signs of meningism include the
presence of positive Kernig's sign or Brudzinski's sign. Kernig's sign is assessed with the patient lying
supine, with the hip and knee flexed to 90 degrees. In a patient with a positive Kernig's sign, pain limits
passive extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes
involuntary flexion of the knee and hip. Although Kernig's and Brudzinski's signs are both commonly used
to screen for meningitis, the sensitivity of these tests is limited. They do, however, have very good
specificity for meningitis: the signs rarely occur in other diseases. Another test, known as the "jolt
accentuation maneuver" helps determine whether meningitis is present in patients reporting fever and
headache. The patient is told to rapidly rotate his or her head horizontally; if this does not make the
headache worse, meningitis is unlikely.
Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be
differentiated from meningitis with other causes by a rapidly spreading petechial rash which may precede
other symptoms. The rash consists of numerous small, irregular purple or red spots ("petechiae") on the
trunk, lower extremities, mucous membranes, conjuctiva, and (occasionally) the palms of the hands or
soles of the feet. The rash is typically non-blanching: the redness does not disappear when pressed with
a finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is
relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria.
Other clues as to the nature of the cause of meningitis may be the skin signs of hand, foot and mouth
disease and genital herpes, both of which are associated with various forms of viral meningitis.
Early complications

A severe case of meningococcal meningitis in which the petechial rash progressed to gangrene and
required amputation of all limbs. The patient, Charlotte Cleverley-Bisman, survived the disease and
became a poster child for a meningitis vaccination campaign in New Zealand.
People with meningitis may develop additional problems in the early stages of their illness. These may
require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may
trigger sepsis, a systemic inflammatory response syndrome of falling blood pressure, fast heart rate, high
or abnormally low temperature and rapid breathing. Very low blood pressure may occur early, especially
but not exclusively in meningococcal illness; this may lead to insufficient blood supply to other organs.
Disseminated intravascular coagulation, the excessive activation of blood clotting, may cause both the
obstruction of blood flow to organs and a paradoxical increase of bleeding risk. In meningococcal
disease, gangrene of limbs can occur. Severe meningococcal and pneumococcal infections may result in
hemorrhaging of the adrenal glands, leading to Waterhouse-Friderichsen syndrome, which is often lethal.
The brain tissue may swell, with increasing pressure inside the skull and a risk of swollen brain tissue
getting trapped. This may be noticed by a decreasing level of consciousness, loss of the pupillary light
reflex, and abnormal positioning. Inflammation of the brain tissue may also obstruct the normal flow of
CSF around the brain (hydrocephalus). Seizures may occur for various reasons; in children, seizures are
common in the early stages of meningitis (30% of cases) and do not necessarily indicate an underlying
cause. Seizures may result from increased pressure and from areas of inflammation in the brain tissue.
Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset seizures
and those that are difficult to control with medication are indicators of a poorer long-term outcome.
The inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves
arising from the brain stem that supply the head and neck area and control eye movement, facial muscles
and hearing, among other functions. Visual symptoms and hearing loss may persist after an episode of
meningitis (see below). Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis),
as well as the formation of blood clots in the veins (cerebral venous thrombosis), may all lead to
weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the
affected area in the brain.
Causes
Meningitis is usually caused by infection by viruses or microorganisms. Most cases are due to infection
with viruses, with bacteria, fungi, and parasites being the next most common causes. It may also result
from various non-infectious causes.
Bacterial
The types of bacteria that cause bacterial meningitis vary by age group. In premature babies and
newborns up to three months old, common causes are group B streptococci (subtypes III which normally
inhabit the vagina and are mainly a cause during the first week of life) and those that normally inhabit the
digestive tract such as Escherichia coli (carrying K1 antigen). Listeria monocytogenes (serotype IVb) may
affect the newborn and occurs in epidemics. Older children are more commonly affected by Neisseria
meningitidis (meningococcus), Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those
under five by Haemophilus influenzae type B (in countries that do not offer vaccination, see below). In
adults, N. meningitidis and S. pneumoniae together cause 80% of all cases of meningitis, with increased
risk of L. monocytogenes in those over 50 years old.
Recent trauma to the skull gives bacteria in the nasal cavity the potential to enter the meningeal space.
Similarly, individuals with a cerebral shunt or related device (such as an extraventricular drain or Ommaya
reservoir) are at increased risk of infection through those devices. In these cases, infections with
staphylococci are more likely, as well as infections by pseudomonas and other Gram-negative bacilli. The
same pathogens are also more common in those with an impaired immune system. In a small proportion
of people, an infection in the head and neck area, such as otitis media or mastoiditis, can lead to
meningitis. Recipients of cochlear implants for hearing loss are at an increased risk of pneumococcal
meningitis.
Tuberculous meningitis, meningitis due to infection with Mycobacterium tuberculosis, is more common in
those from countries where tuberculosis is common, but is also encountered in those with immune
problems, such as AIDS.
Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or
acquired, or by disorders of the immune system. Anatomical defects allow continuity between the external
environment and the nervous system. The most common cause of recurrent meningitis is skull fracture,
particularly fractures that affect the base of the brain or extend towards the sinuses and petrous
pyramids. A literature review of 363 reported cases of recurrent meningitis showed that 59% of cases are
due to such anatomical abnormalities, 36% due to immune deficiencies (such as complement deficiency,
which predisposes especially to recurrent meningococcal meningitis), and 5% due to ongoing infections in
areas adjacent to the meninges.
Aseptic
The term aseptic meningitis refers loosely to all cases of meningitis in which no bacterial infection can be
demonstrated. This is usually due to viruses, but it may be due to bacterial infection that has already been
partially treated, with disappearance of the bacteria from the meninges, or by infection in a space
adjacent to the meninges (e.g. sinusitis). Endocarditis (infection of the heart valves with spread of small
clusters of bacteria through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also
result from infection with spirochetes, a type of bacteria that includes Treponema pallidum (the cause of
syphilis) and Borrelia burgdorferi (known for causing Lyme disease). Meningitis may be encountered in
cerebral malaria (malaria infecting the brain). Fungal meningitis, e.g. due to Cryptococcus neoformans, is
typically seen in people with immune deficiency such as AIDS. Amoebic meningitis, meningitis due to
infection with amoebae such as Naegleria fowleri, is contracted from freshwater sources.
Viral
Viruses that can cause meningitis include enteroviruses, herpes simplex virus type 2 (and less commonly
type 1), varicella zoster virus (known for causing chickenpox and shingles), mumps virus, HIV, and
LCMV.
Non-infectious
Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges
(malignant meningitis) and certain drugs (mainly non-steroidal anti-inflammatory drugs, antibiotics and
intravenous immunoglobulins). It may also be caused by several inflammatory conditions such as
sarcoidosis (which is then called neurosarcoidosis), connective tissue disorders such as systemic lupus
erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood vessel wall) such as
Behçet's disease. Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant matter
into the subarachnoid space. Mollaret's meningitis is a syndrome of recurring episodes of aseptic
meningitis; it is now thought to be caused by herpes simplex virus type 2. Rarely, migraine may cause
meningitis, but this diagnosis is usually only made when other causes have been eliminated.
Mechanism
The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect
the brain and spinal cord (the central nervous system). The pia mater is a very delicate impermeable
membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid
mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia
mater. The subarachnoid space separates the arachnoid and pia mater membranes, and is filled with
cerebrospinal fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is
attached to both the arachnoid membrane and the skull.
In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream
or through direct contact between the meninges and either the nasal cavity or the skin. In most cases,
meningitis follows invasion of the bloodstream by organisms that live upon mucous surfaces such as the
nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier
provided by the mucous surfaces. Once bacteria have entered the bloodstream, they enter the
subarachnoid space in places where the blood-brain barrier is vulnerable—such as the choroid plexus.
Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci; this
phenomenon is less common in adults. Direct contamination of the cerebrospinal fluid may arise from
indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed
a tract with the subarachnoid space (see above); occasionally, congenital defects of the dura mater can
be identified.
The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result
of bacterial infection but can rather largely be attributed to the response of the immune system to the
entrance of bacteria into the central nervous system. When components of the bacterial cell membrane
are identified by the immune cells of the brain (astrocytes and microglia), they respond by releasing large
amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues
to participate in an immune response. The blood-brain barrier becomes more permeable, leading to
"vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels). Large
numbers of white blood cells enter the CSF, causing inflammation of the meninges, and leading to
"interstitial" edema (swelling due to fluid between the cells). In addition, the walls of the blood vessels
themselves become inflamed (cerebral vasculitis), which leads to a decreased blood flow and a third type
of edema, "cytotoxic" edema. The three forms of cerebral edema all lead to an increased intracranial
pressure; together with the lowered blood pressure often encountered in acute infection, this means that it
is harder for blood to enter the brain, and brain cells are deprived of oxygen and undergo apoptosis
(automated cell death).
It is recognized that administration of antibiotics may initially worsen the process outlined above, by
increasing the amount of bacterial cell membrane products released through the destruction of bacteria.
Particular treatments, such as the use of corticosteroids, are aimed at dampening the immune system's
response to this phenomenon.
Diagnosis
CSF findings in different forms of meningitis
Type of meningitis Glucose Protein Cells
PMNs,
Acute bacterial low high
often > 300/mm³
mononuclear,
Acute viral normal normal or high
< 300/mm³
mononuclear and
Tuberculous low high
PMNs, < 300/mm³
Fungal low high < 300/mm³
usually
Malignant low high
mononuclear
Blood tests and imaging
In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g.
C-reactive protein, complete blood count), as well as blood cultures.
The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid through
lumbar puncture (LP, spinal tap). However, lumbar puncture is contraindicated if there is a mass in the
brain (tumor or abscess) or the intracranial pressure (ICP) is elevated, as it may lead to brain herniation.
If someone is at risk for either a mass or raised ICP (recent head injury, a known immune system
problem, localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is
recommended prior to the lumbar puncture. This applies in 45% of all adult cases. If a CT or MRI is
required before LP, or if LP proves difficult, professional guidelines suggest that antibiotics should be
administered first to prevent delay in treatment, especially if this may be longer than 30 minutes. Often,
CT or MRI scans are performed at a later stage to assess for complications of meningitis.
In severe forms of meningitis, monitoring of blood electrolytes may be important; for example,
hyponatremia is common in bacterial meningitis, due to a combination of factors including dehydration,
the inappropriate excretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid
administration.
Lumbar puncture
A lumbar puncture is done by positioning the patient, usually lying on the side, applying local anesthetic,
and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid
(CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a
manometer. The pressure is normally between 6 and 18 cm water (cmH2O); in bacterial meningitis the
pressure is typically elevated. The initial appearance of the fluid may prove an indication of the nature of
the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and
therefore may suggest bacterial meningitis.

Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs
The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content
and glucose level. Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but
absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this
figure is reduced by a further 20% if antibiotics were administered before the sample was taken, and
Gram staining is also less reliable in particular infections such as listeriosis. Microbiological culture of the
sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to
48 hours to become available. The type of white blood cell predominantly present indicates whether
meningitis is due to bacterial or viral infection (see table), although in the beginning of the disease this is
not always a reliable indicator.
The concentration of glucose in CSF is normally above 40% that in blood. In bacterial meningitis it is
typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum
glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis; in the newborn, glucose levels in CSF are
normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal. High levels of lactate in
CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count.
Various more specialized tests may be used to distinguish between various types of meningitis. A latex
agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria
meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not
encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic.
Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is
of limited use unless other tests have been unhelpful. Polymerase chain reaction (PCR) is a technique
used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in
cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting
agent's DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing
the various causes of viral meningitis (enterovirus, herpes simplex virus 2 and mumps in those not
vaccinated for this). Serology (identification of antibodies to viruses) may be useful in viral meningitis. If
tuberculous meningitis is suspected, the sample is processed for Ziehl-Neelsen stain, which has a low
sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly.
Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF;
however, testing for cryptococcal antigen in blood or CSF is more sensitive, particularly in persons with
AIDS.
A diagnostic and therapeutic conundrum is the "partially treated meningitis", where there are meningitis
symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings
may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is
definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR).
Postmortem
Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a
widespread inflammation of the pia mater and arachnoid layers of the meninges covering the brain and
spinal cord. Neutrophil leucocytes tend to have migrated to the cerebrospinal fluid and the base of the
brain, along with cranial nerves and the spinal cord, may be surrounded with pus—as may the meningeal
vessels.
Prevention
For some causes of meningitis, prophylaxis can be provided in the long term with vaccine, or in the short
term with antibiotics.
Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in
their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of
meningitis in young children in those countries. In the countries where the disease burden is highest,
however, the vaccine is still too expensive. Similarly, immunization against mumps has led to a sharp fall
in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of
mumps.
Meningococcus vaccines exist against groups A, C, W135 and Y. In countries where the vaccine for
meningococcus group C was introduced, cases caused by this pathogen have decreased substantially. A
quadrivalent vaccine now exists, which combines all four vaccines. Immunization with the ACW135Y
vaccine against four strains is now a visa requirement for taking part in the Hajj. Development of a
vaccine against group B meningococci has proved much more difficult, as its surface proteins (which
would normally be used to make a vaccine) only elicit a weak response from the immune system, or
cross-react with normal human proteins. Still, some countries (New Zealand, Cuba, Norway and Chile)
have developed vaccines against local strains of group B meningococci; some have shown good results
and are used in local immunization schedules.
Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV),
which is active against seven common serotypes of this pathogen, significantly reduces the incidence of
pneumococcal meningitis. The pneumococcal polysaccharide vaccine, which covers 23 strains, is only
administered in certain groups (e.g. those who have had a splenectomy, the surgical removal of the
spleen); it does not elicit a significant immune response in all recipients, e.g. small children.
Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of
tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better
vaccine.
Short-term antibiotic prophylaxis is also a method of prevention, particularly of meningococcal meningitis.
In cases of meningococcal meningitis, prophylactic treatment of close contacts with antibiotics (e.g.
rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not
protect against future infections.
Treatment
Initial treatment
Meningitis is potentially life-threatening and has a high mortality rate if untreated; delay in treatment has
been associated with a poorer outcome. Thus treatment with wide-spectrum antibiotics should not be
delayed while confirmatory tests are being conducted. If meningococcal disease is suspected in primary
care, guidelines recommend that benzylpenicillin be administered before transfer to hospital. Intravenous
fluids should be administered if hypotension (low blood pressure) or shock are present. Given that
meningitis can cause a number of early severe complications, regular medical review is recommended to
identify these complications early, as well as admission to an intensive care unit if deemed necessary.
Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence of
respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure
may be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments
to decrease the intracranial pressure with medication (e.g. mannitol). Seizures are treated with
anticonvulsants. Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-
term drainage device, such as a cerebral shunt.
Bacterial meningitis
Antibiotics

Structural formula of ceftriaxone, one of the third-generation cefalosporin antibiotics recommended for the
initial treatment of bacterial meningitis.
Empiric antibiotics (treatment without exact diagnosis) must be started immediately, even before the
results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends
largely on the kind of bacteria that cause meningitis in a particular place. For instance, in the United
Kingdom empirical treatment consists of a third-generation cefalosporin such as cefotaxime or
ceftriaxone. In the USA, where resistance to cefalosporins is increasingly found in streptococci, addition
of vancomycin to the initial treatment is recommended. Empirical therapy may be chosen on the basis of
the age of the patient, whether the infection was preceded by head injury, whether the patient has
undergone neurosurgery and whether or not a cerebral shunt is present. For instance, in young children
and those over 50 years of age, as well as those who are immunocompromised, addition of ampicillin is
recommended to cover Listeria monocytogenes. Once the Gram stain results become available, and the
broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal
with the presumed group of pathogens.
The results of the CSF culture generally take longer to become available (24–48 hours). Once they do,
empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism
and its sensitivities to antibiotics. For an antibiotic to be effective in meningitis, it must not only be active
against the pathogenic bacterium, but also reach the meninges in adequate quantities; some antibiotics
have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in
meningitis have not been tested directly on meningitis patients in clinical trials. Rather, the relevant
knowledge has mostly derived from laboratory studies in rabbits.
Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is
typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer.
In tuberculous meningitis there is a strong evidence base for treatment with corticosteroids, although this
evidence is restricted to those without AIDS.
Steroids
Adjuvant treatment with corticosteroids (usually dexamethasone) reduces rates of mortality, severe
hearing loss and neurological damage in adolescents and adults from high income countries which have
low rates of HIV. The likely mechanism is suppression of overactive inflammation. Professional guidelines
therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the
first dose of antibiotics is given, and continued for four days. Given that most of the benefit of the
treatment is confined to those with pneumococcal meningitis, some guidelines suggest that
dexamethasone be discontinued if another cause for meningitis is identified.
Adjuvant corticosteroids have a different role in children than in adults. Though the benefit of
corticosteroids has been demonstrated in adults as well as in children from high-income countries, their
use in children from low-income countries is not supported by evidence; the reason for this discrepancy is
not clear. Even in high-income countries, the benefit of corticosteroids is only seen when they are given
prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis, the incidence of
which has decreased dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are
recommended in the treatment of pediatric meningitis if the cause is H. influenzae and only if given prior
to the first dose of antibiotics, whereas other uses are controversial.
Viral and fungal meningitis
Viral meningitis typically requires supportive therapy only; most viruses responsible for causing meningitis
are not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial
meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs
such as aciclovir, but there are no clinical trials that have specifically addressed whether this treatment is
effective. Mild cases of viral meningitis can be treated at home with conservative measures such as fluid,
bedrest, and analgesics. Fungal meningitis, such as cryptococcal meningitis, is treated with long courses
of highly dosed antifungals, such as amphotericin B and flucytosine.
Prognosis
Untreated, bacterial meningitis is almost always fatal. Viral meningitis, in contrast, tends to resolve
spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis
depends on the age of the patient and the underlying cause. Of the newborn patients, 20–30% may die
from an episode of bacterial meningitis. This risk is much lower in older children, whose mortality is about
2%, but rises again to about 19–37% in adults. Risk of death is predicted by various factors apart from
age, such as the pathogen and the time it takes for the pathogen to be cleared from the cerebrospinal
fluid, the severity of the generalized illness, decreased level of consciousness or abnormally low count of
white blood cells in the CSF. Meningitis caused by H. influenza and meningococci has a better prognosis
compared to cases caused by group B streptococci, coliforms and S. pneumoniae. In adults, too,
meningococcal meningitis has a lower mortality (3–7%) than pneumococcal disease.
In children there are several potential disabilities which result from damage to the nervous system.
Sensorineural hearing loss, epilepsy, learning and behavioral difficulties, as well as decreased
intelligence, occur in about 15% of survivors. Some of the hearing loss may be reversible. In adults, 66%
of all cases emerge without disability. The main problems are deafness (in 14%) and cognitive
impairment (in 10%).
Encephalitis

Encephalitis is an acute inflammation of the brain.

Encephalitis with meningitis is known as meningoencephalitis.
Causes
Viral
Viral encephalitis can be due either to the direct effects of an acute infection, or as one of the sequelae of
a latent infection. A common cause of encephalitis in humans is herpes (HSE).
Bacterial and other
It can be caused by a bacterial infection such as bacterial meningitis spreading directly to the brain
(primary encephalitis), or may be a complication of a current infectious disease syphilis (secondary
encephalitis). Certain parasitic or protozoal infestations, such as toxoplasmosis, malaria, or primary
amoebic meningoencephalitis, can also cause encephalitis in people with compromised immune systems.
Lyme disease and/or Bartonella henselae may also cause encephalitis.
Another cause is granulomatous amoebic encephalitis.
Symptoms
Patients with encephalitis suffer from fever, headache and photophobia with weakness and seizures also
common. Less commonly, stiffness of the neck (nuchal rigidity) can occur with rare cases of patients also
suffering from stiffness of the limbs, slowness in movement and clumsiness depending on which specific
part of the brain is involved. The symptoms of encephalitis are caused by the brain's defense
mechanisms activating to get rid of the infection. Other symptoms can include drowsiness and coughing.
Diagnosis
Adult patients with encephalitis present with acute onset of fever, headache, confusion, and sometimes
seizures. Younger children or infants may present irritability, poor appetite and fever.
Neurological examinations usually reveal a drowsy or confused patient. Stiff neck, due to the irritation of
the meninges covering the brain, indicates that the patient has either meningitis or meningoncephalitis.
Examination of the cerebrospinal fluid obtained by a lumbar puncture procedure usually reveals increased
amounts of protein and white blood cells with normal glucose, though in a significant percentage of
patients, the cerebrospinal fluid may be normal. CT scan often is not helpful, as cerebral abscess is
uncommon. Cerebral abscess is more common in patients with meningitis than encephalitis. Bleeding is
also uncommon except in patients with herpes simplex type 1 encephalitis. Magnetic resonance imaging
offers better resolution. In patients with herpes simplex encephalitis, electroencephalograph may show
sharp waves in one or both of the temporal lobes. Lumbar puncture procedure is performed only after the
possibility of prominent brain swelling is excluded by a CT scan examination. Diagnosis is often made
with detection of antibodies in the cerebrospinal fluid against a specific viral agent (such as herpes
simplex virus) or by polymerase chain reaction that amplifies the RNA or DNA of the virus responsible
(such as varicella zoster virus).
Treatment
Treatment is usually symptomatic. Reliably tested specific antiviral agents are available only for a few
viral agents (e.g. acyclovir for herpes simplex virus) and are used with limited success for most infection
except herpes simplex encephalitis. In patients who are very sick, supportive treatment, such as
mechanical ventilation, is equally important. Corticosteroids (e.g. methylprednisolone) are used to reduce
brain swelling and inflammation. Sedatives may be needed for irritability or restlessness. Anticonvulsants
are used to prevent and treat seizures.
Encephalitis lethargica
Encephalitis lethargica is an atypical form of encephalitis which caused an epidemic from 1917 to 1928,
resulting in millions of deaths worldwide. Those who survived sank into a semi-conscious state that lasted
for decades until the Parkinsons drug L-DOPA was used to revive those still alive in the late 1960s by
Oliver Sacks.
There have been only a small number of isolated cases in the years since, though in recent years a few
patients have shown very similar symptoms. The cause is now thought to be either a bacterial agent or an
autoimmune response following infection.
Limbic system encephalitis
In a large number of cases, called limbic encephalitis, the pathogens responsible for encephalitis attack
primarily the limbic system (a collection of structures at the base of the brain responsible for emotions and
many other basic functions).

Herpesviral encephalitis
Herpesviral encephalitis is encephalitis associated with herpes simplex virus.
Herpes simplex encephalitis (HSE) is a severe viral infection of the human central nervous system. It is
estimated to affect at least 1 in 500,000 individuals per year. About 1 in 3 cases of HSE result from
primary HSV-1 infection, predominantly occurring in individuals under the age of 18; 2 in 3 cases occur in
seropositive persons, few of whom have history of recurrent orofacial herpes. Approximately 50% of
individuals that develop HSE are over 50 years of age.
HSE is thought to be caused by the retrograde transmission of virus from a peripheral site on the face
following HSV-1 reactivation, along a nerve axon, to the brain. The virus lies dormant in the ganglion of
the trigeminal cranial nerve, but the reason for reactivation, and its pathway to gain access to the brain,
remains unclear. The olfactory nerve may also be involved in HSE, which may explain its predilection for
the temporal lobes of the brain, as the olfactory nerve sends branches there. In horses, a single-
nucleotide polymorphism is sufficient to allow the virus to cause neurological disease; but no similar
mechanism has been found in humans.
Most individuals with HSE show a decrease in their level of consciousness and an altered mental state
presenting as confusion, and changes in personality. Increased numbers of white blood cells can be
found in patient's cerebrospinal fluid, without the presence of pathogenic bacteria and fungi. Patients
typically have a fever. and may have seizures. The electrical activity of the brain changes as the disease
progresses, first showing abnormalities in one temporal lobe of the brain, which spread to the other
temporal lobe 7–10 days later.
Without treatment, HSE results in rapid death in approximately 70% of cases. HSE is fatal in around 20%
of cases treated, and causes serious long-term neurological damage in over half of survivors. Only a
small population of survivors (2.5%) regain completely normal brain function.
West Nile virus

West Nile virus (WNV) is a virus of the family Flaviviridae. Part of the Japanese encephalitis (JE)
antigenic complex of viruses, it is found in both tropical and temperate regions. It mainly infects birds, but
is known to infect humans, horses, dogs, cats, bats, chipmunks, skunks, squirrels, and domestic rabbits.
The main route of human infection is through the bite of an infected mosquito.
Image reconstructions and cryoelectron microscopy reveal a 45–50 nm virion covered with a relatively
smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus
Flavivirus within the family Flaviviridae. The genetic material of WNV is a positive-sense, single strand of
RNA, which is between 11,000 and 12,000 nucleotides long; these genes encode seven non-structural
proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12 kDa
protein blocks; the capsid is contained within a host-derived membrane altered by two viral glycoproteins.
Symptoms
WNV has three different effects on humans. The first is an asymptomatic infection; the second is a mild
febrile syndrome termed West Nile Fever; the third is a neuroinvasive disease termed West Nile
meningitis or encephalitis. In many infected individuals the ratio between the three states is roughly
110:30:1.
The second, febrile stage has an incubation period of 2 to 8 days followed by fever, headache, chills,
diaphoresis (excessive sweating), weakness, lymphadenopathy (swollen lymph nodes), drowsiness, pain
in the joints and symptoms like those of influenza or the flu. Occasionally there is a short-lived truncal
rash and some patients experience gastrointestinal symptoms including nausea, vomiting, loss of
appetite, or diarrhea. All symptoms are resolved within 7 to 10 days, although fatigue can last for some
weeks and lymphadenopathy can take up to two months to resolve.
The more dangerous encephalitis is characterized by similar early symptoms but also a decreased level
of consciousness, sometimes approaching near-coma. Deep tendon reflexes are hyperactive at first, later
diminished. There are also extrapyramidal disorders. Recovery is marked by a long convalescence with
fatigue. An atypical case of West Nile encephalitis presenting as jaw pain has been described.
More recent outbreaks have resulted in a deeper study of the disease and other, rarer, outcomes have
been identified. The spinal cord may be infected, marked by anterior myelitis with or without encephalitis.
WNV-associated Guillain-Barré syndrome has been identified and other rare effects include multifocal
chorioretinitis (which has 100% specificity for identifying WNV infection in patients with possible WNV
encephalitis), hepatitis, myocarditis, nephritis, pancreatitis, and splenomegaly.
Mortality rate
There is no way for the government to accurately measure the number of worldwide cases at this time.
However, the United States keeps records of West Nile infection cases. In 2009, there were 663 cases.
335 of these cases were Encephalitis or Meningitis infections, a reaction to the virus that approximately 1
in 150 people who get the virus will show. 302 cases were filed for West Nile fever, the most likely
symptom of the virus. 26 cases were unspecified. The state of Texas had the most cases, with 104 total.
The total mortality rate for 2009 was 30 deaths of the 663 reported serious cases. That is a 4.5% casualty
rate, but only of the severe infections. Approximately 80% of cases have no symptoms, and therefore the
total casualty rate would be less than 1% of total infections in the U.S. This data and earlier years data is
available from the CDC here: </ref>
Transmission and susceptibility
Transmission
The proboscis of an Aedes albopictus mosquito feeding on human blood. Under experimental conditions,
the Aedes albopictus mosquito (also known as the Asian Tiger Mosquito) has been found to be a vector
of West Nile Virus.
The virus is transmitted through mosquito vectors, which bite and infect birds. The birds are amplifying
hosts, developing sufficient viral levels to transmit the infection to other biting mosquitoes which go on to
infect other birds (in the Western hemisphere the American robin and the American crow are the most
common carriers) and also humans. The infected mosquito species vary according to geographical area;
in the US Culex pipiens (Eastern US), Culex tarsalis (Midwest and West), and Culex quinquefasciatus
(Southeast) are the main sources.
In mammals the virus does not multiply as readily (i.e. does not develop high viremia during infection),
and it is believed that mosquitoes biting infected mammals do not ingest sufficient virus to become
infected, making mammals so-called dead-end infections.
A 2004 paper in Science found that Culex pipiens mosquitoes existed in two populations in Europe, one
which bites birds and one which bites humans. In North America 40% of Culex pipiens were found to be
hybrids of the two types which bite both birds and humans, providing a vector for WNV. This is argued to
provide an explanation of why the West Nile disease has spread more quickly in North America than
Europe. However, these conclusions have been disputed.
Susceptibility
It was initially believed that direct human-to-human transmission was only caused by occupational
exposure, or conjunctival exposure to infected blood. The US outbreak revealed novel transmission
methods, through blood transfusion, organ transplant, intrauterine exposure, and breast feeding. Since
2003, blood banks in the US routinely screen for the virus amongst their donors. As a precautionary
measure, the UK's National Blood Service runs a test for this disease in donors who donate within 28
days of a visit to the United States or Canada.
The more severe outcomes of WNV infection are clearly associated with advancing age and a patient
history of organ transplantation and diabetes. A genetic factor also appears to increase susceptibility to
West Nile disease. A mutation of the gene CCR5 gives some protection against HIV but leads to more
serious complications of WNV infection. Carriers of two mutated copies of CCR5 made up 4 to 4.5% of a
sample of West Nile disease sufferers while the incidence of the gene in the general population is only
1%.
Recently, the potential for mosquito saliva to impact the course of WNV disease was demonstrated.
Mosquitoes inoculate their saliva into the skin while obtaining blood. Mosquito saliva is a pharmacologic
cocktail of secreted molecules, principally proteins, that can affect vascular constriction, blood
coagulation, platelet aggregation, inflammation, and immunity. It has become clear that mosquito saliva
alters the immune response in a manner that may be advantageous to a virus. Studies have shown that it
can specifically modulate the immune response during early virus infection, and mosquito feeding can
exacerbate WNV infection leading to higher viremia and more severe forms of disease. It is unknown
what benefit, if any, the mosquito receives by assisting the virus in this manner, so it is likely that the virus
is simply exploiting the preexisting qualities of mosquito saliva developed for other purposes.
There is no vaccine for humans. A vaccine for horses (ATCvet code: QI05AA10) based on killed viruses
exists; some zoos have given this vaccine to their birds, although its effectiveness there is unknown.
Dogs and cats show few if any signs of infection. There have been no known cases of direct canine-
human or feline-human transmission; although these pets can become infected, it is unlikely that they are
in turn capable of infecting native mosquitoes and thus continuing the disease cycle.
Avoiding mosquito bites is the most straightforward means to avoid infection—remaining indoors (while
preventing mosquitoes from entering) at dawn and dusk, wear light-colored clothing that covers arms and
legs as well as trunk, use insect repellents on both skin and clothing (such as DEET, picaradin, or oil of
lemon eucalyptus for skin and permethrin for clothes). If one becomes infected, generally, treatment is
purely supportive: analgesia for the pain of neurologic diseases; rehydration for nausea, vomiting, or
diarrhea; encephalitis may also require airway protection and seizure management.
Reported cases in the U.S. in 2005 exceeded those in 2004, and cases in 2006 exceeded 2005's totals.
On August 19, 2006, the LA Times reported that the expected incidence rate of WNV was dropping as the
local population becomes exposed to the virus. "In countries like Egypt and Uganda, where West Nile
was first detected, people became fully immune to the virus by the time they reached adulthood", federal
health officials said. However, just days later, the CDC said that WNV cases could reach a three-year
high because hot temperatures had allowed a larger brood of mosquitoes.
History
Studies of phylogenetic lineages have determined that WNV emerged as a distinct virus around 1000
years ago. This initial virus developed into two distinct lineages, Lineage 1 and its multiple profiles is the
source of the epidemic transmission in Africa and throughout the world, while Lineage 2 remains as an
Africa zoonose.
WNV has been posited as one of the possible causes of Alexander the Great's early death based on
reports of avian deaths before his illness period.
WNV was first isolated from a feverish 37 year old woman at Omogo in the West Nile District of Uganda
in 1937 during research on yellow fever virus. A series of serosurveys in 1939 in central Africa found anti-
WNV positive results ranging from 1.4% (Congo) to 46.4% (White Nile region, Sudan). It was
subsequently identified in Egypt (1942) and India (1953), a 1950 serosurvey in Egypt found 90% of those
over 40 years in age had WNV antibodies. The ecology was characterized in 1953 with studies in Egypt
and Israel. The virus became recognized as a cause of severe human meningoencephalitis in elderly
patients during an outbreak in Israel in 1957. The disease was first noted in horses in Egypt and France
in the early 1960s and found to be widespread in southern Europe, southwest Asia and Australia.
The first appearance of WNV in the Western hemisphere was in 1999 with encephalitis reported in
humans, dogs, cats, and horses, and the subsequent spread in the United States may be an important
milestone in the evolving history of this virus. The American outbreak began in the New York City area
(specifically, College Point, Queens) and was later seen in New Jersey and Connecticut; the virus is
believed to have entered in an infected bird or mosquito, although there is no clear evidence. The US
virus was very closely related to a lineage 1 strain found in Israel in 1998. Since the first North American
cases in 1999, the virus has been reported throughout the United States, Canada, Mexico, the Caribbean
and Central America. There have been human cases and horse cases, and many birds are infected. The
Barbary Macaque, Macaca sylvanus was the first non-human primate to contract WNV. Both the US and
Israeli strains are marked by high mortality rates in infected avian populations, the presence of dead
birds—especially corvidae—can be an early indicator of the arrival of the virus.
A high level of media coverage through 2001/2002 raised public awareness of WNV. This coverage was
most likely the result of successive appearances of the virus in new areas, and had the unintended effect
of increasing funding for research on this virus and related arthropod-borne viruses. Such research has
expanded our understanding of viruses transmitted by mosquitoes.
Overwintering mechanism
Vertical transmission of West Nile Virus from female Culex pipiens mosquitoes to their progeny has been
demonstrated in the laboratory. It has been not suggested that vertically infected Culex could survive the
winter to initiate a WNV amplification cycle the following spring. Culex mosquitoes spend the winter
hibernating in protected structures such as root cellars, bank barns, caves, abandoned tunnels and other
subterranean locations. The first overwintering adult mosquitoes to test positive for WNV were collected
in New York, 2000. Since then, positive samples have been identified in New Jersey, 2003 and in
Pennsylvania, 2003, 2004 and 2005.
Geographic distribution
West Nile virus has been described in Africa, Europe, the Middle East, west and central Asia, Oceania
(subtype Kunjin), and most recently, North America.
Recent outbreaks of West Nile virus encephalitis in humans have occurred in Algeria (1994), Romania
(1996 to 1997), the Czech Republic (1997), Congo (1998), Russia (1999), the United States (1999 to
2009), Canada (1999–2003), and Israel (2000).
Epizootics of disease in horses occurred in Morocco (1996), Italy (1998), the United States (1999 to
2001), and France (2000). In 2003, West Nile virus was found in horses in Mexico.
In the US in 2008, West Nile virus was reported in animals in 47 states, D.C. and Puerto Rico. 45 states
and D.C. reported human cases in 2008 with only Maine, Alaska and Hawaii having never had a human
case. (Maine has had occasional animal cases.)
Recent outbreaks
United States: From 1999 through 2001, the CDC confirmed 149 West Nile virus infections, including 18
deaths. In 2002, a total of 4,156 cases were reported, including 284 fatalities. 13 cases in 2002 were
contracted through blood transfusion. The cost of WNV-related health care in 2002 was estimated at
$200 million. The first human West Nile disease in 2003 occurred in June and one West Nile-infected
blood transfusion was also identified that month. In the 2003 outbreak, 9,862 cases and 264 deaths were
reported by the CDC. At least 30% of those cases were considered severe involving meningitis or
encephalitis. In 2004, there were only 2,539 reported cases and 100 deaths. In 2005, there was a slight
increase in the number of cases, with 3,000 cases and 119 deaths reported. 2006 saw another increase,
with 4,269 cases and 177 deaths. In 2007, the number of cases reported decreased to 3,623 and the
number of deaths dropped to 124. In 2007, 1,227 cases of wnv neuroinvasion disease and 117 deaths
occurred. In 2008, West Nile surveillance data reported to CDC, a total of 28 states have reported 236
cases of human WNV illness. A total of 137 cases for which such data were available occurred in males,
median age patients was 48 years. Dates of illness onset ranged from Jan. 17 to Aug. 14: Two cases
were fatal.
Canada: One human death occurred in 1999. In 2002, ten human deaths out of 416 confirmed and
probable cases were reported by Canadian health officials. In 2003, 14 deaths and 1,494 confirmed and
probable cases were reported. Cases were reported in 2003 in Nova Scotia, Quebec, Ontario, Manitoba,
Saskatchewan, Alberta, British Columbia, and the Yukon. In 2004, only 26 cases were reported and two
deaths; however, 2005 saw 239 cases and 12 deaths. By October 28, 2006, 127 cases and no deaths
had been reported. One case was asymptomatic and only discovered through a blood donation. In 2007,
445 Manitobans had confirmed cases of WNV and two people died with a third unconfirmed but
suspected. 17 people have either tested positive or are suspected of having the virus in Saskatchewan,
and only one person has tested positive in Alberta. Saskatchewan has reported 826 cases of WNV plus
three deaths.. The spread of West Nile Virus infected mosquitoes to British Columbia for the first time was
reported in 2009
Israel: In 2000, the CDC found that there were 417 confirmed cases with 326 hospitalizations. 33 of these
people died. The main clinical presentations were encephalitis (57.9%), febrile disease (24.4%), and
meningitis (15.9%).
Romania: In 1996–1997 about 500 cases occurred in Romania with a fatality rate of nearly 10%.
Surveillance methods
West Nile virus can be sampled from the environment by the pooling of trapped mosquitoes, testing avian
blood samples drawn from wild birds and dogs and sentinel monkeys, as well as testing brains of dead
birds found by various animal control agencies and the public. Testing of the mosquito samples requires
the use of RT-PCR to directly amplify and show the presence of virus in the submitted samples. When
using the blood sera of wild bird and sentinel chickens, samples must be tested for the presence of WNV
antibodies by use of immunohistochemistry (IHC) or Enzyme-Linked Immunosorbent Assay (ELISA).
Dead birds, after necropsy, have their various tissues tested for virus by either RT-PCR or
immunohistochemistry, where virus shows up as brown stained tissue because of a substrate-enzyme
reaction.
Control
West Nile control is achieved through mosquito control, by elimination of mosquito breeding sites,
larviciding active breeding areas and encouraging personal use of mosquito repellents. The public is also
encouraged to spend less time outdoors, wear long covering clothing, apply bug repellant that contains
DEET and ensure that mosquitoes cannot enter buildings. Environmentalists have condemned attempts
to control the transmitting mosquitoes by spraying pesticide, saying that the detrimental health effects of
spraying outweigh the relatively few lives which may be saved, and that there are more environmentally
friendly ways of controlling mosquitoes. They also question the effectiveness of insecticide spraying, as
they believe mosquitoes that are resting or flying above the level of spraying will not be killed; the most
common vector in the northeastern U.S., Culex pipiens, is a canopy feeder.
An effective horse vaccine was introduced by Fort Dodge Animal Health (Wyeth).
Treatment research
AMD3100, which had been proposed as an antiretroviral drug for HIV, has shown promise against West
Nile encephalitis. Morpholino antisense oligos conjugated to cell penetrating peptides have been shown
to partially protect mice from WNV disease. There have also been attempts to treat infections using
ribavirin, intravenous immunoglobulin, or alpha interferon. GenoMed, a U.S. biotech company, has found
that blocking angiotensin II can treat the "cytokine storm" of West Nile virus encephalitis as well as other
viruses.
In 2007 the World Community Grid launched the Discovering Dengue Drugs – Together project. This
uses a distributed network of volunteers' computers via the Berkeley Open Infrastructure for Network
Computing (BOINC) to perform computer simulations of interacting molecules. Thousands of small
molecules are screened for potential anti-viral properties with respect to West Nile and related viruses.
Tick-borne encephalitis
Tick-borne meningoencephalitis or Tick-borne encephalitis is a tick-borne viral infection of the central
nervous system affecting humans as well as most other mammals. It is caused by the tick-borne
encephalitis virus.
The number of cases has been increasing in most countries, except Austria.
Presentation
The virus can infect the brain (encephalitis), the membrane that surrounds the brain and spinal cord
(meningitis) or both (meningoencephalitis).
Transmission

Sheep ticks such as this Ixodes ricinus transmit the disease

It is transmitted by the bite of infected deer- or sheep ticks or (rarely) through the non-pasteurized milk of
infected cows. Sexual transmission has been documented in mice with vertical transmission to progeny.
Sexual transmission with humans has never been documented.
Ticks involved in transmission include Ixodes persulcatus and Ixodes ricinus.
Etiology
Russia and Europe report between 10-12,000 human cases annually. The disease is incurable once
manifest, but infection can be prevented by vaccination. In humans, the disease is lethal in approximately
1% of cases and leaves 10-20% of its survivors with permanent neurological damage.
The former Soviet Union did a great deal of research on all tick borne disease including TBE viruses.
Diagnosis
The TBE virus may be present in a seronegative strain or subtype. In such cases a marker for TBE
infection is elevated IFN-g in CSF.
Treatment
There are four main categories of treatment for TBE:
 interferon treatment (similar to interferon used for the treatment of Hepatitis C)
 antibiotic treatment for possible tickborne coinfections
Stroke
Stroke

CT scan slice of the brain showing a right-hemispheric

ischemic stroke (left side of image).
A stroke (sometimes called an acute cerebrovascular attack) is the rapidly developing loss of brain
function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of
glucose & oxygen supply) caused by thrombosis or embolism or due to a hemorrhage. As a result, the
affected area of the brain is unable to function, leading to inability to move one or more limbs on one side
of the body, inability to understand or formulate speech, or inability to see one side of the visual field.
A stroke is a medical emergency and can cause permanent neurological damage, complications, and
death. It is the leading cause of adult disability in the United States and Europe. It is the number two
cause of death worldwide and may soon become the leading cause of death worldwide. Risk factors for
stroke include advanced age, hypertension (high blood pressure), previous stroke or transient ischemic
attack (TIA), diabetes, high cholesterol, cigarette smoking and atrial fibrillation. High blood pressure is the
most important modifiable risk factor of stroke.
The traditional definition of stroke, devised by the World Health Organization in the 1970s, is a
"neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death
within 24 hours". This definition was supposed to reflect the reversibility of tissue damage and was
devised for the purpose, with the time frame of 24 hours being chosen arbitrarily. The 24-hour limit
divides stroke from transient ischemic attack, which is a related syndrome of stroke symptoms that
resolve completely within 24 hours. With the availability of treatments that, when given early, can reduce
stroke severity, many now prefer alternative concepts, such as brain attack and acute ischemic
cerebrovascular syndrome (modeled after heart attack and acute coronary syndrome respectively), that
reflect the urgency of stroke symptoms and the need to act swiftly.
A stroke is occasionally treated with thrombolysis ("clot buster"), but usually with supportive care (speech
and language therapy, physiotherapy and occupational therapy) in a "stroke unit" and secondary
prevention with antiplatelet drugs (aspirin and often dipyridamole), blood pressure control, statins, and in
selected patients with carotid endarterectomy and anticoagulation.
Classification

A slice of brain from the autopsy of a person who suffered an acute middle cerebral artery (MCA) stroke
Strokes can be classified into two major categories: ischemic and hemorrhagic. Ischemic strokes are
those that are due to interruption of the blood supply, while hemorrhagic strokes are the ones which are
due to rupture of a blood vessel or an abnormal vascular structure. 80% of strokes are due to ischemia;
the remainder are due to hemorrhage. Some hemorrhages develop inside areas of ischemia
("hemorrhagic transformation"). It is unknown how many hemorrhages actually start off as ischemic
stroke.
Ischemic stroke
In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of the brain
tissue in that area. There are four reasons why this might happen:
1. Thrombosis (obstruction of a blood vessel by a blood clot forming locally)
2. Embolism (obstruction due to an embolus from elsewhere in the body, see below),
3. Systemic hypoperfusion (general decrease in blood supply, e.g. in shock)
4. Venous thrombosis.
Stroke without an obvious explanation is termed "cryptogenic" (of unknown origin); this constitutes 30-
40% of all ischemic strokes.
There are various classification systems for acute ischemic stroke. The Oxford Community Stroke Project
classification (OCSP, also known as the Bamford or Oxford classification) relies primarily on the initial
symptoms; based on the extent of the symptoms, the stroke episode is classified as total anterior
circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) or posterior
circulation infarct (POCI). These four entities predict the extent of the stroke, the area of the brain
affected, the underlying cause, and the prognosis. The TOAST (Trial of Org 10172 in Acute Stroke
Treatment) classification is based on clinical symptoms as well as results of further investigations; on this
basis, a stroke is classified as being due to (1) thrombosis or embolism due to atherosclerosis of a large
artery, (2) embolism of cardiac origin, (3) occlusion of a small blood vessel, (4) other determined cause,
(5) undetermined cause (two possible causes, no cause identified, or incomplete investigation).
Hemorrhagic stroke

CT scan showing an intracerebral hemorrhage with associated intraventricular hemorrhage.

Intracranial hemorrhage is the accumulation of blood anywhere within the skull vault. A distinction is
made between intra-axial hemorrhage (blood inside the brain) and extra-axial hemorrhage (blood inside
the skull but outside the brain). Intra-axial hemorrhage is due to intraparenchymal hemorrhage or
intraventricular hemorrhage (blood in the ventricular system). The main types of extra-axial hemorrhage
are epidural hematoma (bleeding between the dura mater and the skull), subdural hematoma (in the
subdural space) and subarachnoid hemorrhage (between the arachnoid mater and pia mater). Most of
the hemorrhagic stroke syndromes have specific symptoms (e.g. headache, previous head injury).
Intracerebral hemorrhage (ICH) is bleeding directly into the brain tissue, forming a gradually enlarging
hematoma (pooling of blood).
Signs and symptoms
Stroke symptoms typically start suddenly, over seconds to minutes, and in most cases do not progress
further. The symptoms depend on the area of the brain affected. The more extensive the area of brain
affected, the more functions that are likely to be lost. Some forms of stroke can cause additional
symptoms: in intracranial hemorrhage, the affected area may compress other structures. Most forms of
stroke are not associated with headache, apart from subarachnoid hemorrhage and cerebral venous
thrombosis and occasionally intracerebral hemorrhage.
Early recognition
Various systems have been proposed to increase recognition of stroke by patients, relatives and
emergency first responders. A systematic review, updating a previous systematic review from 1994,
looked at a number of trials to evaluate how well different physical examination findings are able to
predict the presence or absence of stroke. It was found that sudden-onset face weakness, arm drift,(ask
the person to raise both arms. If one arm drifts down, that could indicate a stroke.) , and abnormal speech
are the findings most likely to lead to the correct identification of a case of stroke (+ likelihood ratio of 5.5
when at least one of these is present). Similarly, when all three of these are absent, the likelihood of
stroke is significantly decreased (– likelihood ratio of 0.39). While these findings are not perfect for
diagnosing stroke, the fact that they can be evaluated relatively rapidly and easily make them very
valuable in the acute setting.
Proposed systems include FAST (face, arm, speech, and time), as advocated by the Department of
Health (United Kingdom) and The Stroke Association, the Los Angeles Prehospital Stroke Screen
(LAPSS) and the Cincinnati Prehospital Stroke Scale (CPSS). Use of these scales is recommended by
professional guidelines.
For people referred to the emergency room, early recognition of stroke is deemed important as this can
expedite diagnostic tests and treatments. A scoring system called ROSIER (recognition of stroke in the
emergency room) is recommended for this purpose; it is based on features from the medical history and
physical examination.
Subtypes
If the area of the brain affected contains one of the three prominent Central nervous system pathways—
the spinothalamic tract, corticospinal tract, and dorsal column (medial lemniscus), symptoms may include:
 hemiplegia and muscle weakness of the face
 numbness
 reduction in sensory or vibratory sensation
In most cases, the symptoms affect only one side of the body (unilateral). The defect in the brain is
usually on the opposite side of the body (depending on which part of the brain is affected). However, the
presence of any one of these symptoms does not necessarily suggest a stroke, since these pathways
also travel in the spinal cord and any lesion there can also produce these symptoms.
In addition to the above CNS pathways, the brainstem also consists of the 12 cranial nerves. A stroke
affecting the brain stem therefore can produce symptoms relating to deficits in these cranial nerves:
 altered smell, taste, hearing, or vision (total or partial)
 drooping of eyelid (ptosis) and weakness of ocular muscles
 decreased reflexes: gag, swallow, pupil reactivity to light
 decreased sensation and muscle weakness of the face
 balance problems and nystagmus
 altered breathing and heart rate
 weakness in sternocleidomastoid muscle with inability to turn head to one side
 weakness in tongue (inability to protrude and/or move from side to side)
If the cerebral cortex is involved, the CNS pathways can again be affected, but also can produce the
following symptoms:
 aphasia (inability to speak or understand language from involvement of Broca's or Wernicke's
area)
 apraxia (altered voluntary movements)
 visual field defect
 memory deficits (involvement of temporal lobe)
 hemineglect (involvement of parietal lobe)
 disorganized thinking, confusion, hypersexual gestures (with involvement of frontal lobe)
 anosognosia (persistent denial of the existence of a, usually stroke-related, deficit)
If the cerebellum is involved, the patient may have the following:
 trouble walking
 altered movement coordination
 vertigo and or disequilibrium
Associated symptoms
Loss of consciousness, headache, and vomiting usually occurs more often in hemorrhagic stroke than in
thrombosis because of the increased intracranial pressure from the leaking blood compressing on the
brain.
If symptoms are maximal at onset, the cause is more likely to be a subarachnoid hemorrhage or an
embolic stroke.
Causes
Thrombotic stroke
In thrombotic stroke a thrombus (blood clot) usually forms around atherosclerotic plaques. Since blockage
of the artery is gradual, onset of symptomatic thrombotic strokes is slower. A thrombus itself (even if non-
occluding) can lead to an embolic stroke (see below) if the thrombus breaks off, at which point it is called
an "embolus." Two types of thrombosis can cause stroke:
 Large vessel disease involves the common and internal carotids, vertebral, and the Circle of
Willis. Diseases that may form thrombi in the large vessels include (in descending incidence):
atherosclerosis, vasoconstriction (tightening of the artery), aortic, carotid or vertebral artery
dissection, various inflammatory diseases of the blood vessel wall (Takayasu arteritis, giant cell
arteritis, vasculitis), noninflammatory vasculopathy, Moyamoya disease and fibromuscular
dysplasia.
 Small vessel disease involves the smaller arteries inside the brain: branches of the circle of Willis,
middle cerebral artery, stem, and arteries arising from the distal vertebral and basilar artery.
Diseases that may form thrombi in the small vessels include (in descending incidence):
lipohyalinosis (build-up of fatty hyaline matter in the blood vessel as a result of high blood
pressure and aging) and fibrinoid degeneration (stroke involving these vessels are known as
lacunar infarcts) and microatheroma (small atherosclerotic plaques).
Sickle cell anemia, which can cause blood cells to clump up and block blood vessels, can also lead to
stroke. A stroke is the second leading killer of people under 20 who suffer from sickle-cell anemia.
Embolic stroke
An embolic stroke refers to the blockage of an artery by an embolus, a travelling particle or debris in the
arterial bloodstream originating from elsewhere. An embolus is most frequently a thrombus, but it can
also be a number of other substances including fat (e.g. from bone marrow in a broken bone), air, cancer
cells or clumps of bacteria (usually from infectious endocarditis).
Because an embolus arises from elsewhere, local therapy only solves the problem temporarily. Thus, the
source of the embolus must be identified. Because the embolic blockage is sudden in onset, symptoms
usually are maximal at start. Also, symptoms may be transient as the embolus is partially resorbed and
moves to a different location or dissipates altogether.
Emboli most commonly arise from the heart (especially in atrial fibrillation) but may originate from
elsewhere in the arterial tree. In paradoxical embolism, a deep vein thrombosis embolises through an
atrial or ventricular septal defect in the heart into the brain.
Cardiac causes can be distinguished between high and low-risk:
 High risk: atrial fibrillation and paroxysmal atrial fibrillation, rheumatic disease of the mitral or
aortic valve disease, artificial heart valves, known cardiac thrombus of the atrium or vertricle, sick
sinus syndrome, sustained atrial flutter, recent myocardial infarction, chronic myocardial infarction
together with ejection fraction <28 percent, symptomatic congestive heart failure with ejection
fraction <30 percent, dilated cardiomyopathy, Libman-Sacks endocarditis, Marantic endocarditis,
infective endocarditis, papillary fibroelastoma, left atrial myxoma and coronary artery bypass graft
(CABG) surgery
 Low risk/potential: calcification of the annulus (ring) of the mitral valve, patent foramen ovale
(PFO), atrial septal aneurysm, atrial septal aneurysm with patent foramen ovale, left ventricular
aneurysm without thrombus, isolated left atrial "smoke" on echocardiography (no mitral stenosis
or atrial fibrillation), complex atheroma in the ascending aorta or proximal arch
Systemic hypoperfusion
Systemic hypoperfusion is the reduction of blood flow to all parts of the body. It is most commonly due to
cardiac pump failure from cardiac arrest or arrhythmias, or from reduced cardiac output as a result of
myocardial infarction, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia (low blood
oxygen content) may precipitate the hypoperfusion. Because the reduction in blood flow is global, all parts
of the brain may be affected, especially "watershed" areas - border zone regions supplied by the major
cerebral arteries. Blood flow to these areas does not necessarily stop, but instead it may lessen to the
point where brain damage can occur. This phenomenon is also referred to as "last meadow" to point to
the fact that in irrigation the last meadow receives the least amount of water.
Venous thrombosis
Cerebral venous sinus thrombosis leads to stroke due to locally increased venous pressure, which
exceeds the pressure generated by the arteries. Infarcts are more likely to undergo hemorrhagic
transformation (leaking of blood into the damaged area) than other types of ischemic stroke.
Intracerebral hemorrhage
It generally occurs in small arteries or arterioles and is commonly due to hypertension, intracranial
vascular malformations (including cavernous angiomas or arteriovenous malformations), cerebral amyloid
angiopathy, or infarcts into which secondary haemorrhage has occurred. Other potential causes are
trauma, bleeding disorders, amyloid angiopathy, illicit drug use (e.g. amphetamines or cocaine). The
hematoma enlarges until pressure from surrounding tissue limits its growth, or until it decompresses by
emptying into the ventricular system, CSF or the pial surface. A third of intracerebral bleed is into the
brain's ventricles. ICH has a mortality rate of 44 percent after 30 days, higher than ischemic stroke or
even the very deadly subarachnoid hemorrhage (which, however, also may be classified as a type of
stroke).
Pathophysiology
Ischemic
Ischemic stroke occurs due to a loss of blood supply to part of the brain, initiating the ischemic cascade.
Brain tissue ceases to function if deprived of oxygen for more than 60 to 90 seconds and after a few
hours will suffer irreversible injury possibly leading to death of the tissue, i.e., infarction. Atherosclerosis
may disrupt the blood supply by narrowing the lumen of blood vessels leading to a reduction of blood
flow, by causing the formation of blood clots within the vessel, or by releasing showers of small emboli
through the disintegration of atherosclerotic plaques. Embolic infarction occurs when emboli formed
elsewhere in the circulatory system, typically in the heart as a consequence of atrial fibrillation, or in the
carotid arteries. These break off, enter the cerebral circulation, then lodge in and occlude brain blood
vessels.
Due to collateral circulation, within the region of brain tissue affected by ischemia there is a spectrum of
severity. Thus, part of the tissue may immediately die while other parts may only be injured and could
potentially recover. The ischemia area where tissue might recover is referred to as the "ischemic
penumbra".
As oxygen or glucose becomes depleted in ischemic brain tissue, the production of high energy
phosphate compounds such as adenosine triphosphate (ATP) fails, leading to failure of energy-
dependent processes (such as ion pumping) necessary for tissue cell survival. This sets off a series of
interrelated events that result in cellular injury and death. A major cause of neuronal injury is release of
the excitatory neurotransmitter glutamate. The concentration of glutamate outside the cells of the nervous
system is normally kept low by so-called uptake carriers, which are powered by the concentration
gradients of ions (mainly Na+) across the cell membrane. However, stroke cuts off the supply of oxygen
and glucose which powers the ion pumps maintaining these gradients. As a result the transmembrane ion
gradients run down, and glutamate transporters reverse their direction, releasing glutamate into the
extracellular space. Glutamate acts on receptors in nerve cells (especially NMDA receptors), producing
an influx of calcium which activates enzymes that digest the cells' proteins, lipids and nuclear material.
Calcium influx can also lead to the failure of mitochondria, which can lead further toward energy depletion
and may trigger cell death due to apoptosis.
Ischemia also induces production of oxygen free radicals and other reactive oxygen species. These react
with and damage a number of cellular and extracellular elements. Damage to the blood vessel lining or
endothelium is particularly important. In fact, many antioxidant neuroprotectants such as uric acid and
NXY-059 work at the level of the endothelium and not in the brain per se. Free radicals also directly
initiate elements of the apoptosis cascade by means of redox signaling.
These processes are the same for any type of ischemic tissue and are referred to collectively as the
ischemic cascade. However, brain tissue is especially vulnerable to ischemia since it has little respiratory
reserve and is completely dependent on aerobic metabolism, unlike most other organs.
Brain tissue survival can be improved to some extent if one or more of these processes is inhibited. Drugs
that scavenge reactive oxygen species, inhibit apoptosis, or inhibit excitotoxic neurotransmitters, for
example, have been shown experimentally to reduce tissue injury due to ischemia. Agents that work in
this way are referred to as being neuroprotective. Until recently, human clinical trials with neuroprotective
agents have failed, with the probable exception of deep barbiturate coma. However, more recently NXY-
059, the disulfonyl derivative of the radical-scavenging spintrap phenylbutylnitrone, is reported to be
neuroprotective in stroke. This agent appears to work at the level of the blood vessel lining or
endothelium. Unfortunately, after producing favorable results in one large-scale clinical trial, a second trial
failed to show favorable results.
In addition to injurious effects on brain cells, ischemia and infarction can result in loss of structural
integrity of brain tissue and blood vessels, partly through the release of matrix metalloproteases, which
are zinc- and calcium-dependent enzymes that break down collagen, hyaluronic acid, and other elements
of connective tissue. Other proteases also contribute to this process. The loss of vascular structural
integrity results in a breakdown of the protective blood brain barrier that contributes to cerebral edema,
which can cause secondary progression of the brain injury.
As is the case with any type of brain injury, the immune system is activated by cerebral infarction and
may under some circumstances exacerbate the injury caused by the infarction. Inhibition of the
inflammatory response has been shown experimentally to reduce tissue injury due to cerebral infarction,
but this has not proved out in clinical studies.
Hemorrhagic

Head CT showing deep intracerebral hemorrhage due to bleeding within the cerebellum, approximately
30 hours old.
Hemorrhagic strokes result in tissue injury by causing compression of tissue from an expanding
hematoma or hematomas. This can distort and injure tissue. In addition, the pressure may lead to a loss
of blood supply to affected tissue with resulting infarction, and the blood released by brain hemorrhage
appears to have direct toxic effects on brain tissue and vasculature.
Diagnosis
Stroke is diagnosed through several techniques: a neurological examination, CT scans (most often
without contrast enhancements) or MRI scans, Doppler ultrasound, and arteriography. The diagnosis of
stroke itself is clinical, with assistance from the imaging techniques. Imaging techniques also assist in
determining the subtypes and cause of stroke. There is yet no commonly used blood test for the stroke
diagnosis itself, though blood tests may be of help in finding out the likely cause of stroke.
Imaging
For diagnosing ischemic stroke in the emergency setting:
 CT scans (without contrast enhancements)
sensitivity= 16%
specificity= 96%
 MRI scan
sensitivity= 83%
specificity= 98%
For diagnosing hemorrhagic stroke in the emergency setting:
 CT scans (without contrast enhancements)
sensitivity= 89%
specificity= 100%
 MRI scan
sensitivity= 81%
specificity= 100%
For detecting chronic hemorrhages, MRI scan is more sensitive.
For the assessment of stable stroke, nuclear medicine scans SPECT and PET/CT may be helpful.
SPECT documents cerebral blood flow and PET with FDG isotope the metabolic activity of the neurons.
Underlying etiology
When a stroke has been diagnosed, various other studies may be performed to determine the underlying
etiology. With the current treatment and diagnosis options available, it is of particular importance to
determine whether there is a peripheral source of emboli. Test selection may vary, since the cause of
stroke varies with age, comorbidity and the clinical presentation. Commonly used techniques include:
 an ultrasound/doppler study of the carotid arteries (to detect carotid stenosis) or dissection of the
precerebral arteries
 an electrocardiogram (ECG) and echocardiogram (to identify arrhythmias and resultant clots in
the heart which may spread to the brain vessels through the bloodstream)
 a Holter monitor study to identify intermittent arrhythmias
 an angiogram of the cerebral vasculature (if a bleed is thought to have originated from an
aneurysm or arteriovenous malformation)
 blood tests to determine hypercholesterolemia, bleeding diathesis and some rarer causes such
as homocysteinuria
Prevention
Given the disease burden of stroke, prevention is an important public health concern. Primary prevention
is less effective than secondary prevention (as judged by the number needed to treat to prevent one
stroke per year). Recent guidelines detail the evidence for primary prevention in stroke. Because stroke
may indicate underlying atherosclerosis, it is important to determine the patient's risk for other
cardiovascular diseases such as coronary heart disease. Conversely, aspirin prevents against first stroke
in patients who have suffered a myocardial infarction or patients with a high cardiovascular risk.
Risk factors
The most important modifiable risk factors for stroke are high blood pressure and atrial fibrillation
(although magnitude of this effect is small: the evidence from the Medical Research Council trials is that
833 patients have to be treated for 1 year to prevent one stroke). Other modifiable risk factors include
high blood cholesterol levels, diabetes, cigarette smoking (active and passive), heavy alcohol
consumption and drug use, lack of physical activity, obesity and unhealthy diet. Alcohol use could
predispose to ischemic stroke, and intracerebral and subarachnoid hemorrhage via multiple mechanisms
(for example via hypertension, atrial fibrillation, rebound thrombocytosis and platelet aggregation and
clotting disturbances). The drugs most commonly associated with stroke are cocaine, amphetamines
causing hemorrhagic stroke, but also over-the-counter cough and cold drugs containing
sympathomimetics.
No high quality studies have shown the effectiveness of interventions aimed at weight reduction,
promotion of regular exercise, reducing alcohol consumption or smoking cessation. Nonetheless, given
the large body of circumstantial evidence, best medical management for stroke includes advice on diet,
exercise, smoking and alcohol use. Medication or drug therapy is the most common method of stroke
prevention; carotid endarterectomy can be a useful surgical method of preventing stroke.
Blood pressure
Hypertension accounts for 35-50% of stroke risk. Epidemiological studies suggest that even a small blood
pressure reduction (5 to 6 mmHg systolic, 2 to 3 mmHg diastolic) would result in 40% fewer strokes.
Lowering blood pressure has been conclusively shown to prevent both ischemic and hemorrhagic
strokes. It is equally important in secondary prevention. Even patients older than 80 years and those with
isolated systolic hypertension benefit from antihypertensive therapy. Studies show that intensive
antihypertensive therapy results in a greater risk reduction. The available evidence does not show large
differences in stroke prevention between antihypertensive drugs —therefore, other factors such as
protection against other forms of cardiovascular disease should be considered and cost.
Atrial fibrillation
Patients with atrial fibrillation have a risk of 5% each year to develop stroke, and this risk is even higher in
those with valvular atrial fibrillation. Depending on the stroke risk, anticoagulation with medications such
as coumarins or aspirin is warranted for stroke prevention.
Blood lipids
High cholesterol levels have been inconsistently associated with (ischemic) stroke. Statins have been
shown to reduce the risk of stroke by about 15%. Since earlier meta-analyses of other lipid-lowering
drugs did not show a decreased risk, statins might exert their effect through mechanisms other than their
lipid-lowering effects.
Diabetes mellitus
Patients with diabetes mellitus are 2 to 3 times more likely to develop stroke, and they commonly have
hypertension and hyperlipidemia. Intensive disease control has been shown to reduce microvascular
complications such as nephropathy and retinopathy but not macrovascular complications such as stroke.
Anticoagulation drugs
Oral anticoagulants such as warfarin have been the mainstay of stroke prevention for over 50 years.
However, several studies have shown that aspirin and antiplatelet drugs are highly effective in secondary
prevention after a stroke or transient ischemic attack. Low doses of aspirin (for example 75–150 mg) are
as effective as high doses but have fewer side-effects; the lowest effective dose remains unknown.
Thienopyridines (clopidogrel, ticlopidine) are modestly more effective than aspirin and have a decreased
risk of gastrointestinal bleeding, but they are more expensive. Their exact role remains controversial.
Ticlopidine has more skin rash, diarrhea, neutropenia and thrombotic thrombocytopenic purpura.
Dipyridamole can be added to aspirin therapy to provide a small additional benefit, even though
headache is a common side-effect. Low-dose aspirin is also effective for stroke prevention after
sustaining a myocardial infarction. > Oral anticoagulants are not advised for stroke prevention —any
benefit is offset by bleeding risk.
In primary prevention however, antiplatelet drugs did not reduce the risk of ischemic stroke while
increasing the risk of major bleeding. Further studies are needed to investigate a possible protective
effect of aspirin against ischemic stroke in women.
Surgery
Surgical procedures such as carotid endarterectomy or carotid angioplasty can be used to remove
significant atherosclerotic narrowing (stenosis) of the carotid artery, which supplies blood to the brain.
There is a large body of evidence supporting this procedure in selected cases. Endarterectomy for a
significant stenosis has been shown to be useful in the secondary prevention after a previous
symptomatic stroke. Carotid artery stenting has not been shown to be equally useful. Patients are
selected for surgery based on age, gender, degree of stenosis, time since symptoms and patients'
preferences. Surgery is most efficient when not delayed too long —the risk of recurrent stroke in a patient
who has a 50% or greater stenosis is up to 20% after 5 years, but endarterectomy reduces this risk to
around 5%. The number of procedures needed to cure one patient was 5 for early surgery (within two
weeks after the initial stroke), but 125 if delayed longer than 12 weeks.
Screening for carotid artery narrowing has not been shown to be a useful screening test in the general
population. Studies of surgical intervention for carotid artery stenosis without symptoms have shown only
a small decrease in the risk of stroke. To be beneficial, the complication rate of the surgery should be
kept below 4%. Even then, for 100 surgeries, 5 patients will benefit by avoiding stroke, 3 will develop
stroke despite surgery, 3 will develop stroke or die due to the surgery itself, and 89 will remain stroke-free
but would also have done so without intervention.
Nutritional and metabolic interventions
Nutrition, specifically the Mediterranean-style diet, has the potential of more than halving stroke risk.
With regards to lowering homocysteine, a meta-analysis of previous trials has concluded that lowering
homocysteine with folic acid and other supplements may reduce stroke risk. However, the two largest
randomized controlled trials included in the meta-analysis had conflicting results. One reported positve
results; whereas the other was negative.
The European Society of Cardiology and the European Association for Cardiovascular Prevention and
Rehabilitation have developed an interactive tool for prediction and managing the risk of heart attack and
stroke in Europe. HeartScore is aimed at supporting clinicians in optimising individual cardiovascular risk
reduction. The Heartscore Programme is available in 12 languages and offers web based or PC version
().
Treatment
Stroke unit
Ideally, people who have had a stroke are admitted to a "stroke unit", a ward or dedicated area in hospital
staffed by nurses and therapists with experience in stroke treatment. It has been shown that people
admitted to a stroke unit have a higher chance of surviving than those admitted elsewhere in hospital,
even if they are being cared for by doctors with experience in stroke.
When an acute stroke is suspected by history and physical examination, the goal of early assessment is
to determine the cause. Treatment varies according to the underlying cause of the stroke,
thromboembolic (ischemic) or hemorrhagic. A non-contrast head CT scan can rapidly identify a
hemorrhagic stroke by imaging bleeding in or around the brain. If no bleeding is seen, a presumptive
diagnosis of ischemic stroke is made.
Treatment of ischemic stroke
Ischemic stroke is caused by a thrombus (blood clot) occluding blood flow to an artery supplying the
brain. Definitive therapy is aimed at removing the blockage by breaking the clot down (thrombolysis), or
by removing it mechanically (thrombectomy). The more rapidly blood flow is restored to the brain, the
fewer brain cells die.
Other medical therapies are aimed at minimizing clot enlargement or preventing new clots from forming.
To this end, treatment with medications such as aspirin, clopidogrel and dipyridamole may be given to
prevent platelets from aggregating.
In addition to definitive therapies, management of acute stroke includes control of blood sugars, ensuring
the patient has adequate oxygenation and adequate intravenous fluids. Patients may be positioned with
their heads flat on the stretcher, rather than sitting up, to increase blood flow to the brain. It is common for
the blood pressure to be elevated immediately following a stroke. Although high blood pressure may
cause some strokes, hypertension during acute stroke is desirable to allow adequate blood flow to the
brain.
Thrombolysis
In increasing numbers of primary stroke centers, pharmacologic thrombolysis ("clot busting") with the
drug tissue plasminogen activator (tPA), is used to dissolve the clot and unblock the artery. However, the
use of tPA in acute stroke is controversial. On one hand, it is endorsed by the American Heart
Association and the American Academy of Neurology as the recommended treatment for acute stroke
within three hours of onset of symptoms as long as there are not other contraindications (such as
abnormal lab values, high blood pressure, or recent surgery). This position for tPA is based upon the
findings of two studies by one group of investigators which showed that tPA improves the chances for a
good neurological outcome. When administered within the first three hours, 39% of all patients who were
treated with tPA had a good outcome at three months, only 26% of placebo controlled patients had a
good functional outcome. A recent study using alteplase for thrombolysis in ischemic stroke suggests
clinical benefit with administration 3 to 4.5 hours after stroke onset. However, in the NINDS trial 6.4% of
patients with large strokes developed substantial brain hemorrhage as a complication from being given
tPA. tPA is often misconstrued as a "magic bullet" and it is important for patients to be aware that despite
the study that supports its use, some of the data were flawed and the safety and efficacy of tPA is
controversial. A recent study found the mortality to be higher among patients receiving tPA versus those
who did not. Additionally, it is the position of the American Academy of Emergency Medicine that
objective evidence regarding the efficacy, safety, and applicability of tPA for acute ischemic stroke is
insufficient to warrant its classification as standard of care.
Mechanical thrombectomy
Merci Retriever L5.
Another intervention for acute ischemic stroke is removal of the offending thrombus directly. This is
accomplished by inserting a catheter into the femoral artery, directing it into the cerebral circulation, and
deploying a corkscrew-like device to ensnare the clot, which is then withdrawn from the body. Mechanical
embolectomy devices have been demonstrated effective at restoring blood flow in patients who were
unable to receive thrombolytic drugs or for whom the drugs were ineffective, though no differences have
been found between newer and older versions of the devices. The devices have only been tested on
patients treated with mechanical clot embolectomy within eight hours of the onset of symptoms.
Angioplasty and stenting
Angioplasty and stenting have begun to be looked at as possible viable options in treatment of acute
ischemic stroke. In a systematic review of six uncontrolled, single-center trials, involving a total of 300
patients, of intra-cranial stenting in symptomatic intracranial arterial stenosis, the rate of technical success
(reduction to stenosis of <50%) ranged from 90-98%, and the rate of major peri-procedural complications
ranged from 4-10%. The rates of restenosis and/or stroke following the treatment were also favorable.
This data suggests that a large, randomized controlled trial is needed to more completely evaluate the
possible therapeutic advantage of this treatment.
Therapeutic hypothermia
Most of the data concerning therapeutic hypothermia’s effectiveness in treating ischemic stroke is limited
to animal studies. These studies have focused primarily on ischemic as opposed to hemorrhagic stroke,
as hypothermia has been associated with a lower clotting threshold. In these animal studies investigating
the effect of temperature decline following ischemic stroke, hypothermia has been shown to be an
effective all-purpose neuroprotectant. This promising data has led to the initiation of a variety of human
studies. At the time of this article’s publishing, this research has yet to return results. However, in terms of
feasibility, the use of hypothermia to control intracranial pressure (ICP) after an ischemic stroke was
found to be both safe and practical. The device used in this study was called the Arctic Sun.
Secondary prevention of ischemic stroke
Anticoagulation can prevent recurrent stroke. Among patients with nonvalvular atrial fibrillation,
anticoagulation can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%.. However,
a recent meta-analysis suggests harm from anti-coagulation started early after an embolic stroke. Stroke
prevention treatment for atrial fibrillation is determined according to the CHADS/CHADS2 system.
If studies show carotid stenosis, and the patient has residual function in the affected side, carotid
endarterectomy (surgical removal of the stenosis) may decrease the risk of recurrence if performed
rapidly after stroke.
Treatment of hemorrhagic stroke
Patients with intracerebral hemorrhage require neurosurgical evaluation to detect and treat the cause of
the bleeding, although many may not need surgery. Anticoagulants and antithrombotics, key in treating
ischemic stroke, can make bleeding worse and cannot be used in intracerebral hemorrhage. Patients are
monitored and their blood pressure, blood sugar, and oxygenation are kept at optimum levels.
Care and rehabilitation
Stroke rehabilitation is the process by which patients with disabling strokes undergo treatment to help
them return to normal life as much as possible by regaining and relearning the skills of everyday living. It
also aims to help the survivor understand and adapt to difficulties, prevent secondary complications and
educate family members to play a supporting role.
A rehabilitation team is usually multidisciplinary as it involves staff with different skills working together to
help the patient. These include nursing staff, physiotherapy, occupational therapy, speech and language
therapy, and usually a physician trained in rehabilitation medicine. Some teams may also include
psychologists, social workers, and pharmacists since at least one third of the patients manifest post
stroke depression. Validated instruments such as the Barthel scale may be used to assess the likelihood
of a stroke patient being able to manage at home with or without support subsequent to discharge from
hospital.
Good nursing care is fundamental in maintaining skin care, feeding, hydration, positioning, and monitoring
vital signs such as temperature, pulse, and blood pressure. Stroke rehabilitation begins almost
immediately.
For most stroke patients, physical therapy (PT) and occupational therapy (OT) are the cornerstones of the
rehabilitation process, but in many countries Neurocognitive Rehabilitation is used, too. Often, assistive
technology such as a wheelchair, walkers, canes, and orthosis may be beneficial. PT and OT have
overlapping areas of working but their main attention fields are; PT involves re-learning functions as
transferring, walking and other gross motor functions. OT focusses on exercises and training to help
relearn everyday activities known as the Activities of daily living (ADLs) such as eating, drinking, dressing,
bathing, cooking, reading and writing, and toileting. Speech and language therapy is appropriate for
patients with problems understanding speech or written words, problems forming speech and problems
with swallowing.
Patients may have particular problems, such as complete or partial inability to swallow, which can cause
swallowed material to pass into the lungs and cause aspiration pneumonia. The condition may improve
with time, but in the interim, a nasogastric tube may be inserted, enabling liquid food to be given directly
into the stomach. If swallowing is still unsafe after a week, then a percutaneous endoscopic gastrostomy
(PEG) tube is passed and this can remain indefinitely.
Stroke rehabilitation should be started as immediately as possible and can last anywhere from a few days
to over a year. Most return of function is seen in the first few days and weeks, and then improvement falls
off with the "window" considered officially by U.S. state rehabilitation units and others to be closed after
six months, with little chance of further improvement. However, patients have been known to continue to
improve for years, regaining and strengthening abilities like writing, walking, running, and talking. Daily
rehabilitation exercises should continue to be part of the stroke patient's routine. Complete recovery is
unusual but not impossible and most patients will improve to some extent : a correct diet and exercise are
known to help the brain to self-recover.
Prognosis
Disability affects 75% of stroke survivors enough to decrease their employability. Stroke can affect
patients physically, mentally, emotionally, or a combination of the three. The results of stroke vary widely
depending on size and location of the lesion. Dysfunctions correspond to areas in the brain that have
been damaged.
Some of the physical disabilities that can result from stroke include paralysis, numbness, pressure sores,
pneumonia, incontinence, apraxia (inability to perform learned movements), difficulties carrying out daily
activities, appetite loss, speech loss, vision loss, and pain. If the stroke is severe enough, or in a certain
location such as parts of the brainstem, coma or death can result.
Emotional problems resulting from stroke can result from direct damage to emotional centers in the brain
or from frustration and difficulty adapting to new limitations. Post-stroke emotional difficulties include
anxiety, panic attacks, flat affect (failure to express emotions), mania, apathy, and psychosis.
30 to 50% of stroke survivors suffer post stroke depression, which is characterized by lethargy, irritability,
sleep disturbances, lowered self esteem, and withdrawal. Depression can reduce motivation and worsen
outcome, but can be treated with antidepressants.
Emotional lability, another consequence of stroke, causes the patient to switch quickly between emotional
highs and lows and to express emotions inappropriately, for instance with an excess of laughing or crying
with little or no provocation. While these expressions of emotion usually correspond to the patient's actual
emotions, a more severe form of emotional lability causes patients to laugh and cry pathologically, without
regard to context or emotion. Some patients show the opposite of what they feel, for example crying when
they are happy. Emotional lability occurs in about 20% of stroke patients.
Cognitive deficits resulting from stroke include perceptual disorders, speech problems, dementia, and
problems with attention and memory. A stroke sufferer may be unaware of his or her own disabilities, a
condition called anosognosia. In a condition called hemispatial neglect, a patient is unable to attend to
anything on the side of space opposite to the damaged hemisphere.
Up to 10% of all stroke patients develop seizures, most commonly in the week subsequent to the event;
the severity of the stroke increases the likelihood of a seizure.
Epidemiology
Stroke could soon be the most common cause of death worldwide. Stroke is currently the second leading
cause of death in the Western world, ranking after heart disease and before cancer, and causes 10% of
deaths worldwide. Geographic disparities in stroke incidence have been observed, including the
existence of a "stroke belt" in the southeastern United States, but causes of these disparities have not
been explained.
The incidence of stroke increases exponentially from 30 years of age, and etiology varies by age.
Advanced age is one of the most significant stroke risk factors. 95% of strokes occur in people age 45
and older, and two-thirds of strokes occur in those over the age of 65. A person's risk of dying if he or she
does have a stroke also increases with age. However, stroke can occur at any age, including in fetuses.
Family members may have a genetic tendency for stroke or share a lifestyle that contributes to stroke.
Higher levels of Von Willebrand factor are more common amongst people who have had ischemic stroke
for the first time. The results of this study found that the only significant genetic factor was the person's
blood type. Having had a stroke in the past greatly increases one's risk of future strokes.
Men are 25% more likely to suffer strokes than women, yet 60% of deaths from stroke occur in women.
Since women live longer, they are older on average when they have their strokes and thus more often
killed (NIMH 2002). Some risk factors for stroke apply only to women. Primary among these are
pregnancy, childbirth, menopause and the treatment thereof (HRT).
Myasthenia gravis
Myasthenia gravis (from Greek μύς "muscle", ἀσθένεια "weakness", and Latin gravis "serious";
abbreviated MG) is an autoimmuneneuromuscular disease leading to fluctuating muscle weakness
and fatigability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that
block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of
the neurotransmitter acetylcholine. Myasthenia is treated medically with cholinesterase
inhibitors or immunosuppressants, and, in selected cases, thymectomy. The disease prevalence is 3–30 cases
per million and rising due to increased awareness. MG must be distinguished from congenital myasthenic
syndromes that can present similar symptoms but offer no response to immunosuppressive treatments.
Classification
The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America
Clinical Classification:
 Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
 Class II: Eye muscle weakness of any severity, mild weakness of other muscles
 Class IIa: Predominantly limb or axial muscles
 Class IIb: Predominantly bulbar and/or respiratory muscles
 Class III: Eye muscle weakness of any severity, moderate weakness of other muscles
 Class IIIa: Predominantly limb or axial muscles
 Class IIIb: Predominantly bulbar and/or respiratory muscles
 Class IV: Eye muscle weakness of any severity, severe weakness of other muscles
 Class IVa: Predominantly limb or axial muscles
 Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube
without intubation)
 Class V: Intubation needed to maintain airway
Signs and symptoms

Blepharoptosis of the left eye.

The hallmark of myasthenia gravis is fatigability. Muscles become progressively weaker during periods of
activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial
expressions, chewing, talking, and swallowing are especially susceptible. The muscles that
control breathing and neck and limb movements can also be affected. Often the physical examination yields
results within normal limits.
The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of myasthenia gravis
may be delayed if the symptoms are subtle or variable.
In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing
and slurred speech may be the first signs. The degree of muscle weakness involved in MG varies greatly
among patients, ranging from a localized form that is limited to eye muscles (ocular myasthenia), to a severe
and generalized form in which many muscles - sometimes including those that control breathing - are affected.
Symptoms, which vary in type and severity, may include asymmetrical ptosis (a drooping of one or
both eyelids), diplopia (double vision) due to weakness of the muscles that control eye movements, an
unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial
expression,dysphagia (difficulty in swallowing), shortness of breath and dysarthria (impaired speech, often
nasal due to weakness of the velar muscles).
In myasthenic crisis a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain
life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an
adverse reaction to medication, or emotional stress. Since the heart muscle is only regulated by the autonomic
nervous system, it is generally unaffected by MG.
Pathophysiology
A juvenile thymus. It shrinks with age.
Myasthenia gravis is an autoimmune channelopathy: it features antibodies directed against the body's own
proteins. While various similar diseases have been linked to immunologic cross-reaction with an infective
agent, there is no known causative pathogen that could account for myasthenia. There is a slight genetic
predisposition: particular HLA types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular
myasthenia). Up to 75% of patients have an abnormality of the thymus; 25% have a thymoma, a tumor (either
benign or malignant) of the thymus, and other abnormalities are frequently found. The disease process
generally remains stationary after thymectomy (removal of the thymus).

The acetylcholine receptor.

In MG, the auto-antibodies most commonly against the nicotinic acetylcholine
receptor (nAChR), the receptor in the motor end plate for theneurotransmitter acetylcholine that stimulates
muscular contractions. Some forms of the antibody impair the ability of acetylcholine to bind to receptors.
Others lead to the destruction of receptors, either by complement fixation or by inducing the muscle cell to
eliminate the receptors through endocytosis.
The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into plasma cells by T-
helper cell stimulation. In order to carry out this activation, T-helpers must first be activated themselves, which
is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment
(epitope) resting within the major histocompatibility complex of an antigen presenting cells. Since the thymus
plays an important role in the development of T-cells and the selection of TCR myasthenia gravis is closely
associated with thymoma . The exact mechanisms are however not convincingly clarified although resection of
the thymus (thymectomy) in MG patients without a thymus neoplasm often have positive results.
In normal muscle contraction, cumulative activation of the nAChR leads to influx of sodium ions which in turn
causes the depolarization of muscle cell and subsequent opening of voltage gated sodium channels. This ion
influx then travels down the cell membranes via T-tubules and, via calcium channel complexes leads to the
release of calcium from the sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are
high enough will it contract. Decreased numbers of functioning nAChRs therefore impairs muscular contraction
by limiting depolarization. In fact, MG causes the motor neuron action potential to muscular twitch ratio to vary
from the non-pathological one to one ratio.
It has recently been realized that a second category of gravis is due to auto-antibodies against the MuSK
protein (muscle specific kinase), a tyrosine kinase receptor which is required for the formation of
the neuromuscular junction. Antibodies against MuSK inhibit the signaling of MuSK normally induced by its
nerve-derived ligand, agrin. The result is a decrease in patency of the neuromuscular junction, and the
consequent symptoms of MG.
People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of
MG, but both the symptoms and the titer disappear when drug administration is discontinued.
MG is more common in families with other autoimmune diseases. A familial predisposition is found in 5% of the
cases. This is associated with certain genetic variations such as an increased frequency of HLA-B8 and DR3.
People with MG suffer from co-existing autoimmune diseases at a higher frequency than members of the
general population. Of particular mention is co-existing thyroid disease where episodes of hypothyroidism may
precipitate a severe exacerbation.
The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research in which might
eventually lead to new treatment options.
Associated condition
Myasthenia Gravis is associated with various autoimmune diseases, including:
 Thyroid diseases, including Hashimoto's thyroiditis and Graves' disease
 Diabetes mellitus type 1
 Rheumatoid arthritis
 Lupus, and
 Demyelinating CNS diseases
Seropositive and "double-seronegative" patients often have thymoma or thymic hyperplasia. However, anti-
MuSK positive patients do not have evidence of thymus pathology.
In pregnancy
In the long term, pregnancy does not affect myasthenia gravis. Up to 10% of infants with parents affected by
the condition are born with transient (periodic) neonatal myasthenia (TNM) which generally produces feeding
and respiratory difficulties. TNM usually presents as poor sucking and generalized hypotonia (low muscle
tone). Other reported symptoms include a weak cry, facial diplegia (paralysis of one part of the body)
or paresis (impaired or lack of movement) and mild respiratory distress. A child with TNM typically responds
very well toacetylcholinesterase inhibitors. The mothers themselves suffer from exacerbated myasthenia in a
third of cases and in those for whom it does worsen, it usually occurs in the first trimester of pregnancy. Signs
and symptoms in pregnant mothers tend to improve during the second and third trimester.
Complete remission can occur in some mothers.Immunosuppressive therapy should be maintained throughout
pregnancy as this reduces the chance of neonatal muscle weakness, as well as controlling the mother's
myasthenia.
Very rarely, an infant can be born with arthrogryposis multiplex congenita, secondary to profound intrauterine
weakness. This is due to maternal antibodies that target an infant'sacetylcholine receptors. In some cases, the
mother remains asymptomatic.
Diagnosis
Myasthenia can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both
normal variants and other neurological disorders. A thorough physical examination can reveal easy
fatiguability, with the weakness improving after rest and worsening again on repeat of the exertion testing.
Applying ice to weak muscle groups characteristically leads to improvement in strength of those muscles.
Additional tests are often performed, as mentioned below. Furthermore, a good response to medication can
also be considered a sign of autoimmune pathology.
Physical examination
Muscle fatigability can be tested for many muscles. A thorough investigation includes:
 looking upward and sidewards for 30 seconds: ptosis and diplopia.
 looking at the feet while lying on the back for 60 seconds
 keeping the arms stretched forward for 60 seconds
 10 deep knee bends
 walking 30 steps on both the toes and the heels
 5 situps, lying down and sitting up completely
 "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) start to
separate and the sclera starts to show
Blood tests
If the diagnosis is suspected, serology can be performed in a blood test to identify certain antibodies:
 One test is for antibodies against the acetylcholine receptor. The test has a reasonable sensitivity of
80–96%, but in MG limited to the eye muscles (ocular myasthenia) the test may be negative in up to 50%
of the cases.
 A proportion of the patients without antibodies against the acetylcholine receptor have antibodies
against the MuSK protein.
 In specific situations (decreased reflexes which increase on facilitation, co-existing autonomic features,
suspected presence of neoplasm, especially of the lung, presence of increment or facilitation on repetitive
EMG testing) testing is performed for Lambert-Eaton syndrome, in which other antibodies (against a
voltage-gated calcium channel) can be found.
Neurophysiology
Muscle fibers of patients with MG are easily fatigued, and thus do not respond as well as muscles in healthy
individuals to repeated stimulation. By repeatedly stimulating a muscle with electrical impulses, the fatiguability
of the muscle can be measured. This is called the repetitive nerve stimulation test. In single
fiber electromyography, which is considered to be the most sensitive (although not the most specific) test for
MG, a thin needle electrode is inserted into a muscle to record the electric potentials of individual muscle fibers.
By finding two muscle fibers belonging to the same motor unit and measuring the temporal variability in their
firing patterns (i.e. their 'jitter'), the diagnosis can be made.
Edrophonium test
Photograph of a patient showing right partial ptosis (left picture). The left lid shows compensatory pseudo lid retraction
because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation). Right picture: after an
edrophonium test, note the improvement in ptosis.
The "edrophonium test" is infrequently performed to identify MG; its application is limited to the situation when
other investigations do not yield a conclusive diagnosis. This test requires the intravenous administration
of edrophonium chloride (Tensilon, Reversol) or neostigmine (Prostigmin), drugs that block the breakdown of
acetylcholine by cholinesterase (cholinesterase inhibitors) and temporarily increases the levels of acetylcholine
at the neuromuscular junction. In people with myasthenia gravis involving the eye muscles, edrophonium
chloride will briefly relieve weakness.
Imaging

A chest CT-scan showing a thymoma (red circle).

A chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton
syndrome due to a lung tumor) and comorbidity. It may also identify widening of the mediastinum suggestive
of thymoma, but computed tomography (CT) or magnetic resonance imaging (MRI) are more sensitive ways to
identify thymomas, and are generally done for this reason.
Pulmonary function test
Spirometry (lung function testing) may be performed for the assessing of respiratory function if there are
concerns about a patient's ability to breathe adequately. The forced vital capacity may be monitored at intervals
in order not to miss a gradual worsening of muscular weakness. Acutely, negative inspiratory force (NIF) may
be used to determine adequacy of ventilation. Severe myasthenia may cause respiratory failuredue to
exhaustion of the respiratory muscles.
Pathological findings
Muscle biopsy is only performed if the diagnosis is in doubt and a muscular condition is
suspected. Immunofluorescence shows IgG antibodies on the neuromuscular junction. (Note that it is not the
antibody which causes myasthenia gravis that fluoresces, but rather a secondary antibody directed against it.)
Muscle electron microscopy shows receptor infolding and loss of the tips of the folds, together with widening of
the synaptic clefts. Both these techniques are currently used for research rather than diagnostically.
Treatment
Treatment is by medication and/or surgery. Medication consists mainly of cholinesterase inhibitors to directly
improve muscle function and immunosuppressant drugs to reduce the autoimmune process. Thymectomy is a
surgical method to treat MG. For emergency treatment, plasmapheresis or IVIG can be used as a temporary
measure to remove antibodies from the blood circulation.
Medication

Neostigmine, chemical structure.

 Acetylcholinesterase inhibitors: neostigmine and pyridostigmine can improve muscle function by
slowing the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate; the
neurotransmitter is therefore around longer to stimulate its receptor. Usually doctors will start with a low
dose, e.g. 3x20mg pyridostigmine, and increase until the desired result is achieved. If taken 30 minutes
before a meal, symptoms will be mild during eating. Side effects, like perspiration and diarrhea can be
countered by adding atropine. Pyridostigmine is a short-lived drug with a half-life of about 4 hours.
Azathioprine, chemical structure.
 Immunosuppressive drugs: prednisone, cyclosporine, mycophenolate mofetil and azathioprine may be
used. It is common for patients to be treated with a combination of these drugs with a cholinesterase
inhibitor. Treatments with some immunosuppressives take weeks to months before effects are noticed.
Other immunomodulating substances, such as drugs that prevent acetylcholine receptor modulation by the
immune system, are currently being researched.
Plasmapheresis and IVIG
If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the putative antibody
from the circulation. Also, Intravenous immunoglobulins (IVIG) can be used to bind the circulating antibodies.
Both of these treatments have relatively short-lived benefits, typically measured in weeks.
Surgery
Main article: thymectomy
Thymectomy, the surgical removal of the thymus, is essential in cases of thymoma in view of the potential
neoplastic effects of the tumor. However, the procedure is more controversial in patients who do not show
thymic abnormalities. Although some of these patients improve following thymectomy, some patients
experience severe exacerbations and the highly controversial concept of "therapeutic thymectomy" for patients
with thymus hyperplasia is disputed by many experts and efforts are underway to unequivocally answer this
important question.
There are a number of surgical approaches to the removal of the thymus gland: transsternal (through
the sternum, or breast bone), transcervical (through a small neck incision), and transthoracic (through one or
both sides of the chest). The transsternal approach is most common and uses the same length-wise incision
through the sternum (breast bone)used for most open-heart surgery. The transcervical approach is a less
invasive procedure that allows for removal of the entire thymus gland through a small neck incision. There has
been no difference in success in symptom improvement between the transsternal approach and the minimally
invasive transcervical approach. However for patients with a thymoma it is important that all the tissue is
removed as thymic tissue can regrow. Thymomas can be malignant and are thought to be the onset of other
diseases as well. For this reason, many surgeons will only recommend the full sternotomy approach to a
thymectomy.
Thymoma is relatively rare in younger (<40) patients, but paradoxically especially younger patients with
generalized MG without thymoma benefit from thymectomy. Of course, resection is also indicated for those
with a thymoma, but it is less likely to improve the MG symptoms.
Prognosis
With treatment, patients have a normal life expectancy, except for those with a malignant thymoma (whose
lesser life expectancy is on account of the thymoma itself and is otherwise unrelated to the myasthenia).
Quality of life can vary depending on the severity and the cause. The drugs used to control MG either diminish
in effectiveness over time (cholinesterase inhibitors) or cause severe side effects of their own
(immunosuppressants). A small percentage (around 10%) of MG patients are found to have tumors in
their thymus glands, in which case a thymectomy is a very effective treatment with long-term remission.
However, most patients need treatment for the remainder of their lives, and their abilities vary greatly. It should
be noted that MG is not usually a progressive disease. The symptoms may come and go, but the symptoms do
not always get worse as the patient ages. For some, the symptoms decrease after a span of 3–5 years.
Epidemiology
Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects women under 40 -
and people from 50 to 70 years old of either sex, but it has been known to occur at any age. Younger patients
rarely have thymoma. The prevalence in the United States is estimated at 20 cases per 100,000. Risk factors
are the female gender with ages 20 – 40, familial myasthenia gravis, D-penicillamine ingestion (drug induced
myasthenia), and having other autoimmune diseases.
Three types of myasthenic symptoms in children can be distinguished:
1. Neonatal: In 12% of the pregnancies with a mother with MG, she passes the antibodies to the infant
through the placenta causing neonatal myasthenia gravis. The symptoms will start in the first two days
 and disappear within a few weeks after birth. With the mother it is not uncommon for the symptoms to
even improve during pregnancy, but they might worsen after labor.
2. Congenital: Children of a healthy mother can, very rarely, develop myasthenic symptoms beginning at
birth. This is called congenital myasthenic syndrome or CMS. Other than myasthenia gravis, CMS is
not caused by an autoimmune process, but due to synaptic malformation, which in turn is caused by
genetic mutations. Thus, CMS is a hereditary disease. More than 11 different mutations have been
identified and the inheritance pattern is typically autosomal recessive.
3. Juvenile myasthenia gravis: myasthenia occurring in childhood but after the peripartum period.
The congenital myasthenias cause muscle weakness and fatigability similar to those of MG. The symptoms of
CMS usually begin within the first two years of life, although in a few forms patients can develop their first
symptoms as late as the seventh decade of life. A diagnosis of CMS is suggested by the following:
 Onset of symptoms in infancy or childhood.
 Weakness which increases as muscles tire.
 A decremental EMG response, on low frequency, of the compound muscle action potential (CMAP).
 No anti-AChR or MuSK antibodies.
 No response to immunosuppressant therapy.
 Family history of symptoms which resemble CMS.
The symptoms of CMS can vary from mild to severe. It is also common for patients with the same form, even
members of the same family, to be affected to differing degrees. In most forms of CMS weakness does not
progress, and in some forms, the symptoms may diminish as the patient gets older. Only rarely do symptoms
of CMS become worse with time.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (abbreviated ALS, also referred to as Lou Gehrig's disease) is a form
of motor neuron disease. ALS is aprogressive, fatal, neurodegenerative disease caused by the
degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary
muscle movement. The condition is often called Lou Gehrig's disease in North America, after the
famous New York Yankees baseball player who was diagnosed with the disease in 1939. Today,
renowned physicist Stephen Hawking, guitarist Jason Becker and bassist Mike Porcaro are the best-
known living ALS patients.
Signs and symptoms
The disorder causes muscle weakness and atrophy throughout the body caused by degeneration of
the upper and lower motor neurons. Unable to function, the muscles weaken and atrophy. Affected
individuals may ultimately lose the ability to initiate and control all voluntary movement; bladder and bowel
sphincters and the muscles responsible for eye movement are usually, but not always, spared.
Cognitive function is generally spared for most patients although some (~5%) also have frontotemporal
dementia. A higher proportion of patients (~30-50%) also have more subtle cognitive changes which may
go unnoticed but are revealed by detailed neuropsychological testing. Sensory nerves and the autonomic
nervous system, which controls functions like sweating, are generally unaffected but may be involved for
some patients.
Initial symptoms
The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting
symptoms include muscle fasciculation (twitching), cramping, or stiffness of affected muscles; muscle
weakness affecting an arm or a leg; and/or slurred and nasal speech. The parts of the body affected by
early symptoms of ALS depend on which motor neurons in the body are damaged first. About 75% of
people contracting the disease experience "limb onset" ALS i.e. first symptoms in the arms ("upper limb",
not to be confused with "upper motor neuron") or legs ("lower limb", not to be confused with "lower motor
neuron"). Patients with the leg onset form may experience awkwardness when walking or running or
notice that they are tripping or stumbling, often with a "dropped foot" which drags along the ground. Arm-
onset patients may experience difficulty with tasks requiring manual dexterity such as buttoning a shirt,
writing, or turning a key in a lock. Occasionally, the symptoms remain confined to one limb for a long
period of time or for the whole course of the illness; this is known as monomelic amyotrophy.
About 25% of cases are "bulbar onset" ALS. These patients first notice difficulty speaking clearly or
swallowing. Speech may become slurred, nasal in character, or quieter. Other symptoms include difficulty
swallowing, and loss of tongue mobility. A smaller proportion of patients experience "respiratory onset"
ALS where the intercostal muscles that support breathing are affected first.
Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to
other parts of the body as the disease progresses. Patients experience increasing difficulty moving,
swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron
involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including
an overactive gag reflex. An abnormal reflex commonly called Babinski's sign (the big toe extends upward
and other toes spread out) also indicates upper motor neuron damage. Symptoms of lower motor neuron
degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles
that can be seen under the skin (fasciculations). Around 15–45% of patients experience pseudobulbar
affect, also known as "emotional lability", which consists of uncontrollable laughter, crying or smiling,
attributable to degeneration of bulbar upper motor neurons resulting in exaggeration of motor expressions
of emotion.
To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor
neuron damage that cannot be attributed to other causes.
Disease progression
Although the sequence of emerging symptoms and the rate of disease progression vary from person to
person, eventually most patients are not able to stand or walk, get in or out of bed on their own, or use
their hands and arms. Difficulty swallowing and chewing impair the patient's ability to eat normally and
increase the risk of choking. Maintaining weight can then become a problem. Because the disease
usually does not affect cognitive abilities, patients are aware of their progressive loss of function and may
become anxious and depressed. A small percentage of patients go on to develop frontotemporal
dementia characterized by profound personality changes; this is more common among those with a family
history of dementia. A larger proportion of patients experience mild problems with word-generation,
attention, or decision-making. Cognitive function may be affected as part of the disease process or could
be related to poor breathing at night (nocturnal hypoventilation). Health care professionals need to explain
the course of the disease and describe available treatment options so that patients can make informed
decisions in advance.
As the diaphragm and intercostal muscles (rib cage) weaken, forced vital capacity and inspiratory
pressure diminish. In bulbar onset ALS, this may occur before significant limb weakness is apparent.
Bilevel positive pressure ventilation (frequently referred to by the tradename BiPAP) is frequently used to
support breathing, first at night, and later during the daytime as well. It is recommended that long before
BiPAP becomes insufficient, patients must decide whether to have a tracheostomy and long term
mechanical ventilation. At this point, some patients choose palliative hospice care. Most people with ALS
die of respiratory failure or pneumonia. Death usually occurs within two to five years of diagnosis.
Although the disease can strike at any age, most people are between forty and seventy years of age
when the disease strikes and men are affected slightly more frequently than women. An estimated 5,000
people in the United States are diagnosed with the disease each year. ALS, a progressive disease, leads
to death in half of the people diagnosed within three years and ninety percent within six years.
ALS predominantly affects the motor neurons, and in the majority of cases the disease does not impair a
patient's mind, personality, intelligence, or memory. Nor does it affect a person's ability to see, smell,
taste, hear, or feel touch. Control of eye muscles is the most preserved function, although some patients
with an extremely long duration of disease (20+ years) may lose eye control too. Unlike multiple sclerosis,
bladder and bowel control are usually preserved in ALS, although as a result of immobility and diet
changes, intestinal problems such as constipation can require intensive management.
Cause
For patients without a family history of the disease, which includes ~95% of cases, there is no known
cause for ALS.
There is a known hereditary factor in familial ALS (FALS), where the condition is known to run in families,
although this only accounts for around 5% of all cases. An inherited genetic defect on chromosome 21
(coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS. This
mutation is believed to be autosomal dominant. The most common ALS causing SOD1 mutation in North
America is A4V, characterized by an exceptionally rapid progression from onset to death. The children of
those diagnosed with familial ALS have a higher risk factor for developing the disease; however, those
who have close family members who have been diagnosed with sporadic ALS have no greater a risk
factor than the general population, suggesting again an environmental or other non-genetic cause.
Some environmental causative factors have been suggested for the increased incidence in the western
Pacific. Prolonged exposure to a dietary neurotoxin called BMAA is one suspected risk factor
in Guam; this neurotoxin produced by cyanobacteria is one of several possible neurotoxic compounds
found in the seed of the cycad Cycas circinalis, a tropical plant found in Guam, which was used in the
human food supply during the 1950s and early 1960s.
The very high incidence of the disease among Italian soccer players (more than five times higher than
normally expected) has raised the concern of a possible link between the disease and the use of
pesticides on the soccer fields (several of which have been linked to neuronal toxicity).
According to the ALS Association, military veterans are at an increased risk of contracting ALS (again,
possibly implying a link to neurotoxic chemical exposure). In its report ALS in the Military, the group
pointed to an almost 60% greater chance of the disease in military veterans than the general population.
For Gulf War veterans, the chance is seen as twice that of veterans not deployed to the Persian Gulf in a
joint study by the Veterans Affairs Administration and the DOD, another epidemiologic association
suggesting a link to toxic exposure.
A 2010 study has raised questions about the diagnosis of ALS in some veterans and athletes, suggesting
that repeated concussions may cause a chronic traumatic encephalopathy that mimics ALS; this might
explain the higher rate of ALS diagnoses in those populations.unreliable medical source?
Pathophysiology
The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the
brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop
proteinaceous inclusions in their cell bodies and axons. These inclusions often contain ubiquitin, and
generally incorporate one of the ALS-associated proteins: SOD1,TAR DNA binding protein (TDP-43, or
TARDBP), or FUS. Interestingly, these inclusions do not stain with the dyes Congo Red or Thioflavin S,
and are therefore non-amyloidaggregates. This is in contrast to the aggregates and plaques seen in many
other neurodegenerative diseases of protein aggregation, including Alzheimer's disease, Parkinson's
disease, Huntington's disease, and prion diseases.
SOD1
The cause of ALS is not known, though an important step toward determining the cause came in 1993
when scientists discovered that mutations in the gene that produces the Cu/Znsuperoxide
dismutase (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This
enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free
radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells
during normal metabolism again largely by the mitochondria. Free radicals can accumulate and cause
damage to both mitochondrial and nuclear DNA and proteins within cells. To date, over 110 different
mutations in SOD1 have been linked with the disease, some of which have a very long clinical course
(e.g. H46R), while others, such as A4V, being exceptionally aggressive. Evidence suggests that failure of
defenses against oxidative stress up-regulates programmed cell death (apoptosis), among many other
possible consequences. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron
degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty
functioning of this gene. Current research, however, indicates that motor neuron death is not likely a
result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other
way (a gain of function).
Studies involving transgenic mice have yielded several theories about the role of SOD1 in mutant SOD1
familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily develop
ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a
shortened lifespan (see article on superoxide dismutase). This indicates that the toxic properties of the
mutant SOD1 are a result of a gain in function rather than a loss of normal function. In addition,
aggregation of proteins has been found to be a common pathological feature of both familial and sporadic
ALS (see article on proteopathy). Interestingly, in mutant SOD1 mice (most commonly, the G93A mutant),
aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and
greater amounts were detected during motor neuron degeneration. It is speculated that aggregate
accumulation of mutant SOD1 plays a role in disrupting cellular functions by
damaging mitochondria, proteasomes, protein folding chaperones, or other proteins. Any such disruption,
if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1
toxicity. Critics have noted that in humans, SOD1 mutations cause only 2% or so of overall cases and the
etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. To
date, the ALS-SOD1 mice remain the best model of the disease for preclinical studies but it is hoped that
more useful models will be developed.
Other factors
Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the
chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy
people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Riluzole is currently
the only FDA approved drug for ALS and targets glutamate transporters. It only has a modest effect on
survival, however, suggesting that excess glutamate is not the sole cause of the disease.
Diagnosis
No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron
signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the
symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases.
Physicians obtain the patient's full medical history and usually conduct a neurologic examination at
regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles,
hyperreflexia, and spasticity are getting progressively worse.

MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule,
consistent with the clinical diagnosis of ALS.
Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or
disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these
tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles.
Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve
conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the
patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease)
rather than ALS. The physician may order magnetic resonance imaging (MRI), a noninvasive procedure
that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although
these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that
may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the
neck, syringomyelia, or cervical spondylosis.
Based on the patient's symptoms and findings from the examination and from these tests, the physician
may order tests on blood and urinesamples to eliminate the possibility of other diseases as well as routine
laboratory tests. In some cases, for example, if a physician suspects that the patient may have a
myopathy rather than ALS, a muscle biopsy may be performed.
Infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukaemia virus
(HTLV), Lyme disease, syphilis andtick-borne encephalitis viruses can in some cases cause ALS-like
symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor
neuropathy, CIDP, and spinal muscular atrophy can also mimic certain facets of the disease and should
be considered by physicians attempting to make a diagnosis.
Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can
resemble ALS in the early stages of the disease, patients should always obtain a second neurological
opinion.
Treatment
Slowing progression
The Food and Drug Administration (FDA) has approved only one drug treatment for the
disease: Riluzole (Rilutek). Riluzole is believed to reduce damage to motor neurons by decreasing the
release of glutamate via activation of glutamate transporters. In addition, the drug may offer other
neuroprotective effects, by means of sodium and calcium channel blockades,inhibition of protein kinase
C, and the promotion of NMDA (N-methyl d-aspartate) receptor antagonism. Clinical trials with ALS
patients showed that Riluzole lengthens survival by several months, and may have a greater survival
benefit for those with a bulbar onset. The drug also extends the time before a patient needs ventilation
support. Riluzole does not reverse the damage already done to motor neurons, and patients taking the
drug must be monitored for liver damage (occurring in ~10% of patients taking the drug) and other
possible side effects. Although only a modest first step, Riluzole offers hope that the progression of ALS
may one day be slowed by new medications or a combination of drugs.
Symptomatic
Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients.
This supportive care is best provided by multidisciplinary teams of health care professionals such as
physicians; pharmacists; physical, occupational, and speech therapists; nutritionists; social workers; and
home care and hospice nurses. Working with patients and caregivers, these teams can design an
individualized plan of medical and physical therapy and provide special equipment aimed at keeping
patients as mobile and comfortable as possible.
Physicians can prescribe medications to help reduce fatigue, ease muscle cramps, control spasticity, and
reduce excess saliva and phlegm. Drugs also are available to help patients with pain, depression, sleep
disturbances, and constipation. Pharmacists can advise on best use of medications. This is particularly
helpful with regards to patients with dysphagia, which many ALS patients experience. They would also
monitor a patient's medications to reduce risk of drug interactions.
Physical therapy and special equipment such as assistive technology can enhance patients'
independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercisesuch as
walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular
health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help
prevent painful spasticity and shortening (contracture) of muscles. Physical therapists can recommend
exercises that provide these benefits without overworking muscles. Physiotherapists can suggest devices
such as ramps, braces, walkers, and wheelchairs that help patients remain mobile. Occupational
therapists can provide or recommend equipment and adaptations to enable people to retain as much
independence in activities of daily living as possible.
ALS patients who have difficulty speaking may benefit from working with a speech-language pathologist.
These health professionals can teach patients adaptive strategies such as techniques to help them speak
louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use
of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or
voice output communication devices) and/or low tech communication techniques such as alphabet boards
or yes/no signals. These methods and devices help patients communicate when they can no longer
speak or produce vocal sounds. With the help of occupational Therapists, speech-generating devices can
be activated by switches or mouse emulation techniques controlled by small physical movements of, for
example, the head, finger or eyes.
Patients and caregivers can learn from speech-language pathologists and nutritionists how to plan and
prepare numerous small meals throughout the day that provide enough calories, fiber, and fluid and how
to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess
fluids or saliva and prevent choking. When patients can no longer get enough nourishment from eating,
doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the
risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful
and does not prevent patients from eating food orally if they wish.
When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive
pressure ventilation (IPPV), bilevel positive airway pressure (BIPAP), or biphasic cuirass
ventilation (BCV)) may be used to aid breathing. Such devices artificially inflate the patient's lungs from
various external sources that are applied directly to the face or body. When muscles are no longer able to
maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added
advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by
several positive expiratory breaths. Patients may eventually consider forms of mechanical ventilation
(respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube
that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as
a tracheostomy, in which a plastic breathing tube is inserted directly in the patient's windpipe through an
opening in the neck.
Patients and their families should consider several factors when deciding whether and when to use one of
these options. Ventilation devices differ in their effect on the patient's quality of life and in cost. Although
ventilation support can ease problems with breathing and prolong survival, it does not affect the
progression of ALS. Patients need to be fully informed about these considerations and the long-term
effects of life without movement before they make decisions about ventilation support. Some patients
under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless
tracheostomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough.
This technique preserves speech in some patients with long-term mechanical ventilation.
Social workers and home care and hospice nurses help patients, families, and caregivers with the
medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the
disease. Social workers provide support such as assistance in obtaining financial aid, arranging
durable power of attorney, preparing a living will, and finding support groups for patients and caregivers.
Home nurses are available not only to provide medical care but also to teach caregivers about tasks such
as maintaining respirators, giving feedings, and moving patients to avoid painful skin problems and
contractures. Home hospice nurses work in consultation with physicians to ensure proper medication,
pain control, and other care affecting the quality of life of patients who wish to remain at home. The home
hospice team can also counsel patients and caregivers about end-of-life issues.
Researchers have stated that "ALS patients have a chronically deficient intake of energy and
recommended augmentation of energy intake." Both animal and human research suggest that ALS
patients should be encouraged to consume as many calories as possible and not to restrict their calorie
intake.
Many ALS patients use complementary and alternative medicines in an attempt to slow their disease.
This may include popular vitamin supplements such as Vitamin C, high doses of vitamins and nutrients
("mega-dosing"), traditional Chinese medicine, or other forms of therapy such as acupuncture, reiki, or
massage. To date there have been no studies demonstrating that such treatment approaches have an
effect on the progression of the disease. Given the lack of therapeutic options, people with ALS can be
vulnerable to snake oil scams involving complicated medical terminology or potentially exciting
technologies such as stem cell transplantation. Practitioners of these scams promise amazing results but
carry out little or no real follow up or study of the patients they have treated in order to prove their
assertions. The risks of false hope, financial harm, and potentially medically harm, are a threat to the
wellbeing of ALS patients and their families.
Prognosis
Eventually most people with ALS are not able to stand or walk, get in or out of bed on their own, use their
hands and arms, or communicate. In later stages of the disease, individuals have difficulty breathing as
the muscles of the respiratory system weaken. Although ventilation support can ease problems with
breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die from
respiratory failure, usually within three to five years from the onset of symptoms. However, about 10–20
percent of those individuals with ALS survive 10 or more years.
Epidemiology
ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic
backgrounds are affected. One or two out of 100,000 people develop ALS each year. ALS most
commonly strikes people between 40 and 60 years of age, but younger and older people can also
develop the disease. Men are affected slightly more often than women.
"Familial ALS" accounts for approximately 5%–10% of all ALS cases and is caused by genetic factors. Of
these, approximately 1 in 10 is linked to a mutation in copper/zinc superoxide dismutase (SOD1),
an enzyme responsible for scavenging free radicals. A recent study has identified a gene
called FUS ("Fused in Sarcoma", ALS6) as being responsible for 1 in 20 cases of fALS.
Although the incidence of ALS is thought to be regionally uniform, there are three regions in the West
Pacific where there has in the past been an elevated occurrence of ALS. This seems to be declining in
recent decades. The largest is the area of Guam inhabited by the Chamorro people, who have historically
had a high incidence (as much as 143 cases per 100,000 people per year) of a condition called Lytico-
Bodig disease which is a combination of ALS, Parkinsonism, and dementia. Two more areas of increased
incidence are the Kii peninsula of Japan and West Papua.
Although there have been reports of several "clusters" including three American football players from
the San Francisco 49ers, more than fifty football players in Italy, three football-playing friends in the south
of England, and reports of conjugal (husband and wife) cases in the south of France, these are
statistically plausible chance events. Although many authors consider ALS to be caused by a combination
of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a
higher risk with increasing age.
In 2010, a VA study found that head trauma can produce symptoms that resemble ALS but that are
actually chronic traumatic encephalopathy (CTE). Postmortem brain studies conducted on two American
football players showed evidence of CTE, rather than ALS
Etymology
Amyotrophic comes from the Greek language: A- means "no", myo refers to "muscle", and trophic means
"nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the
characteristic atrophication of the sufferer's disused muscle tissue. Lateral identifies the areas in a
person's spinal cord where portions of the nerve cells that are affected are located. As this area
degenerates it leads to scarring or hardening ("sclerosis") in the region.
History
Timeline
Year Event
1850 English scientist Augustus Waller describes the appearance of shriveled nerve fibers
1869 French doctor Jean-Martin Charcot firstdubious – discuss describes ALS in scientific literature
"On Amyotrophic Lateral Sclerosis" is translated into English and published in a three-volume
1881
edition of Lectures on the Diseases of the Nervous System
ALS becomes a cause célèbre in the United States when baseball legend Lou Gehrig's career—
1939
and, two years later, his life—are ended by the disease. He gives his farewell speech on July 4.
1950s ALS epidemic occurs among the Chamorro people on Guam
1991 Researchers link chromosome 21 to FALS (Familial ALS)
1993 SOD1 gene on chromosome 21 found to play a role in some cases of FALS
1996 Rilutek becomes the first FDA-approved drug for ALS
1998 The El Escorial criteria is developed as the standard for classifying ALS patient in clinical research
Research
A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can
be found at ClinicalTrials.gov.
KNS-760704 is under clinical investigation in ALS patients. It is hoped that the drug will have a
neuroprotective effect. It is one enantiomer of pramipexole, which is approved for the treatment of
Parkinson's disease and restless legs syndrome. The single-enantiomer preparation is essentially inactive
at dopamine receptors, is not dose limited by the potent dopaminergic properties of pramipexole. Results
of a Phase II clinical trial conducted by Knopp Neurosciences and involving 102 patients were reported in
2010; the trial found a dose-dependent slowing in loss of function.
Olesoxime (TRO19622) is being tested in a phase 3 clinical study, as part of the MitoTarget Project. The
molecule has a cholesterol-like structure and displays strong neuroprotective properties, and it should be
as effective as a cocktail of three neurotrophic factors in keeping motor neurons alive in culture. The
ongoing clinical study aims to test efficacy, safety, tolerability and plasma levels in patients with ALS, to
see whether a single daily dose of two capsules – under certain circumstances – can improve survival
and symptoms of ALS patients. The trial started in May 2009, all the patients are recruited and results are
expected in the last quarter of 2011. The study is taking place in France, Belgium, Germany, the UK and
Spain.
The new discovery of RNAi has some promise in treating ALS. In recent studies, RNAi has been used in
lab rats to shut off specific genes that lead to ALS. Cytrx Corporation has sponsored ALS research using
RNAi gene silencing technology targeted at the mutant SOD1 gene. Cytrx's orally-administered
drug Arimoclomol is currently in clinical evaluation as a therapeutic treatment for ALS.
Insulin-like growth factor 1 has also been studied as treatment for ALS. Cephalon and Chiron conducted
two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second
was equivocal, and the product has never been approved by the FDA. In January 2007, the Italian
Ministry of Health has requested INSMED corporation's drug, IPLEX, which is a recombinant IGF-1 with
Binding Protein 3(IGF1BP3) to be used in a clinical trial for ALS patients in Italy.
Methylcobalamin is being studied in Japan.